Entitled Detection Kit Early pancreatic cancer or pancreatic cancer precursor lesions or devices and detection methods
Technical field
[0001]
　The present invention is used in a subject inspection of the presence or absence of onset of the early pancreatic cancer or pancreatic cancer precursor lesions, early pancreatic cancer or pancreatic containing specific miRNA specifically bindable nucleic cancer precursor lesions of the detection kit or device, and a method for detecting early pancreatic cancer or pancreatic cancer precursor lesions comprising measuring the expression level of the miRNA with the nucleic acid.
Background technique
[0002]
　Pancreas secretes a digestive juice pancreatic juice, as well as a exocrine glands through pancreatic duct fed to the gastrointestinal tract also has a function of insulin, the hormone such as glucagon as endocrine secreting into the blood.
[0003]
　The pancreas is not only difficult to early detection of cancer because it is surrounded by many organs such as the stomach or duodenum, small intestine, liver, gall bladder, without subjective symptoms, the progress is very fast, spread to other organs It has the nature of such cause, is a very poor prognosis of cancer compared to other cancers. National Research and Development Institute of the National Cancer Research Center for Cancer Control and Information Center (Tokyo, Japan) and is due to the statistics of the site-specific cancer mortality in Japan in 2011 to disclose, mortality of pancreatic cancer 28, climbing to 829 people, site-specific 5-year relative survival rate from 2003 to 2005, pancreatic cancer is the lowest, 7.1% in men and 6.9% for women.
[0004]
　As described in Non-Patent Document 1, the basic of pancreatic cancer therapy surgery by progress, systemic chemotherapy is carried out with radiation therapy or the combination. Although 15-20% of pancreatic cancer patients have been made surgery that can radical, the majority of patients who did not undergo surgery are considered to be or metastasis in progress on a local.
[0005]
　UICC (Unio Internationalis Contra Cancrum) progression of pancreatic cancer by the stage 0, IA, IB, IIA, IIB, III, IVa, are classified into IVb. Stage I-III accounts for more than half of the 5-year survivors, progression at diagnosis accounted for more than 70% Stage IVa and Stage IVb. As described in Non-Patent Document 1, 5-year survival rate Stage IA is 45.8% of pancreatic cancer, Stage IB is 36.3%, Stage IIA is 29.4%, Stage IIB is 10. 6% stage III is 5.9%, a Stage IV is 4.0%, for prognosis of stage III and Stage IV is extremely poor, early it is necessary to detect to treat pancreatic cancer .
[0006]
　As described in Non-Patent Document 2, abdominal ultrasonography in the diagnosis of pancreatic cancer is very useful in outpatient or screening as a simple and low-invasive examination. However, small pancreatic cancer and pancreatic tail side lesions of tumor size are difficult often be visualized. Yes findings rates of pancreatic image by ultrasonography in normal health check is about 1%, pancreatic cancer detection rate less and less about 0.06%. Further, the tumor marker for pancreatic cancer detection, for example, CA19-9 as carbohydrate antigens, Span-1, CA50, CA242, Dupan-2, TAG-72, urinary fucose etc., antigens other than sugar chains CEA, POA, TPS and the like are known as. The use of these tumor markers, the cancer is suspected when the blood concentration is higher or lower than a reference value that has been provided in advance. For example, as described in Non-Patent Document 3, the reference value of CEA is 5 ng / mL, the reference value of CA19-9 is set to 37U / mL, to indicate more values, pancreatic cancer is suspected, including you. However, evaluation of tumor markers are considered in many progressive pancreatic cancer, often do not show abnormal values ​​in the early pancreatic cancer. Also, pancreatic cancer detection rate even if the tumor markers and abdominal ultrasonography examination is low, there is a problem implementation of these screening in terms of cost-effectiveness for pancreatic cancer detection.
[0007]
　On the other hand, cystic disease occurring pancreas is known to progress to invasive carcinoma and malignant, it can be viewed as pancreatic cancer precursor lesions. As described in Non-Patent Document 4, malignancy cyst diameter of cystic disease, wall thickening, the main pancreatic duct diameter, mural nodules, main pancreatic duct stenosis, lymphadenopathy, and, evaluated the like cystic lesions is, in the case of intraductal papillary mucinous neoplasm is a type of cystic disease, malignant 40.4%, the invasive cancer is poor 30.8% and prognosis, follow-up even if a low-grade during discovery and excision has been recommended.
[0008]
　Albeit at the research stage, Patent Documents 1-5, as shown in Non-Patent Document 4, the expression level of a micro RNA in a biological sample, including blood (miRNA), or the expression amount and other protein markers of miRNA by combining the expression level, there is a report that determines pancreatic cancer.
[0009]
　Patent Document 1, hsa-miR-125a-3p in the blood, hsa-miR-204-3p, a method for detecting a pancreatic cancer hsa-miR-3648 in combination with other several miRNA is shown ing.
[0010]
　Patent Document 2 shows hsa-miR-1908-5p in blood, hsa-miR-6729-5p, a method for detecting a pancreatic cancer by combining miRNA, such as hsa-miR-5195-3p is .
[0011]
　Patent Document 3, a method for detecting a pancreatic cancer miR-23a-3p in the blood in combination with other dozens of miRNA is shown.
[0012]
　Patent Document 4, hsa-miR-1268a as miRNA whose expression level increased in pancreatic cancer patients in the blood from a healthy body, hsa-miR-939-5p, and include hsa-miR-642b-3p and it has, and a method for detecting a pancreatic cancer in combination with other dozens of miRNA, a method of assessing the risk of developing pancreatic cancer are shown.
[0013]
　Patent Document 5, the hsa-miR-296-5p in the blood in combination with other dozens of miRNA and method for detecting a pancreatic cancer or pancreatic cancer precursor lesions, the risk of developing pancreatic cancer method of evaluating is shown.
[0014]
　Non-Patent Document 5, and the like hsa-miR-638, hsa-miR-3196, hsa-miR-1225-3p as miRNA whose expression level increased in pancreatic cancer patients in the blood from a healthy body are mentioned a method for detecting pancreatic cancer by combining several of these miRNA is shown.
CITATION
Patent Document
[0015]
Patent Document 1: JP 2015-107091 Patent Publication
Patent Document 2: WO 2015/182781
Patent Document 3: U.S. Patent Application Publication No. 2015/0011414 Pat
Patent Document 4: JP-T 2015-502176 Patent Publication
JP 5: International Publication No. WO 2015/153679
Non-Patent Document
[0016]
Non-Patent Document 1: Tetsuya Mine, "pancreas", Japan pancreas Society, 2007, Vol. 22, p10-13
Non-Patent Document 2: Japan Pancreas Society "scientific evidence pancreatic cancer clinical practice guidelines 2009 edition based on the" CQ1 diagnostic method http: // www. suizou. org / PCMG2009 / cq1 / cq1-3. html
Non-Patent Document 3: Kurokawa Shilla editing, clinical test data book, 2013, p633,636 (Igaku Shoin, Tokyo, Japan)
Non-Patent Document 4: International pancreas Society working group al., IPMN / MCN international clinical practice guidelines < 2012 Edition>, p6,8
non-Patent Document 5: Miyamae M, et al., 2015, British Journal of Cancer, vol. 113, (10) p1467-1476
Summary of the Invention
Problems that the Invention is to Solve
[0017]
　An object of the present invention is to find a novel early pancreatic cancer or pancreatic cancer precursor lesions tumor markers, early pancreatic cancer or pancreatic cancer precursor lesions effectively using specific bindable nucleic acid the marker it is to provide a method capable of detecting. As described in Non-Patent Document 2, the tumor marker for pancreatic cancer detection, for example, CA19-9 as carbohydrate antigens, Span-1, CA50, CA242, Dupan-2, TAG-72, urinary such as medium-fucose, or, CEA as the antigen other than sugar chains, POA, TPS and the like are known. Pancreatic cancer detection sensitivity of these tumor markers, CA19-9 is 70 ~ 80%, Span-1 is 70 ~ 80%, Dupan-2 is 50 ~ 60%, CEA is 30 ~ 60%, CA50 60% , and the addition specificity is not so high, false positives 20 ~ for 30% and higher, other cancers and / or pancreas and / or pancreatic peripheral organs benign tumors and / or the like be an erroneous detection benign sex may be considered. In particular sensitivity of early pancreatic cancer is generally low, because the following pancreatic cancer 2cm is prevalence CA19-9 only 52% and half, not useful for the detection of early pancreatic cancer . Also, tumor markers by carbohydrate antigens, in Lewis blood type negative cases is unsuitable testing in some subjects exhibits a false negative not produced the antigen. Furthermore, 19.9% ​​respectively, detection rate by MRI and CT for intraductal papillary mucinous neoplasm is pancreatic cancer precursor lesions, 1.2 to 2.6% and not sufficient, for the detection of pancreatic cancer precursor lesions the use of tumor markers is not recommended.
[0018]
　Although reports that although the research stage to determine pancreatic cancer using the expression level of a micro RNA (miRNA) in a biological sample, including blood is as follows, both early pancreatic cancer or pancreatic not put to practical use as a method of detecting a cancer precursor lesions.
[0019]
　In Patent Document 1, miR-125a-3p in the blood, miR-204-3p, a method for detecting a pancreatic cancer miR-3648 in combination with other several miRNA is shown, pancreatic cancer is used as a negative control healthy body only, not described for cancer and benign diseases of organs other than the pancreas is not described a method of detecting a specific pancreatic cancer precursor lesions with blood .
[0020]
　In Patent Document 2, hsa-miR-1908-5p in blood, hsa-miR-6729-5p, a method for detecting a pancreatic cancer by combining miRNA, such as hsa-miR-5195-3p is shown early pancreatic cancer patients has not been included only a few analytes, specific precision for early pancreatic cancer, sensitivity, no description of the detection performance of such specificity, specific pancreatic cancer using blood method of detecting precursor lesions not described.
[0021]
　In Patent Document 3, a method for detecting pancreatic cancer in combination hsa-miR-23a-3p in the blood with another dozens of miRNA is shown, specific precision for early pancreatic cancer, sensitivity, no description of the detection performance of such specificity, not described for cancer other than upper gastrointestinal pancreatic around as a negative control group of pancreatic cancer, a method for detecting a pancreatic cancer precursor lesions have also been described Absent.
[0022]
　In Patent Document 4, hsa-miR-1268a, hsa-miR-939-5p, and detecting pancreatic cancer and pancreatic cancer precursor lesions in combination hsa-miR-642b-3p and other dozens of miRNA a method of is shown, specific accuracy for pancreatic cancer, the sensitivity, there is no description of the detection performance of such specificity, the description for cancer organs other than the pancreas as a negative control group of pancreatic cancer Nor.
[0023]
　Patent Document 5, a method of the hsa-miR-296-5p in the blood in combination with other dozens of miRNA detecting a pancreatic cancer or pancreatic cancer precursor lesions are shown, early pancreatic cancer specific accuracy, sensitivity, no description of the detection performance of such specificity, not measured cancer and benign diseases of organs other than the pancreas as a negative control group of pancreatic cancer precursor lesions for, concrete not also been described specificity.
[0024]
　Non-Patent Document 5, hsa-miR-638, hsa-miR-3196, hsa-miR-1225-3p like are mentioned as the miRNA expression level is increased in pancreatic cancer patients in the blood from a healthy body, a method for detecting a pancreatic cancer by combining several of these miRNA is shown, there is no description of the cancer of an organ other than the pancreas as a negative control group of pancreatic cancer.
[0025]
　Thus, in the detection of early pancreatic cancer or pancreatic cancer precursor lesions, either because an existing tumor markers its performance is low, also the method of performance and detection for marker research stage is not specifically shown , the case of using these, implementation and wasteful additional inspection due to erroneous detection healthy body early pancreatic cancer or pancreatic cancer precursor lesions patients, overlook the early pancreatic cancer or pancreatic cancer precursor lesions patients there is a possibility that the loss occurs therapeutic opportunity by. In addition, since it is to increase the inspection cost to measure miRNA consisting of several tens to several hundreds, difficult to use for large-scale screening, such as health diagnosis. Further, since high undesirable invasive to the patient taking a pancreatic tissue In order to measure the tumor marker can be detected from the blood can be collected in a minimally invasive, early pancreatic cancer or pancreatic cancer precursor lesions and early pancreatic cancer or pancreatic cancer precursor lesions patients patients healthy body correctly judged healthy body, high early pancreatic cancer or pancreatic cancer precursor lesions marker of accuracy is required. In particular, pancreatic cancer because resection early detection is the only curative treatment, high early pancreatic cancer or pancreatic cancer precursor lesions markers sensitive has been desired.
Means for Solving the Problems
[0026]
　The present inventors have result of intensive studies to solve the above problems, it found several genes that can be used from the blood that can be collected in less invasive to the detection marker of early pancreatic cancer or pancreatic cancer precursor lesions, specifically to the use of bondable nucleic found that can significantly detect early pancreatic cancer or pancreatic cancer precursor lesions, and have completed the present invention.
[0027]

　In other words, the present invention has the following characteristics.
(1) an early pancreatic cancer or pancreatic cancer precursor lesions marker, miR-6784-5p, miR-1181, miR-671-5p, miR-6857-5p, miR-4276, miR-1914-3p, miR -149-3p, miR-937-5p, miR-4675, miR-6795-5p, miR-4731-5p, miR-5090, miR-3620-5p, miR-1343-5p, miR-6717-5p, miR -6825-5p, miR-6738-5p, miR-6769a-5p, miR-4728-5p, miR-652-5p, miR-4257, miR-6785-5p, miR-7110-5p, miR-6887-5p , miR-887-3p, miR-1228-5p, miR-5572, miR-67 2-5p, miR-4298, miR-6786-5p, miR-5010-5p, miR-6087, miR-6765-5p, miR-6732-5p, miR-6787-5p, miR-6737-5p, miR- 128-2-5p, miR-4270, miR-6861-5p, miR-6756-5p, miR-1229-5p, miR-6891-5p, miR-6848-5p, miR-1237-5p, miR-30c- 1-3p, miR-1233-5p, miR-211-3p, miR-4758-5p, miR-614, miR-6746-5p, miR-1915-5p, miR-4688, miR-3917, miR-5787, miR-4632-5p, miR-6126, miR-135a-3p, miR 8063, miR-5698, miR-6089, miR-498, miR-296-3p, miR-4419b, miR-6802-5p, miR-6829-5p, miR-6803-5p, miR-1199-5p, miR- 6840-3p, miR-6752-5p, miR-6798-5p, miR-6131, miR-4667-5p, miR-6510-5p, miR-4690-5p, miR-920, miR-
[0028]
(2) miR-6784-5p is hsa-miR-6784-5p, miR-1181 is hsa-miR-1181, miR-671-5p is hsa-miR-671-5p, miR-6857 -5p is hsa-miR-6857-5p, miR-4276 is hsa-miR-4276, miR-1914-3p is hsa-miR-1914-3p, miR-149-3p is hsa-miR is a -149-3p, miR-937-5p is hsa-miR-937-5p, miR-4675 is hsa-miR-4675, miR-6795-5p is located in hsa-miR-6795-5p , miR-4731-5p is hsa-miR-4731-5p, miR-5090 is hsa- Is a iR-5090, miR-3620-5p is hsa-miR-3620-5p, miR-1343-5p is hsa-miR-1343-5p, miR-6717-5p is hsa-miR-6717- is 5p, miR-6825-5p is hsa-miR-6825-5p, miR-6738-5p is hsa-miR-6738-5p, miR-6769a-5p is in hsa-miR-6769a-5p Yes, miR-4728-5p is hsa-miR-4728-5p, miR-652-5p is hsa-miR-652-5p, miR-4257 is hsa-miR-4257, miR-6785- 5p is hsa-miR-6785-5p, miR-7110-5p is hsa-m An R-7110-5p, miR-6887-5p is hsa-miR-6887-5p, miR-887-3p is hsa-miR-887-3p, miR-1228-5p is hsa-miR is a 1228-5p, miR-5572 is hsa-miR-5572, miR-6782-5p is hsa-miR-6782-5p, miR-4298 is hsa-miR-4298, miR-6786 -5p is hsa-miR-6786-5p, miR-5010-5p is hsa-miR-5010-5p, miR-6087 is hsa-miR-6087, miR-6765-5p is hsa-miR is a -6765-5p, miR-6732-5p is hsa-miR-6732-5p, miR-6787-5p is hsa-miR-6787-5p, miR-6737-5p is hsa-miR-6737 is a -5p, miR-128-2-5p is hsa-miR-128-2-5p, miR-4270 is hsa-miR-4270, miR-6861-5p is hsa-miR-6861-5p in it, miR-6756-5p is hsa-miR-6756-5p, miR-1229-5 There is a hsa-miR-1229-5p, miR-6891-5p is hsa-miR-6891-5p, miR-6848-5p is hsa-miR-6848-5p, miR-1237-5p is hsa is a -miR-1237-5p, miR-30c-1-3p is hsa-miR-30c-1-3p, miR-1233-5p is hsa-miR-1233-5p, miR-211-3p There is hsa-miR-211-3p, miR-4758-5p is hsa-miR-4758-5p, miR-614 is hsa-miR-614, miR-6746-5p is hsa-miR-6746 is a -5p, miR-1915-5p is hsa-miR-1915-5p, miR-4688 is h Is a a-miR-4688, miR-3917 is hsa-miR-3917, miR-5787 is hsa-miR-5787, miR-4632-5p is hsa-miR-4632-5p, miR- 6126 is hsa-miR-6126, miR-135a-3p is hsa-miR-135a-3p, miR-8063 is hsa-miR-8063, miR-5698 is hsa-miR- Is 5698, miR-6089 is hsa-miR-6089, miR-498 is hsa-miR-498, miR-296-3p is hsa-miR-296-3p, is miR-4419b hsa- is a miR-4419b, miR-6802-5p is hsa-miR-6802-5p, miR-6829-5p is hsa-miR-6829-5p, miR-6803-5p is hsa-miR-6803- is 5p, miR-1199-5p is hsa-miR-1199-5p, miR-6840-3p is hsa-miR-6840-3p, miR-6752-5p is in hsa-miR-6752-5p Yes, miR-6798-5p is hsa-miR-6798-5p, miR- 131 is hsa-miR-6131, miR-4667-5p is hsa-miR-4667-5p, miR-6510-5p is hsa-miR-6510-5p, the miR-4690-5p hsa- is a miR-4690-5p, miR-920 is hsa-miR-920, miR-23b-3p is hsa-miR-23b-3p, miR-4448 is hsa-miR-4448, miR- 2110 is hsa-miR-2110, miR-4706 is hsa-miR-4706, miR-7845-5p is hsa-miR-7845-5p, miR-6808-5p is hsa-miR-6808- is 5p, miR-4447 is hsa-miR-4447, miR-6 69-5p is a hsa-miR-6869-5p, miR-6794-5p is a hsa-miR-6794-5p, miR-6511a-5p is a hsa-miR-6511a-5p, miR-6824- 5p is hsa-miR-6824-5p, miR-6766-3p is hsa-miR-6766-3p, miR-6511a-5p is hsa-miR-6511a-5p, miR-6749-
[0029]
(3) the nucleic acid, polynucleotide in any of the following (a) -
(e): represented by any one of (a) SEQ ID NO: 1 ~ 83,227 ~ 229,246,248, and 250 polynucleotides, a variant thereof u in the nucleotide sequence or the nucleotide sequence consisting of the nucleotide sequence is t, the fragment comprising the derivative, or 15 or more continuous nucleotides,
(b) SEQ ID NO: 1 ~ 83,227 ~ 229 , 246, 248, and polynucleotides comprising a nucleotide sequence shown in any of the
250, the nucleotide sequence or represented by any one of (c) SEQ ID NO: 1 ~ 83,227 ~ 229,246,248, and 250 polynucleotides u in the nucleotide sequence consisting of a nucleotide sequence complementary to the nucleotide sequence which is t, a variant thereof, a derivative thereof, or contains more than 15 consecutive bases Fragments
thereof, the nucleotide sequence complementary to the nucleotide sequence u is t in the nucleotide sequence or the nucleotide sequence represented by any one of (d) SEQ ID NO: 1 ~ 83,227 ~ 229,246,248, and 250 polynucleotides, and
(e) above (a) ~ any polynucleotide under stringent conditions with a polynucleotide hybridizing in (d),
a polynucleotide selected from the group consisting of, (1) or the kit according to (2).
[0030]
(4) the kit is another early pancreatic cancer or pancreatic cancer precursor lesions marker, miR-1908-5p, miR-6729-5p, miR-5195-3p, miR-638, miR-6125, miR -3178, miR-3196, miR-8069, miR-4723-5p, miR-4746-3p, miR-4689, miR-6816-5p, miR-6757-5p, miR-7109-5p, miR-6724-5p , miR-1225-3p, miR-6875-5p, miR-7108-5p, miR-4508, miR-6085, miR-6779-5p, miR-642a-3p, miR-4695-5p, miR-7847-3p , miR-3197, miR-6769b-5p, miR-7641, miR-1 7-5p, miR-3185, miR-2861, miR-3940-5p, miR-1203, miR-615-5p, miR-4787-5p, miR-1343-3p, miR-6813-5p, miR-1225- 5p, miR-602, miR-4488, miR-125a-3p, miR-5100, miR-4294, miR-1231, miR-6765-3p, miR-4442, miR-718, miR-6780b-5p, miR- 6090, miR-6845-5p, miR-4741, miR-4467, miR-4707-5p, miR-4271, miR-4673, miR-3184-5p, miR-1469, miR-4640-5p, miR-663a, miR-6791-5p, miR-6826 5p, miR-4433b-3p, miR-1915-3p, miR-4417, miR-4449, miR-4707-3p, miR-3180-3p, miR-5585-3p, miR-1268a, miR-8072, miR- 296-5p, miR-204-3p, miR-4454, miR-6722-3p, miR-1290, miR-3622a-5p, miR-939-5p, miR-675-5p, miR-3 131, miR-4648, miR-1268b, miR-6741-5p, miR-6893-5p, miR-3162-5p, miR-642b-3p, miR-4734, miR-150-3p, miR-8089, miR 6805-3p, miR-7113-3p, miR-6850-5p, miR-6799-5p, miR-6768-5p, miR-92b-5p, miR-3679-5p, miR-4792, miR-3656, miR 92a-2-5p, miR-4466, miR-4513, miR-6781-5p, miR-4649-5p, miR-6775-5p, miR-4651, miR-3195, miR-6726-5p, miR-6872- 3p, miR-371a-5p, miR-6777-5p miR-6789-5p, miR-7975, miR-6821-5p, miR-4534, miR-619-5p, miR-7107-5p, miR-1228-3p, miR-6774-5p, miR-6805-5p, miR-23a-3p, miR-4665-5p, miR-4505, miR-4638-5p, miR-24-3p, miR-3135b, miR-4745-5p, miR-128-1-5p, miR-4476, miR-4687-3p, miR-3665, miR-6806-5p, miR-3937, miR-711, miR-3141, miR-3188, miR-4281, miR-5196-5p, miR-6880-5p, miR 3960, miR-3648, miR-6721-5p, Wed. -4492, miR-744-5p, miR-7704, miR-4749-5p, miR-762, miR-6836-3p, miR-6727-5p, miR-4739, miR-7977, miR-4484, miR-6515 3P, miR-373-5p, miR-4258, miR-4674, miR-3180, miR-6076, miR-1238-5p, miR-4463, miR-4486, miR-473
[0031]
(5) miR-1908-5p is hsa-miR-1908-5p, miR-6729-5p is hsa-miR-6729-5p, miR-5195-3p is located in hsa-miR-5195-3p , miR-638 is hsa-miR-638, miR-6125 is hsa-miR-6125, miR-3178 is hsa-miR-3178, miR-3196 is hsa-miR-3196, miR -8069 is hsa-miR-8069, miR-4723-5p is hsa-miR-4723-5p, miR-4746-3p is hsa-miR-4746-3p, miR-4689 is hsa-miR is -4689, miR-6816-5p is hsa-miR-6816-5p Yes, miR-6757-5p is hsa-miR-6757-5p, miR-7109-5p is hsa-miR-7109-5p, miR-6724-5p is hsa-miR-6724-5p, miR-1225-3p is hsa-miR-1225-3p, miR-6875-5p is hsa-miR-6875-5p, miR-7108-5p is hsa-miR-7108-5p, miR- 4508 is hsa-miR-4508, miR-6085 is hsa-miR-6085, miR-6779-5p is hsa-miR-6779-5p, miR-642a-3p is hsa-miR-642a- is a 3p, miR-4695-5p is hsa-miR-4695-5p, iR-7847-3p is hsa-miR-7847-3p, miR-3197 is hsa-miR-3197, miR-6769b-5p is hsa-miR-6769b-5p, miR-7641 is hsa- a miR-7641, miR-187-5p is hsa-miR-187-5p, miR-3185 is hsa-miR-3185, miR-2861 is hsa-miR-2861, m iR-3940-5p is hsa-miR-3940-5p, miR-1203 is hsa-miR-1203, miR-615-5p is hsa-miR-615-5p, is miR-4787-5p is hsa-miR-4787-5p, miR-1343-3p is hsa-miR-1343-3p, miR-6813-5p is hsa-miR-6813-5p, is miR-1225-5p hsa- is a miR-1225-5p, miR-602 is hsa-miR-602, miR-4488 is hsa-miR-4488, miR-125a-3p is hsa-miR-125a-3p, miR- 5100 is hsa-miR-5100, miR-4294 is hsa-miR-4294 Yes, miR-1231 is hsa-miR-1231, miR-6765-3p is hsa-miR-6765-3p, miR-4442 is hsa-miR-4442, miR-718 is hsa-miR- is 718, miR-6780b-5p is hsa-miR-6780b-5p, miR-6090 is hsa-miR-6090, miR-6845-5p is hsa-miR-6845-5p, miR- 4741 is hsa-miR-4741, miR-4467 is hsa-miR-4467, miR-4707-5p is hsa-miR-4707-5p, miR-4271 is hsa-miR-4271, miR-4673 is hsa-miR-4673, miR-3 84-5p is a hsa-miR-3184-5p, miR-1469 is a hsa-miR-1469, miR-4640-5p is a hsa-miR-4640-5p, miR-663a is hsa-miR- is 663a, miR-6791-5p is hsa-miR-6791-5p, miR-6826-5p is hsa-miR-6826-5p, miR-4433b-3p is hsa-miR-4433 A b-3p, miR-1915-3p is hsa-miR-1915-3p, miR-4417 is hsa-miR-4417, miR-4449 is hsa-miR-4449, miR-4707- 3p is hsa-miR-4707-3p, miR-3180-3p is hsa-miR-3180-3p, miR-5585-3p is hsa-miR-5585-3p, it is miR-1268a hsa- is a miR-1268a, miR-8072 is hsa-miR-8072, miR-296-5p is hsa-miR-296-5p, miR-204-3p is hsa-miR-204-3p, miR-4454 is hsa-miR-4454, is miR-6722-3p hsa- Is a iR-6722-3p, miR-1290 is hsa-miR-1290, miR-3622a-5p is hsa-miR-3622a-5p, miR-939-5p is in hsa-miR-939-5p Yes, miR-675-5p is hsa-miR-675-5p, miR-3131 is hsa-miR-3131, miR-4648 is hsa-miR-4648, miR-1268b is hsa-miR- is 1268b, miR-6741-5p is hsa-miR-6741-5p, miR-6893-5p is hsa-miR-6893-5p, miR-3162-5p is in hsa-miR-3162-5p There, miR-642b-3p is hsa-miR-642b-3p, m R-4734 is hsa-miR-4734, miR-150-3p is hsa-miR-150-3p, miR-8089 is hsa-miR-8089, miR-6805-3p is hsa-miR is a 6805-3p, miR-7113-3p is hsa-miR-7113-3p, miR-6850-5p is hsa-miR-6850-5p, miR-6799-5p is hsa-miR-679 Is 9-5p, miR-6768-5p is hsa-miR-6768-5p, miR-92b-5p is hsa-miR-92b-5p, miR-3679-5p is hsa-miR-3679- is 5p, miR-4792 is hsa-miR-4792, miR-3656 is hsa-miR-3656, miR-92a-2-5p is hsa-miR-92a-2-5p, miR- 4466 is hsa-miR-4466, miR-4513 is hsa-miR-4513, miR-6781-5p is hsa-miR-6781-5p, miR-4649-5p is hsa-miR-4649- is 5p, miR-6775-5p is hsa-miR-6775-5p, miR-4651 Is hsa-miR-4651, miR-3195 is hsa-miR-3195, miR-6726-5p is hsa-miR-6726-5p, miR-6872-3p is in hsa-miR-6872-3p Yes, miR-371a-5p is hsa-miR-371a-5p, miR-6777-5p is hsa-miR-6777-5p, miR-6789-5p is hsa-miR-6789-5p, miR-7975 is hsa-miR-7975, miR-6821-5p is hsa-miR-6821-5p, miR-4534 is hsa-miR-4534, miR-619-5p is hsa-miR- is a 619-5p, miR-7107-5p is hsa-miR-7107-5 In it, miR-1228-3p is hsa-miR-1228-3p, miR-6774-5p is hsa-miR-6774-5p, miR-6805-5p is located in hsa-miR-6805-5p , miR-23a-3p is hsa-miR-23a-3p, miR-4665-5p is hsa-miR-4665-5p, miR-4505 is hsa-miR-4505, miR-4638-5p There is a hsa-miR-4638-5p, miR-24-3p is hsa-miR-24-3p, miR-3135b is hsa-miR-3135b, miR-4745-5p is hsa-miR-4745 is a -5p, miR-128-1-5p is hsa-miR-128-1-5p, miR-4476 is hsa-miR-4476, miR-4687-3p is hsa-miR-4687-3p in and, miR-3665 is hsa-miR-3665, miR-6806-5p is hsa-miR-6806-5p, miR-3937 is hsa-miR-3937, miR-711 is hsa-miR is -711, miR-3141 is hsa-miR-3141, miR-3188 is h Is a a-miR-3188, miR-4281 is hsa-miR-4281, miR-5196-5p is hsa-miR-5196-5p, miR-6880-5p is in hsa-miR-6880-5p Yes, miR-3960 is hsa-miR-3960, miR-3648 is hsa-miR-3648, miR-6721-5p is hsa-miR-6721-5p, miR-4492 is hsa-miR- is 4492, miR-744-5p is hsa-miR-744-5p, miR-7704 is hsa-miR-7704, miR-4749-5p is hsa-miR-4749-5p, miR- 762 is hsa-miR-762, miR-6836-3p is hsa-m An R-6836-3p, miR-6727-5p is hsa-miR-6727-5p, miR-4739 is hsa-miR-4739, miR-7977 is hsa-miR-7977, miR- 4484 is hsa-miR-4484, miR-6515-3p is hsa-miR-6515-3p, miR-373-5p is hsa-miR-373-5p, miR-4258 is hsa-m
[0032]
(6) The nucleic acid polynucleotide in any of the following (f) -
(j): (f) SEQ ID NO: 84 ~ 226, 230 ~ 245 and 247, and the base sequence represented by any one of 249 or the polynucleotide comprising the nucleotide sequence u is t in the nucleotide sequence, the fragment comprising the variant, derivative, or 15 or more continuous
nucleotides, (g) SEQ ID NO: 84 to 226 and 230 ~ 245, 247 , and polynucleotides comprising a nucleotide sequence shown in any of the
249, is u in the nucleotide sequence or the nucleotide sequence represented by any one of (h) SEQ ID NO: 84 ~ 226, 230 ~ 245, 247, and 249 polynucleotides, a variant thereof comprising a nucleotide sequence complementary to the nucleotide sequence which is t, the fragment comprising the derivative, or 15 or more contiguous bases,
(I) SEQ ID NO: 84 ~ 226, 230 ~ 245, 247, and polynucleotides comprising a nucleotide sequence complementary to the nucleotide sequence u is t in the nucleotide sequence or the nucleotide sequence shown in any of 249, and
(j) any of the polynucleotides and polynucleotide hybridizing under stringent conditions, said (f) ~ (i)
is a polynucleotide selected from the consisting of group, according to (4) or (5) kit.
[0033]
(7) is an early pancreatic cancer or pancreatic cancer precursor lesions marker, miR-6784-5p, miR-1181, miR-671-5p, miR-6857-5p, miR-4276, miR-1914-3p, miR -149-3p, miR-937-5p, miR-4675, miR-6795-5p, miR-4731-5p, miR-5090, miR-3620-5p, miR-1343-5p, miR-6717-5p, miR -6825-5p, miR-6738-5p, miR-6769a-5p, miR-4728-5p, miR-652-5p, miR-4257, miR-6785-5p, miR-7110-5p, miR-6887-5p , miR-887-3p, miR-1228-5p, miR-5572, miR-67 2-5p, miR-4298, miR-6786-5p, miR-5010-5p, miR-6087, miR-6765-5p, miR-6732-5p, miR-6787-5p, miR-6737-5p, miR- 128-2-5p, miR-4270, miR-6861-5p, miR-6756-5p, miR-1229-5p, miR-6891-5p, miR-6848-5p, miR-1237-5p, miR-30c- 1-3p, miR-1233-5p, miR-211-3p, miR-4758-5p, miR-614, miR-6746-5p, miR-1915-5p, miR-4688, miR-3917, miR-5787, miR-4632-5p, miR-6126, miR-135a-3p, miR 8063, miR-5698, miR-6089, miR-498, miR-296-3p, miR-4419b, miR-6802-5p, miR-6829-5p, miR-6803-5p, miR-1199-5p, miR- 6840-3p, miR-6752-5p, miR-6798-5p, miR-6131, miR-4667-5p, miR-6510-5p, miR-4690-5p, miR-920, miR-
[0034]
(8) miR-6784-5p is hsa-miR-6784-5p, miR-1181 is hsa-miR-1181, miR-671-5p is hsa-miR-671-5p, miR-6857 -5p is hsa-miR-6857-5p, miR-4276 is hsa-miR-4276, miR-1914-3p is hsa-miR-1914-3p, miR-149-3p is hsa-miR is a -149-3p, miR-937-5p is hsa-miR-937-5p, miR-4675 is hsa-miR-4675, miR-6795-5p is located in hsa-miR-6795-5p , miR-4731-5p is hsa-miR-4731-5p, miR-5090 is hsa- Is a iR-5090, miR-3620-5p is hsa-miR-3620-5p, miR-1343-5p is hsa-miR-1343-5p, miR-6717-5p is hsa-miR-6717- is 5p, miR-6825-5p is hsa-miR-6825-5p, miR-6738-5p is hsa-miR-6738-5p, miR-6769a-5p is in hsa-miR-6769a-5p Yes, miR-4728-5p is hsa-miR-4728-5p, miR-652-5p is hsa-miR-652-5p, miR-4257 is hsa-miR-4257, miR-6785- 5p is hsa-miR-6785-5p, miR-7110-5p is hsa-m An R-7110-5p, miR-6887-5p is hsa-miR-6887-5p, miR-887-3p is hsa-miR-887-3p, miR-1228-5p is hsa-miR is a 1228-5p, miR-5572 is hsa-miR-5572, miR-6782-5p is hsa-miR-6782-5p, miR-4298 is hsa-miR-4298, miR-6786 -5p is hsa-miR-6786-5p, miR-5010-5p is hsa-miR-5010-5p, miR-6087 is hsa-miR-6087, miR-6765-5p is hsa-miR is a -6765-5p, miR-6732-5p is hsa-miR-6732-5p, miR-6787-5p is hsa-miR-6787-5p, miR-6737-5p is hsa-miR-6737 is a -5p, miR-128-2-5p is hsa-miR-128-2-5p, miR-4270 is hsa-miR-4270, miR-6861-5p is hsa-miR-6861-5p in it, miR-6756-5p is hsa-miR-6756-5p, miR-1229-5 There is a hsa-miR-1229-5p, miR-6891-5p is hsa-miR-6891-5p, miR-6848-5p is hsa-miR-6848-5p, miR-1237-5p is hsa is a -miR-1237-5p, miR-30c-1-3p is hsa-miR-30c-1-3p, miR-1233-5p is hsa-miR-1233-5p, miR-211-3p There is hsa-miR-211-3p, miR-4758-5p is hsa-miR-4758-5p, miR-614 is hsa-miR-614, miR-6746-5p is hsa-miR-6746 is a -5p, miR-1915-5p is hsa-miR-1915-5p, miR-4688 is h Is a a-miR-4688, miR-3917 is hsa-miR-3917, miR-5787 is hsa-miR-5787, miR-4632-5p is hsa-miR-4632-5p, miR- 6126 is hsa-miR-6126, miR-135a-3p is hsa-miR-135a-3p, miR-8063 is hsa-miR-8063, miR-5698 is hsa-miR- Is 5698, miR-6089 is hsa-miR-6089, miR-498 is hsa-miR-498, miR-296-3p is hsa-miR-296-3p, is miR-4419b hsa- is a miR-4419b, miR-6802-5p is hsa-miR-6802-5p, miR-6829-5p is hsa-miR-6829-5p, miR-6803-5p is hsa-miR-6803- is 5p, miR-1199-5p is hsa-miR-1199-5p, miR-6840-3p is hsa-miR-6840-3p, miR-6752-5p is in hsa-miR-6752-5p Yes, miR-6798-5p is hsa-miR-6798-5p, miR- 131 is hsa-miR-6131, miR-4667-5p is hsa-miR-4667-5p, miR-6510-5p is hsa-miR-6510-5p, the miR-4690-5p hsa- is a miR-4690-5p, miR-920 is hsa-miR-920, miR-23b-3p is hsa-miR-23b-3p, miR-4448 is hsa-miR-4448, miR- 2110 is hsa-miR-2110, miR-4706 is hsa-miR-4706, miR-7845-5p is hsa-miR-7845-5p, miR-6808-5p is hsa-miR-6808- is 5p, miR-4447 is hsa-miR-4447, miR-6 69-5p is a hsa-miR-6869-5p, miR-6794-5p is a hsa-miR-6794-5p, miR-6511a-5p is a hsa-miR-6511a-5p, miR-6824- 5p is hsa-miR-6824-5p, miR-6766-3p is hsa-miR-6766-3p, miR-6511a-5p is hsa-miR-6511a-5p, miR-6749-
[0035]
(9) The nucleic acid polynucleotide in any of the following (a) -
(e): represented by any one of (a) SEQ ID NO: 1 ~ 83,227 ~ 229,246,248, and 250 polynucleotides, a variant thereof u in the nucleotide sequence or the nucleotide sequence consisting of the nucleotide sequence is t, the fragment comprising the derivative, or 15 or more continuous nucleotides,
(b) SEQ ID NO: 1 ~ 83,227 ~ 229 , 246, 248, and polynucleotides comprising a nucleotide sequence shown in any of the
250, the nucleotide sequence or represented by any one of (c) SEQ ID NO: 1 ~ 83,227 ~ 229,246,248, and 250 polynucleotides u in the nucleotide sequence consisting of a nucleotide sequence complementary to the nucleotide sequence which is t, a variant thereof, a derivative thereof, or contains more than 15 consecutive bases Fragments
thereof, the nucleotide sequence complementary to the nucleotide sequence u is t in the nucleotide sequence or the nucleotide sequence represented by any one of (d) SEQ ID NO: 1 ~ 83,227 ~ 229,246,248, and 250 polynucleotides, and
(e) above (a) ~ any polynucleotide under stringent conditions with a polynucleotide hybridizing in (d),
a polynucleotide selected from the group consisting of, (7) or the device according to (8).
[0036]
(10) the device is another early pancreatic cancer or pancreatic cancer precursor lesions marker, miR-1908-5p, miR-6729-5p, miR-5195-3p, miR-638, miR-6125, miR -3178, miR-3196, miR-8069, miR-4723-5p, miR-4746-3p, miR-4689, miR-6816-5p, miR-6757-5p, miR-7109-5p, miR-6724-5p , miR-1225-3p, miR-6875-5p, miR-7108-5p, miR-4508, miR-6085, miR-6779-5p, miR-642a-3p, miR-4695-5p, miR-7847-3p , miR-3197, miR-6769b-5p, miR-7641, miR 187-5p, miR-3185, miR-2861, miR-3940-5p, miR-1203, miR-615-5p, miR-4787-5p, miR-1343-3p, miR-6813-5p, miR-1225- 5p, miR-602, miR-4488, miR-125a-3p, miR-5100, miR-4294, miR-1231, miR-6765-3p, miR-4442, miR-718, miR-6780b-5p, miR- 6090, miR-6845-5p, miR-4741, miR-4467, miR-4707-5p, miR-4271, miR-4673, miR-3184-5p, miR-1469, miR-4640-5p, miR-663a, miR-6791-5p, miR-68 6-5p, miR-4433b-3p, miR-1915-3p, miR-4417, miR-4449, miR-4707-3p, miR-3180-3p, miR-5585-3p, miR-1268a, miR-8072, miR-296-5p, miR-204-3p, miR-4454, miR-6722-3p, miR-1290, miR-3622a-5p, miR-939-5p, miR-675-5p, miR -3131, miR-4648, miR-1268b, miR-6741-5p, miR-6893-5p, miR-3162-5p, miR-642b-3p, miR-4734, miR-150-3p, miR-8089, miR -6805-3p, miR-7113-3p, miR-6850-5p, miR-6799-5p, miR-6768-5p, miR-92b-5p, miR-3679-5p, miR-4792, miR-3656, miR -92a-2-5p, miR-4466, miR-4513, miR-6781-5p, miR-4649-5p, miR-6775-5p, miR-4651, miR-3195, miR-6726-5p, miR-6872 3P, miR-371a-5p, miR-6777- p, miR-6789-5p, miR-7975, miR-6821-5p, miR-4534, miR-619-5p, miR-7107-5p, miR-1228-3p, miR-6774-5p, miR-6805- 5p, miR-23a-3p, miR-4665-5p, miR-4505, miR-4638-5p, miR-24-3p, miR-3135b, miR-4745-5p, miR-128-1-5p, miR 4476, miR-4687-3p, miR-3665, miR-6806-5p, miR-3937, miR-711, miR-3141, miR-3188, miR-4281, miR-5196-5p, miR-6880-5p, miR-3960, miR-3648, miR-6721-5p, iR-4492, miR-744-5p, miR-7704, miR-4749-5p, miR-762, miR-6836-3p, miR-6727-5p, miR-4739, miR-7977, miR-4484, miR 6515-3p, miR-373-5p, miR-4258, miR-4674, miR-3180, miR-6076, miR-1238-5p, miR-4463, miR-4486, miR-4
[0037]
(11) miR-1908-5p is hsa-miR-1908-5p, miR-6729-5p is hsa-miR-6729-5p, miR-5195-3p is located in hsa-miR-5195-3p , miR-638 is hsa-miR-638, miR-6125 is hsa-miR-6125, miR-3178 is hsa-miR-3178, miR-3196 is hsa-miR-3196, miR -8069 is hsa-miR-8069, miR-4723-5p is hsa-miR-4723-5p, miR-4746-3p is hsa-miR-4746-3p, miR-4689 is hsa-miR is -4689, miR-6816-5p is hsa-miR-6816-5 In it, miR-6757-5p is hsa-miR-6757-5p, miR-7109-5p is hsa-miR-7109-5p, miR-6724-5p is located in hsa-miR-6724-5p , miR-1225-3p is hsa-miR-1225-3p, miR-6875-5p is hsa-miR-6875-5p, miR-7108-5p is hsa-miR-7108-5p, miR -4508 is hsa-miR-4508, miR-6085 is hsa-miR-6085, miR-6779-5p is hsa-miR-6779-5p, miR-642a-3p is hsa-miR-642a is a -3p, miR-4695-5p is located in hsa-miR-4695-5p miR-7847-3p is hsa-miR-7847-3p, miR-3197 is hsa-miR-3197, miR-6769b-5p is hsa-miR-6769b-5p, miR-7641 is hsa- is a miR-7641, miR-187-5p is hsa-miR-187-5p, miR-3185 is hsa-miR-3185, miR-2861 is hsa-miR-2861, miR-3940-5p is hsa-miR-3940-5p, miR-1203 is hsa-miR-1203, miR-615-5p is hsa-miR-615-5p, is miR-4787-5p is hsa-miR-4787-5p, miR-1343-3p is hsa-miR-1343-3p, miR-6813-5p is hsa-miR-6813-5p, is miR-1225-5p hsa- is a miR-1225-5p, miR-602 is hsa-miR-602, miR-4488 is hsa-miR-4488, miR-125a-3p is hsa-miR-125a-3p, miR- 5100 is hsa-miR-5100, miR-4294 is hsa-miR-429 In it, miR-1231 is hsa-miR-1231, miR-6765-3p is hsa-miR-6765-3p, miR-4442 is hsa-miR-4442, miR-718 is hsa-miR is -718, miR-6780b-5p is hsa-miR-6780b-5p, miR-6090 is hsa-miR-6090, miR-6845-5p is hsa-miR-6845-5p, miR -4741 is hsa-miR-4741, miR-4467 is hsa-miR-4467, miR-4707-5p is hsa-miR-4707-5p, miR-4271 is located in the hsa-miR-4271 , miR-4673 is hsa-miR-4673, miR- 184-5p is hsa-miR-3184-5p, miR-1469 is hsa-miR-1469, miR-4640-5p is hsa-miR-4640-5p, miR-663a is hsa-miR- is 663a, miR-6791-5p is hsa-miR-6791-5p, miR-6826-5p is hsa-miR-6826-5p, miR-4433b-3p is hsa-miR-443 A 3b-3p, miR-1915-3p is hsa-miR-1915-3p, miR-4417 is hsa-miR-4417, miR-4449 is hsa-miR-4449, miR-4707- 3p is hsa-miR-4707-3p, miR-3180-3p is hsa-miR-3180-3p, miR-5585-3p is hsa-miR-5585-3p, it is miR-1268a hsa- is a miR-1268a, miR-8072 is hsa-miR-8072, miR-296-5p is hsa-miR-296-5p, miR-204-3p is hsa-miR-204-3p, miR-4454 is hsa-miR-4454, miR-6722-3p is hsa Is a miR-6722-3p, miR-1290 is hsa-miR-1290, miR-3622a-5p is hsa-miR-3622a-5p, miR-939-5p is in hsa-miR-939-5p Yes, miR-675-5p is hsa-miR-675-5p, miR-3131 is hsa-miR-3131, miR-4648 is hsa-miR-4648, miR-1268b is hsa-miR- is 1268b, miR-6741-5p is hsa-miR-6741-5p, miR-6893-5p is hsa-miR-6893-5p, miR-3162-5p is in hsa-miR-3162-5p Yes, miR-642b-3p is hsa-miR-642b-3p, iR-4734 is hsa-miR-4734, miR-150-3p is hsa-miR-150-3p, miR-8089 is hsa-miR-8089, miR-6805-3p is hsa-miR- is a 6805-3p, miR-7113-3p is hsa-miR-7113-3p, miR-6850-5p is hsa-miR-6850-5p, miR-6799-5p is hsa-miR-67 Is a 99-5p, miR-6768-5p is hsa-miR-6768-5p, miR-92b-5p is hsa-miR-92b-5p, miR-3679-5p is hsa-miR-3679- is 5p, miR-4792 is hsa-miR-4792, miR-3656 is hsa-miR-3656, miR-92a-2-5p is hsa-miR-92a-2-5p, miR- 4466 is hsa-miR-4466, miR-4513 is hsa-miR-4513, miR-6781-5p is hsa-miR-6781-5p, miR-4649-5p is hsa-miR-4649- is 5p, miR-6775-5p is hsa-miR-6775-5p, miR-465 There is a hsa-miR-4651, miR-3195 is hsa-miR-3195, miR-6726-5p is hsa-miR-6726-5p, miR-6872-3p is hsa-miR-6872-3p in it, miR-371a-5p is hsa-miR-371a-5p, miR-6777-5p is hsa-miR-6777-5p, miR-6789-5p is located in hsa-miR-6789-5p , miR-7975 is hsa-miR-7975, miR-6821-5p is hsa-miR-6821-5p, miR-4534 is hsa-miR-4534, miR-619-5p is hsa-miR is a -619-5p, miR-7107-5p is hsa-miR-7107- A p, miR-1228-3p is hsa-miR-1228-3p, miR-6774-5p is hsa-miR-6774-5p, miR-6805-5p is in hsa-miR-6805-5p Yes, miR-23a-3p is hsa-miR-23a-3p, miR-4665-5p is hsa-miR-4665-5p, miR-4505 is hsa-miR-4505, miR-4638- 5 p is hsa-miR-4638-5p, miR-24-3p is hsa-miR-24-3p, miR-3135b is hsa-miR-3135b, miR-4745-5p is hsa-miR- is a 4745-5p, miR-128-1-5p is hsa-miR-128-1-5p, miR-4476 is hsa-miR-4476, miR-4687-3p is hsa-miR-4687- a 3p, miR-3665 is hsa-miR-3665, miR-6806-5p is hsa-miR-6806-5p, miR-3937 is hsa-miR-3937, miR-711 is hsa- is a miR-711, miR-3141 is hsa-miR-3141, is miR-3188 Is a sa-miR-3188, miR-4281 is hsa-miR-4281, miR-5196-5p is hsa-miR-5196-5p, miR-6880-5p is in hsa-miR-6880-5p Yes, miR-3960 is hsa-miR-3960, miR-3648 is hsa-miR-3648, miR-6721-5p is hsa-miR-6721-5p, miR-4492 is hsa-miR- is 4492, miR-744-5p is hsa-miR-744-5p, miR-7704 is hsa-miR-7704, miR-4749-5p is hsa-miR-4749-5p, miR- 762 is hsa-miR-762, is miR-6836-3p hsa- Is a iR-6836-3p, miR-6727-5p is hsa-miR-6727-5p, miR-4739 is hsa-miR-4739, miR-7977 is hsa-miR-7977, miR- 4484 is hsa-miR-4484, miR-6515-3p is hsa-miR-6515-3p, miR-373-5p is hsa-miR-373-5p, miR-4258 is hsa-
[0038]
(12) The nucleic acid polynucleotide in any of the following (f) -
(j): (f) SEQ ID NO: 84 ~ 226, 230 ~ 245 and 247, and the base sequence represented by any one of 249 or the polynucleotide comprising the nucleotide sequence u is t in the nucleotide sequence, the fragment comprising the variant, derivative, or 15 or more continuous
nucleotides, (g) SEQ ID NO: 84 to 226 and 230 ~ 245, 247 , and polynucleotides comprising a nucleotide sequence shown in any of the
249, is u in the nucleotide sequence or the nucleotide sequence represented by any one of (h) SEQ ID NO: 84 ~ 226, 230 ~ 245, 247, and 249 a polynucleotide consisting of a nucleotide sequence complementary to the nucleotide sequence is t, the fragment comprising the variant, derivative, or 15 or more contiguous bases
(I) SEQ ID NO: 84 ~ 226, 230 ~ 245, 247, and polynucleotides comprising a nucleotide sequence complementary to the nucleotide sequence u is t in the nucleotide sequence or the nucleotide sequence shown in any of 249, and
(j) above (f) any of the polynucleotides under stringent conditions with a polynucleotide hybridizing of ~ (i),
a polynucleotide selected from the consisting of group, according to (10) or (11) of the device.
[0039]
(13) The device is a device for the measurement by hybridization techniques, according to any one of (7) to (12) device.
[0040]
(14) The hybridization techniques, a nucleic acid array technology, as described in (13) device.
[0041]
(15) (1) measuring the kit or (7) to the expression level of target nucleic acid in a specimen of the subject using the device according to any one of (14) as claimed in any one of the - (6), the a measured expression amount, by using the control expression level in healthy body that is measured in the same manner, that the subject is suffering from an early stage pancreatic cancer or pancreatic cancer precursor lesions or early pancreatic cancer or pancreatic that does not suffer from cancer precursor lesions assessed in in vitro, thereby detecting the presence or absence of early pancreatic cancer or pancreatic cancer precursor lesions in a subject, early pancreatic in a subject detection method of I or pancreatic cancer precursor lesions.
[0042]
(16) (1) measuring the expression level of a target gene in a specimen of the subject using the device according to any of the kit or of any one (7) to (14) to (6), early gene expression amount of the specimen from gene expression level and healthy body sample from a subject known to have pancreatic cancer or pancreatic cancer precursor lesions were created as a teacher samples, and early pancreatic cancer or pancreatic cancer precursor lesions and healthy and distinction to determine possible is discriminants to the (discriminant function), by substituting the expression level of a target gene in a sample from said subject, whereby, early pancreatic cancer or it comprises assessing the presence or absence of pancreatic cancer precursor lesions, a method of detecting early pancreatic cancer or pancreatic cancer precursor lesions in a subject.
[0043]
(17) the subject is a human, the method described in (15) or (16).
[0044]
(18) The specimen is blood, serum or plasma, the method according to any one of (15) to (17).
[0045]

　Terms used herein have the following definitions.
[0046]
　The term "pancreatic cancer" as used herein, refers to invasive ductal cancer (invasive ductal carcinomas). Specifically, papillary adenocarcinoma (papillary adenocarcinoma) formed in the pancreas, adenocarcinoma (Tubular adenocarcinoma), poorly differentiated adenocarcinoma (poorly differentiated adenocarcinoma), adenosquamous carcinoma (adenosquamous carcinoma), mucinous (mucious carcinoma ), anaplastic cancer (anaplastic carcinoma), and the like ( "pancreatic cancer handling Rules", 6th edition complement revised edition, 2013, Japan pancreas Society, Kaneharashuppan (Tokyo, Japan), p27-28).
[0047]
　By "pancreatic cancer precursor lesions" as used herein, refers to exocrine tumors formed in the pancreas (Exocrine neoplasms). Specifically, serous cyst tumors (Serouscysticneoplasms: SCNs), serous cystadenoma (Serouscystadenoma: SCA), serous cystadenocarcinoma (Serouscystadenocarcinoma: SCC), mucinous cystic tumors (Mucinouscysticneoplasms: MCNs), mucinous cystadenoma (Mucinouscystadenoma: MCA), mucinous cyst adenocarcinoma (Mucinouscystadenocarcinoma: MCC), intraductal papillary mucinous neoplasm (Intraductalpapillary-mucinousneoplasms: IPMNs), intraductal papillary mucinous adenoma (Intraductalpapillary-mucinousadenoma: IPMA), Tube papillary mucinous carcinoma (Intraductalpapillary-mucinouscarcinoma: IPMC), and the like ( "pancreatic cancer Handling Rules", 6th edition complement revised edition, 2013, Japan pancreas Society, Kaneharashuppan (Tokyo, Japan), p24-27) .
[0048]
　As used herein, the term "progression of pancreatic cancer" main local tumor progression degree, lymph node metastasis, Stage 0, IA by such distant metastasis, IB, IIA, IIB, III, IVa, are classified into IVb ( "pancreatic cancer handling Rules", 6th edition complement revised edition, 2013, Japan pancreas Society, Kaneharashuppan (Tokyo, Japan), p55-57).
[0049]
　The "early pancreatic cancer" as used herein refers to stage 0, IA, IB, IIA, pancreatic cancer IIB.
[0050]
　The "progressive pancreatic cancer" as used herein refers to stage III, IVa, IVb the pancreatic cancer.
[0051]
　The "benign disease" as used herein, refers to a disease of non-malignant tumor on the organ.
[0052]
　Further, "nucleotide" as used herein, "polynucleotide", "DNA", by abbreviations, such as "RNA", "Guidelines for the creation of specification and the like comprising a base sequence or amino acid sequence" (Japanese Patent Office ed.) and shall follow conventional in the art.
[0053]
　A "polynucleotide" as used herein, RNA, DNA, and none of the RNA / DNA (chimeric) used for encompasses nucleic acids. Note that the above-mentioned DNA, include cDNA, genomic DNA, and even synthetic DNA is. Also in the above RNA, total RNA, mRNA, rRNA, miRNA, siRNA, snoRNA, snRNA, which include any non-coding RNA and synthetic RNA. "Synthetic DNA" and "synthetic RNA" herein, on the basis of a predetermined nucleotide sequence (either native sequence or a non-natural sequence good.), For example using an automatic nucleic acid synthesizer, artificial It refers to a fabricated DNA and RNA. "Non-naturally occurring sequence" herein is intended to be used in the broad sense, it differs from the native sequence, e.g., one or more nucleotide substitutions, deletions, insertions and / or sequence comprising additional ( that encompasses variant sequence), sequences comprising one or more modified nucleotides (i.e., modified sequence), and the like. Further, in this specification, the polynucleotide is used nucleic interchangeably.
[0054]
　The term "fragment" as used herein, is a polynucleotide having a nucleotide sequence of contiguous portion of a polynucleotide, 15 bases or more, it is desirable that preferably 17 bases or more, more preferably having 19 or more bases in length .
[0055]
　"Gene" as used herein, RNA, and not double-stranded DNA only, include the single-stranded DNA, such as plus strand constituting it (or sense strand) or complementary strand (or antisense strand) used is intended to. Also not to be particularly limited by its length.
[0056]
　Thus, a "gene", as used herein, unless otherwise noted, single-stranded DNA (complementary with double-stranded DNA, single-stranded DNA (plus strand) complementary to sequences with the positive strand containing a human genomic DNA chain) (e.g. cDNA), micro-RNA (miRNA), and fragments thereof, and any of these transcripts contains. Also the "gene" is not only a "gene" represented by a specific nucleotide sequence (or SEQ ID NO:), RNA RNA and biological functions encoded by these are equivalent, for example, homologs (i.e., homologs or orthologs), variants such as genetic polymorphisms, and "nucleic acid" encoding derivatives are included. Such homologues, the "nucleic acid" encoding a variant or derivative, specifically, under stringent conditions as described later, a nucleotide sequence, or the base represented by any of SEQ ID NO: 1-812 u has a nucleotide sequence, the complementary sequence hybridizing to the nucleotide sequence of t in the sequence may include "nucleic acid". Incidentally, a "gene" does not matter whether another functional area, may comprise for example expression control region, coding region, exon or intron. Also, "gene" may be included in the cell, are released to the outside of the cell may be present alone, or may be in a state of being encapsulated in vesicles called exosomes.
[0057]
　The "exosomes" in the present specification (aka "exosomes"), vesicles wrapped in a lipid bilayer that is secreted from the cell. Exosomes derived from multivesicular endosomes, sometimes when they are released into the extracellular environment, including RNA, biological materials, such as "gene" and protein such as DNA therein. Exosomes are known blood, serum, plasma, may be included in the body fluid such as lymph.
[0058]
　The "transcript" as used herein, refers to a DNA sequence of a gene of RNA synthesized as a template. Binds to a site where RNA polymerase is referred to as a promoter upstream of the gene, RNA is synthesized in a manner going way 3 'end is bound ribonucleotides be complementary to the base sequence of DNA. The RNA not only gene itself, the expression control region, the coding region includes the entire sequence from the transcription initiation point, including exons or introns up to end of the poly A sequence.
[0059]
　Further, "micro RNA (miRNA)", as used herein, unless otherwise noted, are transcribed as RNA precursor hairpin-like structure, it is cut by dsRNA cleavage enzyme having RNase III cleavage activity, a protein complex called RISC incorporated into and used with the intention of non-coding RNA between 15 and 25 bases involved in mRNA translation inhibition. The "miRNA" as used herein not only "miRNA" represented by a specific nucleotide sequence (or SEQ ID NO:), the precursor of the "miRNA" (pre-miRNA, pri-miRNA), and these miRNA biological function equivalent, for example, homologs (i.e., homologs or orthologs), variants such as genetic polymorphisms, and also encompasses derivatives. Such precursors, congeners, the variant or derivative, specifically, can be identified by miRBase release 20 (http://www.mirbase.org/), under stringent conditions as described later , can be cited "miRNA" having any complementary sequences that hybridize to the nucleotide sequence of the specific nucleotide sequence shown in any of SEQ ID NO: 1-812. Furthermore, "miRNA" as used herein may be a gene product of miR genes, such gene products are mature miRNA (e.g., involved in translational repression of the mRNA as described above 15 ~ 25 includes a base, or 19 to 25 bases, non-coding RNA) or miRNA precursor (e.g., the pre-miRNA or pri-miRNA like).
[0060]
　"Probe" as used herein encompasses polynucleotides and / or complementary to the polynucleotide used for specifically detecting the resulting RNA or polynucleotides derived therefrom by the expression of the gene.
[0061]
　The term "primer" as used herein encompasses polynucleotides and / or complementary to the polynucleotide specifically recognizes resulting RNA or polynucleotides derived therefrom by the expression of the gene is amplified.
[0062]
　Here complementary polynucleotide (complementary strand, reverse strand) to the base sequence u is t in the nucleotide sequence or the nucleotide sequence as defined by any of SEQ ID NOs: 812, consisting essentially of polynucleotide full-length sequence, or subsequence thereof, (for convenience here, this is referred to as positive strand) a relative: T (U), G: based on the base pair relation such C, in the base complementary relationship It refers to a polynucleotide. Further, reference to "a polynucleotide comprising a nucleotide sequence complementary" to the nucleotide sequence u is t in the nucleotide sequence or the nucleotide sequence shown in any of SEQ ID NO: 1 to 812 are also basically the same understanding that.
[0063]
　The "stringent conditions" as used herein, than the nucleic acid probe to other sequences, detectable by a large degree (e.g. average background measurements + background SEM × 2 or more measurement values ​​of ) in refers to hybridizing conditions to its target sequence. Stringent conditions are sequence-dependent and will be different depending on the environment hybridization is performed. By controlling the stringency of the hybridization and / or wash conditions, target sequences can be identified which are 100% complementary to the nucleic acid probe. Specific examples of the "stringent conditions" will be described later.
[0064]
　The "Tm value" herein, the double-stranded portion of the polynucleotide is denatured into single-stranded, double-stranded and single-stranded 1: means the temperature that exists in a ratio.
[0065]
　A "variant" as used herein, in the case of nucleic acids, polymorphisms, variants of native caused such a mutation, or any one of the nucleotide sequences of SEQ ID NO: 1 to 812, or is u in the nucleotide sequence nucleotide sequence which is t, or deletion of bases of one or more (e.g., one to several) in the partial sequence, substitution, variants include the addition or insertion, or about the each or a partial sequence of the nucleotide sequence 90% or more, about 95%, about 97% or more, about 98% or more, mutants showing about 99% or more% identity, or the definition polynucleotide or oligonucleotide comprising the nucleotide sequence or a partial sequence means of the hybridizing nucleic acids under stringent conditions.
[0066]
　The term "several" as used herein, means about 10,9,8,7,6,5,4,3 or two integers.
[0067]
　As used herein, mutants, site-directed mutagenesis may be made using well known techniques, such as mutagenesis method using PCR method.
[0068]
　"% Identity" herein, using the retrieval system of the protein or gene according to the above BLAST or FASTA, and introducing gaps, or not introducing gaps, can be determined (Zheng Zhang et al., 2000, J Comput Biol, Vol. 7, p203-214;.... Altschul, S.F et al., 1990, Journal of Molecular Biology, 215 Volume, p403-410;. Pearson, W.R et al., 1988, Proc. Natl. Acad. Sci. U. S. A., 85 Volume, p2444-2448).
[0069]
　"Derivative" as used herein, modified nucleic acids, but not limited to for example, labeled derivatives due fluorophore, modified nucleotides (e.g. halogen, alkyl such as methyl, alkoxy such as methoxy, thio, groups such as carboxymethyl reconstruction of nucleotides and bases including double bond saturation, deamination, derivatives containing nucleotides, etc.) that received such substitution of sulfur molecules oxygen molecules, PNA (peptide nucleic acid; Nielsen, P.E. et al., 1991, Science, No. 254 Vol, p1497-500), LNA (locked nucleic acid;. Obika, S, et al., refers to 1998, Tetrahedron Lett, Vol 39, p5401-5404), and the like. .
[0070]
　As used herein, a polynucleotide specifically bindable "nucleic acid" is selected from the miRNA is an early pancreatic cancer or pancreatic cancer precursor lesions markers above are synthesized or prepared nucleic acid, specifically to include a "nucleic acid probe" or "primer", in order to detect the presence or absence of early pancreatic cancer or pancreatic cancer precursor lesions in a subject, or affected early pancreatic cancer or pancreatic cancer precursor lesions the presence or absence, degree of morbidity, extent whether or improvement of improvement of early pancreatic cancer or pancreatic cancer precursor lesions, in order to diagnose susceptibility to treatment for early pancreatic cancer or pancreatic cancer precursor lesions or early pancreas prevention of I or pancreatic cancer precursor lesions, to screen for useful candidates for improving or treating, is directly or indirectly utilized. In vivo in relation to the onset of these early pancreatic cancer or pancreatic cancer precursor lesions, particularly blood, transcript or cDNA thereof represented by any of SEQ ID NO: 1 to 812 in the sample such as body fluid such as urine nucleotides capable of specifically recognizing and binding the synthetic nucleic acid, including oligonucleotides and polynucleotides. These nucleotides, oligonucleotides and polynucleotides, in a living body based on the properties, as a probe for detecting the gene expressed in such tissues or the cells and also for amplifying the gene expressed in vivo it can be effectively used as a primer.
[0071]
　The term "detection" as used herein, inspection, measurement, judgment, or, may be replaced by the term decision support. Also, the term "evaluation" herein is used in its sense including to help diagnose or evaluated based on the inspection results or measurement results.
[0072]
　"Subject" as used herein includes humans, primates, including chimpanzees, dogs, pet animals such as cats, cows, horses, sheep, farm animals such as goats, rodents such as mice, rats, It refers to a mammal, such as animals kept in zoos. A preferred subject is a human. Also, "healthy body" is also, even in such a mammal, means an animal that is not suffering from cancer to be detected. Preferred healthy body is a human.
[0073]
　Probability used "P" or "P-value" in the statistical test, the extreme statistic is observed than statistics calculated from actual data under the null hypothesis herein It is shown. Therefore the more "P" or "P-value" is small, considered that there are significant differences between the comparison.
[0074]
　As used herein, "sensitivity" means the value of (number of true positives) / (Number of Number + false negatives of true positive). Sensitivity it is possible to discover early pancreatic cancer or pancreatic cancer precursor lesions early Higher, it leads to a decrease in full cancers of resection and recurrence rate.
[0075]
　As used herein, "specificity" refers to the (number of true negatives) / (Number of Number + false positives true negatives). Prevent implementation of wasteful additional testing due to it is high specificity erroneous healthy body early pancreatic cancer or pancreatic cancer precursor lesions patient determination, leading to the reduction of relief and medical expenses of the patient's burden.
[0076]
　As used herein, "accuracy" means the value of (the number of number + true negative true positives) / (total number of cases). Accuracy shows the percentage determination result is correct with respect to all the samples, the first indicator for evaluating the detection performance.
[0077]
　Determined in this specification, it becomes the "analyte" target detection or diagnosis, the generation of early pancreatic cancer or pancreatic cancer precursor lesions, progression of early pancreatic cancer or pancreatic cancer precursor lesions or early pancreatic cancer or refers to tissues and biomaterials gene of the present invention is expressed varies with the exertion of therapeutic effect on pancreatic cancer precursor lesions. Vascular pancreatic tissue and around the in particular, organ lymph nodes and organs, also metastasis is suspected, skin, and blood, urine, saliva, sweat, body fluids such as tissue exudate, sera prepared from blood, plasma refers to other, feces, hair and the like. Furthermore the biological sample, specifically extracted from these refers to a gene, such as RNA or miRNA.
[0078]
　The term is used herein, "hsa-miR-6784-5p gene" or "hsa-miR-6784-5p" is, hsa-miR-6784-5p gene (miRBase Accession described in SEQ ID NO: 1 No. MIMAT0027468), etc. and other species homologs or orthologs are included. Gene can be obtained Ladewig E et al, 2012, Genome Res, 22 vol., By the method described in P1634-1645. Further, "hsa-miR-6784-5p" takes a hairpin-like structure "hsa-mir-6784" (miRBase Accession No.MI0022629, SEQ ID NO: 251) is known as its precursor.
[0079]
　The term is used herein, "hsa-miR-1181 gene" or "hsa-miR-1181" is, hsa-miR-1181 gene described in SEQ ID NO: 2 (miRBase Accession No.MIMAT0005826) and other species such homologue or orthologs are included. Gene can be obtained Subramanian S et al, 2008, Oncogene, 27 vol., By the method described in P2015-2026. Further, "hsa-miR-1181" takes a hairpin-like structure "hsa-mir-1181" (miRBase Accession No.MI0006274, SEQ ID NO: 252) is known as its precursor.
[0080]
　The term is used herein, "hsa-miR-671-5p gene" or "hsa-miR-671-5p" is, hsa-miR-671-5p gene (miRBase Accession described in SEQ ID NO: 3 No. MIMAT0003880), etc. and other species homologs or orthologs are included. Gene can be obtained Berezikov E et al, 2006, Genome Res, 16 vol., By the method described in P1289-1298. Further, "hsa-miR-671-5p" takes a hairpin-like structure "hsa-mir-671" (miRBase Accession No.MI0003760, SEQ ID NO: 253) is known as its precursor.
[0081]
　The term is used herein, "hsa-miR-6857-5p gene" or "hsa-miR-6857-5p" is, hsa-miR-6857-5p gene (miRBase Accession described in SEQ ID NO: 4 No. MIMAT0027614), etc. and other species homologs or orthologs are included. Gene can be obtained Ladewig E et al, 2012, Genome Res, 22 vol., By the method described in P1634-1645. Further, "hsa-miR-6857-5p" takes a hairpin-like structure "hsa-mir-6857" (miRBase Accession No.MI0022703, SEQ ID NO: 254) is known as its precursor.
[0082]
　The term is used herein, "hsa-miR-4276 gene" or "hsa-miR-4276" is, hsa-miR-4276 gene described in SEQ ID NO: 5 (miRBase Accession No.MIMAT0016904) and other species such homologue or orthologs are included. Gene can be obtained Goff LA et al., 2009, PLoS One, 4 vol., By the method described in E7192. Further, "hsa-miR-4276" takes a hairpin-like structure "hsa-mir-4276" (miRBase Accession No.MI0015882, SEQ ID NO: 255) is known as its precursor.
[0083]
　The term is used herein, "hsa-miR-1914-3p gene" or "hsa-miR-1914-3p" is, hsa-miR-1914-3p gene (miRBase Accession described in SEQ ID NO: 6 No. MIMAT0007890), etc. and other species homologs or orthologs are included. Gene, Bar M, et al., 2008, Stem Cells, 26 vol, it may be obtained by the method described in P2496-2505. Further, "hsa-miR-1914-3p" takes a hairpin-like structure "hsa-mir-1914" (miRBase Accession No.MI0008335, SEQ ID NO: 256) is known as its precursor.
[0084]
　The term is used herein, "hsa-miR-149-3p gene" or "hsa-miR-149-3p" is, hsa-miR-149-3p gene (miRBase Accession according to SEQ ID NO: 7 No. MIMAT0004609), etc. and other species homologs or orthologs are included. Gene, Lagos-Quintana M et al., 2002, Curr Biol, 12 vol, may be obtained by the method described in P735-739. Further, "hsa-miR-149-3p" takes a hairpin-like structure "hsa-mir-149" (miRBase Accession No.MI0000478, SEQ ID NO: 257) is known as its precursor.
[0085]
　The term is used herein, "hsa-miR-937-5p gene" or "hsa-miR-937-5p" is, hsa-miR-937-5p gene (miRBase Accession according to SEQ ID NO: 8 No. MIMAT0022938), etc. and other species homologs or orthologs are included. Gene can be obtained Lui WO, et al., 2007, Cancer Res, 67 vol., By the method described in P6031-6043. Further, "hsa-miR-937-5p" takes a hairpin-like structure "hsa-mir-937" (miRBase Accession No.MI0005759, SEQ ID NO: 258) is known as its precursor.
[0086]
　The term is used herein, "hsa-miR-4675 gene" or "hsa-miR-4675" is, hsa-miR-4675 gene described in SEQ ID NO: 9 (miRBase Accession No.MIMAT0019757) and other species such homologue or orthologs are included. Gene can be obtained Persson H, et al., 2011, Cancer Res, 71 vol., By the method described in P78-86. Further, "hsa-miR-4675" takes a hairpin-like structure "hsa-mir-4675" (miRBase Accession No.MI0017306, SEQ ID NO: 259) is known as its precursor.
4286) of the combination
　(58) arranged No. 87 and 12 and 137 and 105 and 237: the combination of (a marker hsa-miR-638 and hsa-miR-5090 and hsa-miR-4673 and hsa-miR-642a-3p and-miR-hsa 373-5P)
　( 59) SEQ ID NO: 87 and 12 and 100 and 109 and 237 (markers: hsa-miR-638 and hsa-miR-5090 and hsa-miR-6875-5p and hsa-miR-6769b-5p and hsa-miR-373- the combination of 5p)
　(60) SEQ ID NO: 87 and 12 and 100 and 109 and 237 (markers: hsa-miR-638 and hsa-miR-5090 and hsa-miR-6875-5p and hsa-miR-6769b-5p and hsa-miR-373 -5p) combination
　(61) SEQ ID NO: 106 and 12 and 137 and 105 and 86 (a marker: hsa-miR-4695-5p and hsa-miR-5090 and hsa-miR-4673 and the hsa-miR-642a-3p hsa-miR-5195-3p) combination
　(62) SEQ ID NO: 106 and 12 and 137 and 105 and 247 (markers: hsa-miR-4695-5p and hsa-miR-5090 and hsa-miR-4673 and hsa-miR the combination of -642a-3p and-MiR-Hsa 4286)
　(63 SEQ ID NO: 106 and 12 and 119 and 105 and 100 (markers: hsa-miR-4695-5p and hsa-miR-5090 and hsa-miR-6813-5p and hsa-miR-642a-3p and hsa-miR-6875- the combination of 5p)
　(64) SEQ ID NO: 106 and 12 and 137 and 105 and 121 (markers: hsa-miR-4695-5p and hsa-miR-5090 and hsa-miR-4673 and hsa-miR-642a-3p and hsa -miR-602 combination of)
[0671]
　Furthermore, without limitation, SEQ ID NO: five polynucleotides selected from a polynucleotide and cancer-species specificity polynucleotide group 1 consisting of the nucleotide sequence or a complementary sequence represented by SEQ ID NO: 28 nucleotide sequence or to illustrate the combination of a polynucleotide consisting of a complementary sequence thereof.
　(1) SEQ ID NO: 137 and 119 and 105 and 28 and 237 (markers: hsa-miR-4673 and hsa-miR-6813-5p and hsa-miR-642a-3p and hsa-miR-6782-5p and hsa-miR -373-5P) a combination of
　(2) SEQ ID NO: 87 and 106 and 119 and 28 and 121 (markers: hsa-miR-638 and hsa-miR-4695-5p and hsa-miR-6813-5p and hsa-miR 6782-5p and hsa-miR-602 combination of)
　(3) SEQ ID NO: 106 and 137 and 119 and 28 and 121 (markers: hsa-miR-4695-5p and hsa-miR-4673 and hsa-miR-6813-5p and hsa-miR-6782-5p and hsa-miR-602 combination of)
　(4 SEQ ID NO: 90 and 119 and 105 and 28 and 237 (markers: hsa-miR-3196 and hsa-miR-6813-5p and hsa-miR-642a-3p and hsa-miR-6782-5p and hsa-miR-373- the combination of 5p)
[0672]
　Furthermore, without limitation, SEQ ID NO: five polynucleotides selected from a polynucleotide and cancer-species specificity polynucleotide group 1 consisting of the nucleotide sequence or a complementary sequence represented by SEQ ID NO: 5 nucleotide sequence or to illustrate the combination of a polynucleotide consisting of a complementary sequence thereof.
　(1) SEQ ID NO: 90, 5, and 137 and 119 and 105 (markers: hsa-miR-3196 and hsa-miR-4276 and hsa-miR-4673 and hsa-miR-6813-5p and hsa-miR-642a-3p the combination of)
　(2) SEQ ID NO: 5 and 137 and 119 and 105 and 237 (markers: and hsa-miR-4276 hsa-miR -4673 and hsa-miR-6813-5p and the hsa-miR-642a-3p hsa- miR-373-5p) combination
　(3) SEQ ID NO: 5 and 137 and 119 and 105 and 32 (a marker: hsa-miR-4276 and hsa-miR-4673 and hsa-miR-6813-5p and hsa-miR-642a the combination of -3p and hsa-miR-6087)
[0673]
　Furthermore, without limitation, SEQ ID NO: five polynucleotides selected from a polynucleotide and cancer-species specificity polynucleotide group 1 consisting of the nucleotide sequence or a complementary sequence represented by SEQ ID NO: 2 nucleotide sequence or to illustrate the combination of a polynucleotide consisting of a complementary sequence thereof.
　(1) SEQ ID NO: 2 and 137 and 119 and 105 and 237 (markers: hsa-miR-1181 and hsa-miR-4673 and hsa-miR-6813-5p and hsa-miR-642a-3p and hsa-miR-373 -5p) combination
　(2) SEQ ID NO: 2 and 87 and 137 and 119 and 105 (markers: and hsa-miR-1181 and hsa-miR-638 and hsa-miR-4673 and hsa-miR-6813-5p hsa- miR-642a-3p) combination
　(3) SEQ ID NO: 2 and 137 and 119 and 105 and 13 (a marker: hsa-miR-1181 and hsa-miR-4673 and hsa-miR-6813-5p and hsa-miR-642a the combination or other cancer and / or the diagnosis in specimens from benign Class II histology constructing a discriminant using the expression level of use gene set. As a result, by measuring the expression level of the diagnostic gene set of the unknown sample, subjects from the unknown specimen including early pancreatic cancer or pancreatic cancer precursor lesions or early pancreatic cancer or pancreatic it does not contain a cancer precursor lesions may be distinguished with 100% accuracy at highest.
Example
[0751]
　More specifically explained by the following examples of the present invention. However, the scope of the present invention shall not be the examples limit.
[0752]
[Reference Example 1]

　obtaining informed consent, pancreatic cancer precursor lesions patient 21 people that are not cancer is found in organs ( 4 example IPMA low grade is, five cases IPMA high grade is, IPMC is 12 cases), early pancreatic cancer patients 31 people in organs other than the pancreas is not cancer was observed (stage IIA is 9 cases, stage IIB 22 example), and, respectively, using the Venoject II vacuum blood collection tube VP-AS109K60 from healthy 123 people (Terumo Corp., Japan) serum was collected and the learning sample group. Similarly, informed consent was obtained, 12 people pancreatic cancer precursor lesions patients whose cancer has not been found in organs (IPMA low grade 3 cases, IPMA high grade 3 cases, 6 cases IPMC is), except the pancreas early pancreatic cancer patients 13 people cancer in the organ has not been approved for (stage IIA in 3 patients, stage IIB is 10 cases), and, Venoject II vacuum blood collection tube VP-AS109K60 from a healthy body 61 people (Terumo Corporation ) respectively were collected and serum was used as a validation sample group.
[0753]

　the learning sample group as a sample, the verification sample group combined pancreatic cancer precursor lesions patient 33 people, healthy body 184 people, and, serum obtained from each of a total of 261 people 44 people early pancreatic cancer patients from 300μL, 3D-Gene (TM) RNA extraction reagent from liquid sample kit ( Toray Industries, Inc., Japan) using an RNA extraction reagent in, to give a total RNA according to the protocol established by the company.
[0754]

　The learning sample group as a sample, the verification sample group combined pancreatic cancer precursor lesions patient 33 people, healthy body 184 people, and, with respect to total RNA obtained from a total 261 people sera 44 early-pancreatic cancer patients, the miRNA fluorescently labeled on the basis of the 3D-Gene (TM) protocol, which the company is determined by using the miRNA labeling kit (Toray Industries, Inc.) (ver2.20). As oligo DNA chip, in a miRNA that are registered in the miRBase release 20, 3D-Gene equipped with a probe having a sequence complementary to 2,555 species of miRNA (registered trademark) Human miRNA Oligo chip (Toray Industries, Inc. ) was performed using washing after hybridization and hybridization under stringent conditions based on protocol company stipulated. The DNA chip using a 3D-Gene (TM) scanner (Toray) scans, and quantify the fluorescence intensity at acquires image 3D-Gene (TM) Extraction (Toray Industries, Inc.). The digitized fluorescence intensity, the bottom is converted to 2 logarithmic values ​​and gene expression level, performs subtraction of the blank value, the missing value from the logarithm of the minimum value of the gene expression level in each DNA chip 0.1 It was replaced by a value obtained by subtracting. As a result, pancreatic cancer precursor lesions patient 33 people, healthy body 184 people, and, to the total 261 people sera early pancreatic cancer patients 46 people, to obtain a gene expression level of exhaustive miRNA. The calculation and statistical analysis using the gene expression levels of digitized miRNA, R Language 3.0.2 (R Development Core Team (2013) R:.. A language and environment for statistical computing R Foundation for Statistical Computing, URL http://www.R-project.org/.) and MASS package 7.3-30 (Venables, W. N. & Ripley
[0755]
[Reference Example 2]

　No cancer is found in other organs that obtaining informed consent, progressive pancreatic cancer patients 61 people, 66 people biliary tract cancer patients, 31 people colon cancer patients, 32 people gastric cancer patients, esophageal cancer patients 34 human, 38 people liver cancer patients, and, gene expression from each of 15 patients pancreatic benign diseases using Venoject II vacuum blood collection tube VP-AS109K60 (Terumo Corp.) was collected serum, also a gene expression information database Omnibus (http://www.ncbi.nlm.nih.gov/geo/) accession numbers: from GSE73002 dataset, 51 breast cancer patients, 35 people prostate cancer patients, prostate benign disease patients 26 people data extract the, reference example 1 of pancreatic cancer precursor lesions patient 21 people (IPMA low grade 4 cases , 5 cases IPMA high grade is, IPMC 12 cases), early pancreatic cancer patients 31 people (Stage IIA eight cases, cases Stage IIB is 22), and was a learning sample group together with healthy bodies 128 people. Similarly, progress pancreatic cancer patients 39 people that are not cancer is found in other organs that obtaining informed consent, 32 people biliary tract cancer patients, 19 people colon cancer patients, 18 people gastric cancer patients, esophageal cancer 16 people, hepatocellular cancer patients 14 patients, and, respectively, from 9 patients pancreatic benign diseases using Venoject II vacuum blood collection tube VP-AS109K60 (Terumo Corp.) was collected serum, also, is a gene expression information database Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo/) accession numbers: from GSE73002 data set of 23 breast cancer patients, 17 people prostate cancer patients, prostate benign disease patients 15 people data extracting, reference example 1 pancreatic cancer precursor lesions 12 patients (IPMA low grade 3 cases, IPMA high grade 3 cases, 6 cases IPMC is), early pancreatic cancer 13 patients (Stage IIA in 3 patients , Stage IIB is 10 cases), and to obtain a verified sample group together with normal body 56 people. Extraction and measurement and analysis of gene expression after the total RNA was performed in the same manner as in Reference Example 1.
[0756]
　[Example 1]

　exemplary in the example, from the learning sample group early pancreatic cancer or pancreatic cancer precursor lesions the positive control group, healthy body selected genetic markers for determining as a negative control group, the independent verification sample group from the learning sample group It was investigated in the sample.
[0757]
　Specifically, normalized by global normalization is first combined miRNA expression level of the validation sample group learning sample group obtained in the above Reference Example.
[0758]
　Next, we selected the diagnostic gene using learning sample group. Here, in order to acquire a more reliable diagnostic markers, early pancreatic cancer or pancreatic cancer precursor lesions group learning sample group, or, in any of the healthy body group learning sample group, sample of 50% or more in were selected only those genes with the sixth power or more gene expression level 2. As genes that are statistical significance for further determination of early pancreatic cancer or pancreatic cancer precursor lesions the patient group and the healthy body group, obtained by two-tailed t-test assuming equal variances for each gene expression level P values ​​were Bonferroni correction, a gene that satisfies p <0.01, acquired as a genetic marker to be used for discriminant explanatory variables, listed in Table 2.
[0759]
　こ の よ う に し て, HSA-miR-6784-5p, HSA-miR-1181, HSA-miR-671-5p, HSA-miR-6857-5p, HSA-miR-4276, HSA-miR-1914-3p, HSA -miR-149-3p, HSA-miR-937-5p, HSA-miR-4675, HSA-miR-6795-5p, HSA-miR-4731-5p, HSA-miR-5090, HSA-miR-3620-5p , HSA-miR-1343-5p, HSA-miR-6717-5p, HSA-miR-6825-5p, HSA-miR-6738-5p, HSA-miR-6769a-5p, HSA-miR-4728-5p, HSA -miR-652-5p, HSA-miR-4257, HSA-miR 6785-5p, HSA-miR-7110-5p, HSA-miR-6887-5p, HSA-miR-887-3p, HSA-miR-1228-5p, HSA-miR-5572, HSA-miR-6782-5p, HSA-miR-4298, HSA-miR-6786-5p, HSA-miR-5010-5p, HSA-miR-6087, HSA-miR-6765-5p, HSA-miR-6732-5p, HSA-miR-6787- 5p, HSA-miR-6737-5p, HSA-miR-128-2-5p, HSA-miR-4270, HSA-miR-6861-5p, HSA-miR-6756-5p, HSA-miR-1229-5p, HSA-miR-6891-5p, HSA-miR-6848-5p, sa-miR-1237-5p, HSA-miR-30c-1-3p, HSA-miR-1233-5p, HSA-miR-211-3p, HSA-miR-4758-5p, HSA-miR-614, hsa- miR-6746-5p, HSA-miR-1915-5p, HSA-miR-4688, HSA-miR-3917, HSA-miR-5787, HSA-miR-4632-5p, HSA-miR-6126, h in-mir-135a-3p, hsa-mir-8063, hsa-mir-5698, hsa-mir-6089, hsa-mir-498, hsa-mir-296-3p, hsa-mir-4419b, hsa-miR- 6802-5p, hsa-mir-6829-5p, hsa-mir-6803-5p, hsa-mir-1199-5p, hsa-mir-6840-3p, hsa-mir-6752-5p, hsa-mir-6798- 5p, hsa-mir-6131, hsa-mir-4667-5p, hsa-mir-6510-5p, hsa-mir-4690-5p, hsa-mir-920, hsa-mir-23b-3p, hsa-miR- 4448, hsa-mir-2110, hsa-mir-4706 hsa-mir-7845-5p, hsa-mir-6808-5p, hsa-mir-4447, hsa-mir-6869-5p, hsa-mir-1908-5p, hsa-mir-6729-5p, hsa-miR- 5195-3p, hsa-mir-638, hsa-mir-6125, hsa-mir-3178, hsa-mir-3196, hsa-mir-8069, hsa-mir-4723-5p, hsa-mir-4746-3p, hsa-mir-4689, hsa-mir-6816-5p, hsa-mir-6757-5p, hsa-mir-7109-5p, hsa-mir-6724-5p, hsa-mir-1225-3p, hsa-miR- 6875-5p, hsa-mir-7108-5p, HS -miR-4508, hsa-mir-6085, hsa-mir-6779-5p, hsa-mir-642a-3p, hsa-mir-4695-5p, hsa-mir-7847-3p, hsa-mir-3197, hsa -miR-6769b-5p, hsa-mir-7641, hsa-mir-187-5p, hsa-mir-3185, hsa-mir-2861, hsa-mir-3940-5p, hsa-I R-1203, hsa-mir-615-5p, hsa-mir-4787-5p, hsa-mir-1343-3p, hsa-mir-6813-5p, hsa-mir-1225-5p, hsa-mir-602, hsa-mir-4488, hsa-mir-125a-3p, hsa-mir-5100, hsa-mir-4294, hsa-mir-1231, hsa-mir-6765-3p, hsa-mir-4442, hsa-miR- 718, hsa-mir-6780b-5p, hsa-mir-6090, hsa-mir-6845-5p, hsa-mir-4741, hsa-mir-4467, hsa-mir-4707-5p, hsa-mir-4271, hsa-mir-4673, hsa-mir-3184 5p, hsa-mir-1469, hsa-mir-4640-5p, hsa-mir-663a, hsa-mir-6791-5p, hsa-mir-6826-5p, hsa-mir-4433b-3p, hsa-miR- 1915-3p, hsa-mir-4417, hsa-mir-4449, hsa-mir-4707-3p, hsa-mir-3180-3p, hsa-mir-5585-3p, hsa-mir-1268a, hsa-miR- 8072, hsa-mir-296-5p, hsa-mir-204-3p, hsa-mir-4454, hsa-mir-6722-3p, hsa-mir-1290, hsa-mir-3622a-5p, hsa-miR- 939-5p, hsa-mir-675-5p, HS -miR-3131, hsa-mir-4648, hsa-mir-1268b, hsa-mir-6741-5p, hsa-mir-6893-5p, hsa-mir-3162-5p, hsa-mir-642b-3p, hsa -miR-4734, hsa-mir-150-3p, hsa-mir-8089, hsa-mir-6805-3p, hsa-mir-7113-3p, hsa-mir-6850-5p, hsa -miR-6799-5p, hsa-mir-6768-5p, hsa-mir-92b-5p, hsa-mir-3679-5p, hsa-mir-4792, hsa-mir-3656, hsa-mir-92a-2 -5p, hsa-mir-4466, hsa-mir-4513, hsa-mir-6781-5p, hsa-mir-4649-5p, hsa-mir-6775-5p, hsa-mir-4651, hsa-mir-3195 , hsa-mir-6726-5p, hsa-mir-6872-3p, hsa-mir-371a-5p, hsa-mir-6777-5p, hsa-mir-6789-5p, hsa-mir-7975, hsa-mir -6821-5p, hsa-mir-4534, hsa-miR- 19-5p, hsa-mir-7107-5p, hsa-mir-1228-3p, hsa-mir-6774-5p, hsa-mir-6805-5p, hsa-mir-23a-3p, hsa-mir-4665- 5p, hsa-mir-4505, hsa-mir-4638-5p, hsa-mir-24-3p, hsa-mir-3135b, hsa-mir-4745-5p, hsa-mir-128-1-5p, hsa- MIR-4476, hsa-mir-4687-3p, hsa-mir-3665, hsa-mir-6806-5p, hsa-mir-3937, hsa-mir-711, hsa-mir-3141, hsa-mir-3188, hsa-mir-4281, hsa-mir-5196-5p, hsa Mir-6880-5p, hsa-mir-3960, hsa-mir-3648, hsa-mir-6721-5p, hsa-mir-4492, hsa-mir-744-5p, hsa-mir-7704, 及 び, hsa- Mir-4749-5p 遺 伝 子, こ れ ら に 関 連 す る 配 列 番号 1 ~ 226 の 塩 基 配 列 を 見 出 し た.
[0760]
　Furthermore, it was created as an index the expression of these genes, a discriminant for determining the presence or absence of early pancreatic cancer or pancreatic cancer precursor lesions by discriminant analysis Fisher. That is, among the 226 genes selected in the learning sample group, the expression level measurements of the polynucleotide consisting of the nucleotide sequence shown in any of SEQ ID NO: 1-83 found in the newly Formula 2 input to create a discriminant, the calculated accuracy, sensitivity and specificity are shown in Table 3. Also it showed discriminant coefficients and constant term at that time in Table 4.
[0761]
　Next, using a discriminant prepared above was calculated precision, sensitivity and specificity in the verification sample group was verified by independent sample discrimination performance of the selected polynucleotides (Table 3). For example, pancreatic cancer precursor lesions patients (21 persons) of the obtained discriminant score learning sample group using the discriminant analysis Fisher from the expression amount measurement value of the base sequence represented by SEQ ID NO: 1, early pancreatic cancer patients ( 31 people), and, when compared with healthy body, it learning sample group is the discriminant score of early pancreatic cancer or pancreatic cancer precursor lesions group is higher significantly to healthy body group are shown (see Fig. 2 left) , were reproduced in still result verification sample group (see FIG. 2 right). In other polynucleotide shown in Similarly SEQ ID NO: 1 to 226, gene expression level measurement of early pancreatic cancer or pancreatic cancer precursor lesions patient group was significantly lower with respect to healthy body group (decreasing) or high ( increase) results (Table 2) are obtained, these results could be verified in the verification sample group. Further, for example, relates to the nucleotide sequence shown in SEQ ID NO 1, hit validation sample group of early pancreatic cancer or pancreatic cancer precursor lesions detected using a threshold (0) to determine both groups set by learning sample group was calculated number, 22 cases true positive, true negative 52 cases, false positive 9 cases, a false negative 4 cases, 85.1% accuracy as detection performance from these values, the sensitivity 84.6%, specificity 85 .2% was obtained. Such was disclosed in any of the polynucleotides of detection performance is calculated to Table 3 shown to the SEQ ID NO: 1-83 in. Of the polynucleotide comprising the nucleotide sequence represented by SEQ ID NO: 1-83 shown in Table 2, for example, SEQ ID NO: 2,3,18,12,20,1,15,50,63,72,5,24,10 , 26 polynucleotide comprising the nucleotide sequence represented by 52,9,11,19,39,61,7,17,22,26,74,21,28, respectively in the verification sample group 100% sensitivity, 92.3%, 92.3%, 76.9%, 80.8%, 84.6%, 76.9%, 84.6%, 73.1%, 80.8%, 88.5%, 88.5%, 88.5%, 73.1%, 73.1%, 76.9%, 61.5%, 65.4%, 84.6%, 92.3%, 73. 1% 61.5% 76.9% 73.1% 80.8% showed 92.3% (Table 3). Here, the comparative examples described later, 20% sensitivity of existing markers CEA in the verification sample group, the sensitivity of CA19-9 from it was 68% (Table 5-2), in the verification sample group, for example, SEQ ID NO: 2,3,18,12,20,1,15,50,63,72,5,24,10,52,9,11,19,39,61,7,17,22,26,74,21, 26 polynucleotide comprising the nucleotide sequence represented by 28 could prove to be discriminated alone exceeds CA19-9 sensitivity or early pancreatic cancer or pancreatic cancer precursor lesions at comparable sensitivity.
[0762]
　Example 2

　In the present embodiment, it was selected in Example 1 Gene and consider how to evaluate the early pancreatic cancer or pancreatic cancer precursor lesions discrimination performance in combination marker.
[0763]
　Specifically, of the polynucleotide consisting of the nucleotide sequence represented by SEQ ID NOs: 226 selected in Example 1, comprising the nucleotide sequence represented by SEQ ID NO: 1-83 found new poly performed discriminant analysis Fisher for two combinations 15,272 as one of the at least one expression level measurements of nucleotides, a discriminant for determining the presence or absence of early pancreatic cancer or pancreatic cancer precursor lesions It was constructed. Next, using a discriminant prepared above was calculated precision, sensitivity and specificity in the verification sample group was verified by independent sample discrimination performance of the selected polynucleotides. For example, by using the expression amount measurement value of the base sequence represented by SEQ ID NO: 1 and SEQ ID NO: 2, pancreatic cancer precursor lesions patients (21 patients) in the training sample, early pancreatic cancer patients (31 patients), and, when compared with healthy body (123 persons), scatter plots of expression level measurement values ​​of healthy body group and early pancreatic cancer or pancreatic cancer precursor lesions patient group is significantly separated to obtain a learning sample group, further result It could also reproduced in the validation sample group. Similarly, the nucleotide sequence represented by SEQ ID NO: 1 to 226 out of the polynucleotide, or expression level measurements of the polynucleotide consisting of the nucleotide sequence represented by SEQ ID NOs: 83 newly discovered two containing at least one, in other combinations, scatter plots significantly separate the gene expression levels measured in healthy body group and early pancreatic cancer or pancreatic cancer precursor lesions patients are obtained, these the results could be verified in the validation sample group. Further, for example, relates to the nucleotide sequence represented by the SEQ ID NO: 1 and SEQ ID NO: 2, the threshold for determining both groups set in the learning sample group (0 = 1.90 × hsa-miR-6784-5p + 1.72 × hsa-miR -1181-34.50) was calculated predictive number of early pancreatic cancer or pancreatic cancer precursor lesions detected using true positives 52 cases in the training sample group, true negative 107 example, false-positive 16 cases, false It is one example negative 90.3% accurate as detection performance from these values, the sensitivity 98.1%, specificity degree of 87% was obtained (see Fig. 3, left). Furthermore this result was also reproducible in the validation sample group (right see Figure 3). Thus, SEQ ID NO: 1 ~ Among the polynucleotide consisting of the nucleotide sequence represented by 226, 2 one of the expression level measurement value of the polynucleotide consisting of the nucleotide sequence represented by SEQ ID NOs: 83 newly discovered comprising at least one to calculate the detection performance of the number of combination whole street. As these examples, ways combination 225 including the expression level measurements of the polynucleotide consisting of the nucleotide sequence represented by SEQ ID NO: 1 and its detection performance as described in Table 6. Note "sequence number" in Table 6 shows the combination of a plurality of polynucleotides used in SEQ ID NO (as in table below of the present application). For example SEQ ID NO: 1 and SEQ ID NO: 2, SEQ ID NO: 1 and SEQ ID NO: 3, SEQ ID NO: 1 and SEQ ID NO: 4 and SEQ ID NO: 1 and SEQ ID NO: 5, in a polynucleotide of the expression level measurement values ​​consisting of the nucleotide sequence represented by the combination of each sensitivity 92.3% in the verification sample group 88.5% 84.6% 88.5% showed 84.6% (Table 6). As a further example, the combination of two polynucleotide consisting of the nucleotide sequence other than SEQ ID NO: 1 set forth in Table 7. For example, as a combination of specific two polynucleotides, SEQ ID NO: 2 and 18, SEQ ID NO: 2 and 53, SEQ ID NO: 2 and 20, SEQ ID NO: 2 and 3, SEQ ID NO: 2 and 50, SEQ ID NO: 85 and 3, SEQ ID NO: 84 and 3, SEQ ID NO: 90 and 3, SEQ ID NO: 87 and 3, SEQ ID NO: 90 and 18, SEQ ID NO: 87 and 18, SEQ ID NO: 89 and 18, SEQ ID NO: 84 and 18, SEQ ID NO: 85 and 12, SEQ ID NO: 85 and 20, SEQ ID NO: 84 and 20, SEQ ID NO: 90 and 20, and SEQ ID NO: 87 20, SEQ ID NO: 87 and 15, SEQ ID NO: 85 and 15, SEQ ID NO: 2 and 15, SEQ ID NO: 85 and 50, and SEQ ID NO: 87 50, SEQ ID NO: 84 and 50, and SEQ ID NO: 106 50, SEQ ID NO: 90 and 50, SEQ ID NO: 2 and 63, SEQ ID NO: 85 and 63, SEQ ID NO: 90 and 63, SEQ ID NO: 87 and 63, SEQ ID NO: 84 and 72, SEQ ID NO: 8 When 72, SEQ ID NO: 88 and 72, SEQ ID NO: 87 and 72, SEQ ID NO: 85 and 5, SEQ ID NO: 87 and 5, SEQ ID NO: 84 and 5, SEQ ID NO: 85 and 10, SEQ ID NO: 90 and 10, SEQ ID NO: 85 and 52 , SEQ ID NO Issue 88 and 52, SEQ ID NO: 87 and 52, SEQ ID NO: 98 and 52, SEQ ID NO: 84 and 52, SEQ ID NO: 87 and 9, SEQ ID NO: 85 and 9, SEQ ID NO: 117 and 9, SEQ ID NO: 88 and 9, SEQ ID NO: 87 When 11, SEQ ID NO: 85 and 11, SEQ ID NO: 102 and 11, SEQ ID NO: 84 and 11, SEQ ID NO: 85 and 19, SEQ ID NO: 87 and 19, SEQ ID NO: 88 and 19, SEQ ID NO: 89 and 19, SEQ ID NO: 87 and 39 , SEQ ID NO: 85 and 39, SEQ ID NO: 2 and 39, SEQ ID NO: 87 and 61, SEQ ID NO: 85 and 61, SEQ ID NO: 88 and 61, SEQ ID NO: 88 and 7, SEQ ID NO: 85 and 7, SEQ ID NO: 87 and 7, SEQ No. 91 and 7, SEQ ID NO: 85 and 17, SEQ ID NO: 87 and 17, SEQ ID NO: 85 and 22, SEQ ID NO: 87 and 22, SEQ ID NO: 117 and 22, SEQ ID NO: 85 and 26, SEQ ID NO: 87 and 26, SEQ ID NO: 84 and 26, SEQ Issue 85 and 74, the combination of SEQ ID NO: 2 and 74, SEQ ID NO: 87 and 74, SEQ ID NO: 84 and 74, SEQ ID NO: 88 and 74, SEQ ID NO: 85 and 28, represented in SEQ ID NO: 84 and 28, the learning sample It showed sensitivity of 95% or more to determine the early pancreatic cancer or pancreatic cancer precursor lesions patients and healthy body in both sample group of the group and the verification sample group. Thus the combination of the expression amount measurement value of the polynucleotide above the sensitivity of CA19-9 is an existing marker (68% from Table 5-2) is obtained 14,079 ways validation sample group, carried in this combination example all nucleotide sequence 1 to 226 shown in Table 2 obtained in 1 it was used at least once. That is, in the verification sample group, two combinations comprising at least one one of the expression level measurement value of the polynucleotide consisting of the nucleotide sequence represented by SEQ ID NOs: 226, early pancreatic sensitivity exceeding CA19-9 We were able to prove to detect the cancer or pancreatic cancer precursor lesions.
[0764]
　In this way, three expression amount measurement value of the polynucleotide consisting of the nucleotide sequence represented by SEQ ID NOS: 1 to 226, 4, 5, 6, 7, 8, 9, 10 or be combined more of the number of said polynucleotide, a marker to detect early pancreatic cancer or pancreatic cancer precursor lesions with excellent sensitivity is obtained. For example, the polynucleotide comprising the nucleotide sequence represented by SEQ ID NOs: 226 selected in Example 1 were ranked in descending order of P values ​​showing statistical significance, was added one by one from the upper miRNA It was calculated detection performance by using a combination of one or more miRNA. As a result, the sensitivity in the verification sample group is 69.2% for two miRNA, 80.8% in the five miRNA, 92.3% in the 10 miRNA, 96.2% in the 20 miRNA, 100% 100 miRNA, was 100% in 226 amino miRNA. These sensitivity since higher than the sensitivity of existing blood tumor markers showed that that can be a good marker even by combining a plurality of miRNA detecting early pancreatic cancer or pancreatic cancer precursor lesions. Here, the combination of a plurality of miRNA is not limited to the case of adding in the order of statistical significance as described above, the detection of any plurality of miRNA combinations also early pancreatic cancer or pancreatic cancer precursor lesions it can be used.
[0765]
　All polynucleotides consisting of the nucleotide sequence of these results with SEQ ID NO: 1 to 226, said to be excellent diagnostic marker.
[0766]
　Incidentally, Table 2 above, Table 3, Table 4, Table 5, Table 6, and Table 7 are as follows.
[0767]
[Table 2]

[0768]

[0769]

[0770]

[0771]

[0772]
[table 3]

[0773]

[0774]
[Table 4]

[0775]

[0776]
[Table 5-1]

[0777]

[0778]
[Table 5-2]

[0779]
[Table 6]

[0780]

[0781]

[0782]

[0783]

[0784]
[Table 7]

[0785]

[0786]

[0787]
　Example 3

　In the present embodiment, the first embodiment and using all specimens integrating analyte learning sample group and the verification sample group was used in 2, was selected and its early pancreatic cancer or pancreatic cancer precursor lesions discrimination performance evaluation of genetic markers.
[0788]
　Specifically, pancreatic cancer precursor lesions patients (33 patients) obtained in the above Reference Example, early pancreatic cancer patients (44 patients), and, for miRNA expression levels to serum of healthy body (184 persons), global It was normalized by normalization. To acquire a more reliable diagnostic markers, early pancreatic cancer or pancreatic cancer precursor lesions group in the selection of genetic markers, or, in any of the healthy body group, 2 of 6 or higher order in the sample 50% or more only the selected genes with the amount of gene expression. To further achieve statistical significance for determining early pancreatic cancer or pancreatic cancer precursor lesions the patient group and the healthy body group, obtained by two-tailed t-test assuming equal variances for each gene expression level P values ​​were Bonferroni correction, described in the selected table 8 as genetic markers using gene that satisfies p <0.01 in discriminant explanatory variables. Thus, in addition to the genes described in Table 2, hsa-miR-6794-5p, hsa-miR-6511a-5p, hsa-miR-6824-5p, hsa-miR-762, hsa-miR-6836- 3p, hsa-miR-6727-5p, hsa-miR-4739, hsa-miR-7977, hsa-miR-4484, hsa-miR-6515-3p, hsa-miR-373-5p, hsa-miR-4258, hsa-miR-4674, hsa-miR-3180, hsa-miR-6076, hsa-miR-1238-5p, hsa-miR-4463, hsa-miR-4486 and,, hsa-miR-4730 gene, associated therewith It found the nucleotide sequence of SEQ ID NO: 227 to 245 to be. Like the base sequence of SEQ ID NO: 1 to 226, even in the polynucleotide shown in SEQ ID NO: 227-245, measurement of early pancreatic cancer or pancreatic cancer precursor lesions patient group was significantly lower with respect to healthy body group ( decrease) or high (increased) results (Table 8) is obtained, these results could be verified in the verification sample group. Therefore, by using the measurement of gene expression levels as described in Table 8 alone or in combination, the specimens obtained are new in the method described in Example 1 and 2
[0789]
[Table 8]

[0790]
[Example 4]

　In the present embodiment, described in Reference Example 2 targeting the learning sample group of the sample group, in the same manner as described in example 1, a pancreatic cancer precursor lesions patients and early pancreatic cancer patients as positive control group, also, healthy body group, progression pancreatic cancer patients, biliary tract cancer patients, breast patients, prostate cancer patients, colon cancer patients, gastric cancer patients, esophageal cancer patients, liver cancer patient group, and the patient pancreatic benign disease group, as a negative control group prostate benign disease patients, to compare the gene expression levels of miRNA in serum, were selected additional diagnostic genetic markers. As a result is selected, the additional specific discrimination performance for diagnostic genetic marker (SEQ ID NO: 246-247) and early pancreatic cancer or pancreatic cancer precursor lesions in combination with a selected gene markers in Example 1 and consider how to evaluate.
[0791]
　Specifically, normalized by global normalization is first combined miRNA expression level of the validation sample group learning sample group obtained in the above Reference Example 2. Next, of the polynucleotide consisting of the nucleotide sequence represented by SEQ ID NO: 1 to 250, from the novel SEQ ID NO: 1 to which the found in 83,227 ~ 229,246,248, and the base sequence represented by 250 polynucleotides, either perform discriminant analysis Fisher for at least one containing 1 to 5 combined expression level measurements, discriminant to determine the presence or absence of early pancreatic cancer or pancreatic cancer precursor lesions comprising It was constructed. Next, pancreatic cancer precursor lesions patients and early pancreatic cancer patients as positive control group, also, healthy body group, advanced pancreatic cancer patients, biliary tract cancer patients, breast patients, prostate cancer patients group, colon cancer patients, gastric cancer patients, esophageal cancer patients, liver cancer patients, pancreatic benign disease patients, and, prostate benign disease patients as a negative sample group, a discriminant prepared above used to calculate the accuracy and sensitivity and specificity in the verification sample group was verified by independent sample discrimination performance of the selected polynucleotides.
[0792]
　(Corresponding to a miRNA markers in Table 1, SEQ ID NO: 1-250) above of SEQ ID NO presence Many polynucleotide consisting represented by the nucleotide sequence or a complementary sequence of early pancreatic cancer or pancreatic cancer precursor lesions higher accuracy in the determination of the presence or absence of sensitivity, on top that can provide specificity was specific identifiable early pancreatic cancer or pancreatic cancer precursor lesions from other cancers and benign diseases . As a target marker and capable of specifically binding a polynucleotide, e.g., SEQ ID NO: 119,12,28,105,137,121,109,87,5,140,106,2,175,90,237,247,103 , 97,124,92,100,32,1,246,84,13,85,153,111,86,141,54, and, a polynucleotide consisting of the nucleotide sequence or a complementary sequence represented by 24 among the combinations of a plurality of polynucleotides selected from the group (cancers specific polynucleotide group 1) comprising, included in the cancer type-specific polynucleotide group 1, preferably SEQ ID NO: 119,12,28, 105,137,121,109,87,5,140,106,2,175,90,237, and the base sequence represented by 247 In combination properly, including at least one polynucleotide selected from the group consisting of a polynucleotide consisting of a complementary sequence (cancer type-specific polynucleotide group 2), with high accuracy, early pancreatic cancer or pancreatic cancer the precursor lesion was specific distinguishable from other cancers and benign diseases.
[0793]
　The number of combinations of a polynucleotide of cancer-species specificity of the, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more possible combination of the number of polynucleotides, but were able to show determination accuracy greater than 92% or 95% or more in 4 or more combinations.
[0794]
　Note probe used for the measurement is the definition of nucleic acids capable of specifically binding with the polynucleotide as a target marker.
[0795]
　Specifically, it shows the determination results when the nucleotide sequence or a polynucleotide consisting of a complementary sequence thereof is represented by SEQ ID NO: 12 were determined using as target markers in Table 9-1. When measured using a polynucleotide one consisting of the nucleotide sequence or a complementary sequence represented by SEQ ID NO: 12 82.6% accurate in the learning sample group showed 82% accuracy in validation sample group. Accuracy also, for example, when measured using the two combination comprising a polynucleotide one consisting of the nucleotide sequence or a complementary sequence represented by SEQ ID NO: 12, 87% accuracy in the learning sample group, in the verification sample group It showed 88%. Further, for example, when measured using three combination comprising a polynucleotide one consisting of the nucleotide sequence or a complementary sequence represented by SEQ ID NO: 12 91.4% accurate in the learning sample group, the verification sample group It showed 86.6% accurate in. Further, for example, when measured using the four combinations comprising a polynucleotide one consisting of the nucleotide sequence or a complementary sequence represented by SEQ ID NO: 12 95.6% accurate in the learning sample group, the verification sample group It showed 95.1% accurate in. Further, for example, when measured using a five combination comprising a polynucleotide one consisting of the nucleotide sequence or a complementary sequence represented by SEQ ID NO: 12, up to accuracy 98.8% in the learning sample group, the verification It showed 98.9% accurate at best in the sample group.
[0796]
　Furthermore, specifically showing the determination results when a polynucleotide consisting of the nucleotide sequence or its complementary sequence in SEQ ID NO: 28 were determined using as target markers in Table 9-2. When measured using a polynucleotide one consisting of the nucleotide sequence or a complementary sequence represented by SEQ ID NO: 28 81.6% accurate in the learning sample group showed 81.7% accuracy in the verification sample group. Further, for example, when measured using two combinations comprising one polynucleotide consisting of the nucleotide sequence or a complementary sequence represented by SEQ ID NO: 28 84.9% accurate in the learning sample group, the verification sample group It showed 85.6% accuracy in. Further, for example, when measured using three combinations comprising one polynucleotide consisting of the nucleotide sequence or a complementary sequence represented by SEQ ID NO: 28 88.8% accurate in the learning sample group, the verification sample group It showed 86.3% accurate in. Further, for example, when measured using the four combinations comprising one polynucleotide consisting of the nucleotide sequence or a complementary sequence represented by SEQ ID NO: 28 92.4% accurate in the learning sample group, the verification sample group It showed 93.6% accurate in. Further, for example, when measured using a five combinations comprising one polynucleotide consisting of the nucleotide sequence or a complementary sequence represented by SEQ ID NO: 28, up to accuracy 97.7% in the learning sample group, the verification It showed 98.6% accuracy at the highest in the sample group.
[0797]
　Furthermore, specifically showing the determination results when a polynucleotide consisting of the nucleotide sequence or its complementary sequence in SEQ ID NO: 5 were determined using as target markers in Table 9-3. When measured using a polynucleotide one consisting of the nucleotide sequence or a complementary sequence represented by SEQ ID NO: 5, accuracy 84% in the learning sample group showed 87% accuracy in validation sample group. Further, for example, when measured using the two combination comprising a polynucleotide one consisting of the nucleotide sequence or a complementary sequence represented by SEQ ID NO: 5 87.9% accurate in the learning sample group, the verification sample group It showed 88.4% accurate in. Further, for example, when measured using three combination comprising a polynucleotide one consisting of the nucleotide sequence or a complementary sequence represented by SEQ ID NO: 5 90.4% accurate in the learning sample group, the verification sample group It showed 90.5% accurate in. Further, for example, when measured using the four combinations comprising a polynucleotide one consisting of the nucleotide sequence or a complementary sequence represented by SEQ ID NO: 5, 93.2% accuracy in the learning sample group, the verification sample group It showed 93.7% accurate in. Further, for example, when measured using a five combination comprising a polynucleotide one consisting of the nucleotide sequence or a complementary sequence represented by SEQ ID NO: 5, the highest accuracy 97.7% in the learning sample group, the verification It showed 98.2% accuracy at the highest in the sample group.
[0798]
　Furthermore, specifically showing the determination results when a polynucleotide consisting of the nucleotide sequence or its complementary sequence in SEQ ID NO: 2 were determined using as target markers in Table 9-4. When measured using one polynucleotide consisting of the nucleotide sequence or a complementary sequence represented by SEQ ID NO: 2, 86.8% accuracy in the learning sample group showed 90.5% accurate in the verification sample group. Further, for example, when measured using two combinations comprising one polynucleotide consisting of the nucleotide sequence or a complementary sequence represented by SEQ ID NO: 2 88.4% accurate in the learning sample group, the verification sample group It showed 90.1% accurate in. Further, for example, when measured using three combinations comprising one polynucleotide consisting of the nucleotide sequence or a complementary sequence represented by SEQ ID NO: 2 90.9% accurate in the learning sample group, the verification sample group It showed 92.6% accuracy in. Accuracy also, for example, when measured using the four combinations comprising polynucleotide one of consisting of the nucleotide sequence or a complementary sequence represented by SEQ ID NO: 2, 93% accuracy in the learning sample group, in the verification sample group It showed a 92.6%. Further, for example, when measured using a five combinations comprising one polynucleotide consisting of the nucleotide sequence or a complementary sequence represented by SEQ ID NO: 2, up to accuracy 97.7% in the learning sample group, the verification It showed 98.2% accuracy at the highest in the sample group.
[0799]
　Furthermore, specifically showing the determination results when a polynucleotide consisting of the nucleotide sequence or its complementary sequence in SEQ ID NO: 12 and 28 were measured using as target markers in Table 9-5. When measured using the two combination comprising a nucleotide sequence or a polynucleotide consisting of a complementary sequence thereof is represented by SEQ ID NO: 12 and 28, accuracy 90% in the learning sample group, the precision in the verification sample group 92.6% showed that. Further, for example, when measured using three combination comprising a nucleotide sequence or a polynucleotide consisting of a complementary sequence thereof is represented by SEQ ID NO: 12 and 28, 92.3% accuracy in the learning sample group, the verification sample group It showed 93.3% accurate in. Further, for example, when measured using the four combinations containing a nucleotide sequence or a polynucleotide consisting of a complementary sequence thereof is represented by SEQ ID NO: 12 and 28, 93.9% accuracy in the learning sample group, the verification sample group It showed 93.7% accurate in. Further, for example, when measured using a five combination comprising a nucleotide sequence or a polynucleotide consisting of a complementary sequence thereof is represented by SEQ ID NO: 12 and 28, the highest accuracy 97.9% in the learning sample group, the verification It showed 97.9% accurate at best in the sample group.
[0800]
　Furthermore, specifically showing the determination results when a polynucleotide consisting of the nucleotide sequence or its complementary sequence in SEQ ID NO: 12 and 5 were measured using as target markers in Table 9-6. When measured using the two combination comprising a nucleotide sequence or a polynucleotide consisting of a complementary sequence thereof is represented by SEQ ID NO: 12 and 5 91.2% accurate in the learning sample group, accuracy 89 in the verification sample group. It showed a 4%. Accuracy also, for example, when measured using three combination comprising a nucleotide sequence or a polynucleotide consisting of a complementary sequence thereof is represented by SEQ ID NO: 12 and 5, 93% accuracy in the learning sample group, in the verification sample group It showed a 92.6%. Further, for example, when measured using the four combinations containing a nucleotide sequence or a polynucleotide consisting of a complementary sequence thereof is represented by SEQ ID NO: 12 and 5 95.1% accurate in the learning sample group, the verification sample group It showed 93% accuracy in. Further, for example, when measured using a five combination comprising a nucleotide sequence or a polynucleotide consisting of a complementary sequence thereof is represented by SEQ ID NO: 12 and 5, the highest accuracy 98.1% in the learning sample group, the verification It showed 97.9% accurate at best in the sample group.
[0801]
　Furthermore, specifically showing the determination results when a polynucleotide consisting of the nucleotide sequence or its complementary sequence in SEQ ID NO: 12 and 2 were measured using as target markers in Table 9-7. When measured using the two combination comprising a nucleotide sequence or a polynucleotide consisting of a complementary sequence thereof is represented by SEQ ID NO: 12 and 2 91.2% accurate in the learning sample group, accuracy 90 in the verification sample group. It showed a 1%. Further, for example, when measured using three combination comprising a nucleotide sequence or a polynucleotide consisting of a complementary sequence thereof is represented by SEQ ID NO: 12 and 2, 93.9% accuracy in the learning sample group, the verification sample group It showed 92.6% accuracy in. Further, for example, when measured using the four combinations containing a nucleotide sequence or a polynucleotide consisting of a complementary sequence thereof is represented by SEQ ID NO: 12 and 2 94.6% accurate in the learning sample group, the verification sample group It showed 93.3% accurate in. Further, for example, when measured using a five combination comprising a nucleotide sequence or a polynucleotide consisting of a complementary sequence thereof is represented by SEQ ID NO: 12 and 2, the highest accuracy 98.1% in the learning sample group, the verification It showed 97.9% accurate at best in the sample group.
[0802]
　Furthermore, specifically showing the determination results when a polynucleotide consisting of the nucleotide sequence or its complementary sequence in SEQ ID NO: 5 and 2 were measured using as target markers in Table 9-8. When measured using the two combination comprising a nucleotide sequence or a polynucleotide consisting of a complementary sequence thereof is represented by SEQ ID NO: 5 and 2, 89.8% accuracy in the learning sample group, accuracy 92 in the verification sample group. It showed a 3%. Further, for example, when measured using three combination comprising a nucleotide sequence or a polynucleotide consisting of a complementary sequence thereof is represented by SEQ ID NO: 5 and 2 92.1% accurate in the learning sample group, the verification sample group It showed 94% accuracy in. Further, for example, when measured using the four combinations containing a nucleotide sequence or a polynucleotide consisting of a complementary sequence thereof is represented by SEQ ID NO: 5 and 2, 93.9% accuracy in the learning sample group, the verification sample group It showed 95.1% accurate in. Further, for example, when measured using a five combination comprising a nucleotide sequence or a polynucleotide consisting of a complementary sequence thereof is represented by SEQ ID NO: 5 and 2, the highest accuracy 97.2% in the learning sample group, the verification It showed 97.9% accurate at best in the sample group.
[0803]
　Furthermore, specifically, shows SEQ ID NO: 12, 28, and the determination results when a polynucleotide consisting of the nucleotide sequence or a complementary sequence represented by 5 was measured using as target markers in Table 9-9 . SEQ ID NO: 12, 28, and, when measured using three combination comprising a polynucleotide consisting of the nucleotide sequence or a complementary sequence represented by 5 93.3% accurate in the learning sample group, the verification sample group It showed 94.4% accurate in. Further, for example, SEQ ID NO: 12, 28, and, when measured using four combination comprising a polynucleotide consisting of the nucleotide sequence or a complementary sequence represented by 5 94.6% accurate in the learning sample group showed 96.5% accuracy in the verification sample group. Further, for example, SEQ ID NO: 12, 28, and, when measured using a five combination comprising a polynucleotide consisting of the nucleotide sequence or a complementary sequence represented by 5, accuracy 97.5% in the training sample group showed 96.8% accurate in the verification sample group.
[0804]
　Furthermore, SEQ ID NO: 106,12,137,119, and, by using the expression amount measurement value of the base sequence represented by 105, pancreatic cancer precursor lesions patient 21 people learning sample group, 31 early-pancreatic cancer patients healthy 128 people, advanced pancreatic cancer patients 61 people, biliary tract cancer patients 66 people, breast cancer patients 51, 35 people prostate cancer patients, 31 who colon cancer patients, 32 people gastric cancer patients, esophageal cancer patients 34 human liver cancer patients 38 people, 15 patients pancreatic benign disease, and, when compared with 26 people prostatic benign disease patients, early pancreatic cancer or pancreatic cancer precursor lesions patient group and the other groups in the learning sample group discriminant score significantly scatter plot of separating is obtained (see FIG. 4 above), further results were also reproducible in the validation sample group (see Figure 4 below).
[0805]
[Table 9-1]

[0806]

[0807]
[Table 9-2]

[0808]
[Table 9-3]

[0809]
[Table 9-4]

[0810]
[Table 9-5]

[0811]
[Table 9-6]

[0812]
[Table 9-7]

[0813]
[Table 9-8]

[0814]
[Table 9-9]

[0815]
Example 5

　In Example 2, genetic markers were selected in Example 1 the combined plurality showed that discrimination performance is improved than the case of using the single genetic marker. Therefore, either in this embodiment, high performance to determine early pancreatic cancer or pancreatic cancer precursor lesions by combining a selected gene marker gene markers was not selected in Example 1 in the first embodiment can be obtained investigated.
[0816]
　Specifically, in any of the healthy body group early pancreatic cancer and pancreatic cancer patient group or learning sample group learning sample group, the gene having the sixth power or more gene expression levels of 2 in sample 50% or more among them, a gene with statistical significance for determining early pancreatic cancer or pancreatic cancer precursor lesions the patient group and the healthy body group, obtained by two-tailed t-test assuming equal variances for each of the gene expression level the P-values ​​were Bonferroni correction was examined genes that satisfies p <0.05, found 248 genes including 226 pieces that are selected in example 1. Performed discriminant analysis Fisher 30,876 ways with one or two above 248 genes, to construct a discriminant to determine the presence or absence of early pancreatic cancer or pancreatic cancer precursor lesions, is selected It was verified by one or two combinations of genes discrimination performance example 2 and similar methods.
[0817]
　As a result, shown in Table 10 parts of a combination of genes that showed more than 85% accurate in both learning sample group and the verification sample group. For example, a polynucleotide consisting of the nucleotide sequence represented by SEQ ID NO: 248-250 found a new at least two combinations comprising any of the polynucleotides comprising the nucleotide sequence represented by SEQ ID NO: 1-226 It is determined early pancreatic cancer or pancreatic cancer precursor lesions and healthy body with that at high discrimination performance to be used as. More specifically, the polynucleotide comprising the nucleotide sequence represented by SEQ ID NO: 248-250, SEQ ID NO: 2,3,18,12,20,1,15,50,63,72,5,24,10 , by using as at least two combined containing either a polynucleotide comprising the nucleotide sequence represented by 52,9,11,19,39,61,7,17,22,26,74,21,28 , it was able to both learning sample group and the verification sample group showing the determination accuracy of 85% or more of early pancreatic cancer or pancreatic cancer precursor lesions and healthy body. Examples of such combinations of two genes, SEQ ID NO: 2 and 248, SEQ ID NO: 3 and 249, SEQ ID NO: 2 and 250, SEQ ID NO: 1 and 249, SEQ ID NO: 5 and 250, SEQ ID NO: 3 and 248, SEQ No. 3 250, SEQ ID NO: 1 and 250, SEQ ID NO: 2 and 249, SEQ ID NO: 21 and 248, SEQ ID NO: 10 and 248, SEQ ID NO: 5 and 248, SEQ ID NO: 11 and 249, SEQ ID NO: 9 and 250, SEQ ID NO: 17 When 250, SEQ ID NO: 21 and 249, SEQ ID NO: 7 and 250, SEQ ID NO: 15 and 248, SEQ ID NO: 5 and 249, SEQ ID NO: 12 and 248, SEQ ID NO: 10 and 249, SEQ ID NO: 28 and 250, SEQ ID NO: 7 and 249 , SEQ ID NO: 18 and 249, SEQ ID NO: 15 and 249, SEQ ID NO: 20 and 249, SEQ ID NO: 24 and 249, SEQ ID NO: 11 and 250, SEQ ID NO: 18 and 248, Awa set of And the like.
[0818]
　In one example, it was tried healthy body and early pancreatic cancer or pancreatic cancer precursor determination of lesion patient using the expression level measurements of the base sequence represented by SEQ ID NO: 2 and SEQ ID NO: 248, the learning sample group accuracy 93.2%, sensitivity 96.2%, specificity 91.9% 95.4% accurate validation sample group, sensitivity 100%, specificity 93.4%, a high discrimination performance such is obtained.
[0819]
　All polynucleotides comprising the nucleotide sequence represented these results with SEQ ID NO: 248-250 are also said to be good diagnostic marker.
[0820]
　Incidentally, Table 10 above are as follows.
[0821]
[Table 10]

[0822]
[Comparative Example 1]

　for the above and validation sample group learning sample group obtained in Reference Example, existing tumor markers CEA and CA19-9 the blood concentration was measured. These tumor markers, in principle, the reference value described in Non-Patent Document 3 (CEA is 5 ng / mL, CA19-9 is 37U / mL) is that there is a high cancer suspect blood levels than . Therefore, blood concentration of CEA and CA19-9 for each specimen to verify whether exceeds the reference value, early pancreatic cancer or pancreatic cancer precursor lesions patients early pancreatic cancer or pancreatic cancer precursor lesions Misadame whether the determination as patients, to calculate the sensitivity of each existing marker in the learning sample group and the verification sample group. The results are shown in Table 5-1 and Table 5-2. The sensitivity of CEA in the learning sample group is 18%, the sensitivity of CA19-9 is 58%, 20% sensitivity of CEA in the verification sample group, there is only sensitivity 68% of CA19-9, any markers early pancreatic It was found to be not useful for detection of cancer or pancreatic cancer precursor lesions (Table 5-1 and Table 5-2). Further, in the learning sample group and the verification sample group, CEA and CA19-9 were not able to detect low IPMA low grade malignant, which is a type of pancreatic cancer precursor lesions at all (Table 5-1 and Table 5-2) .
[0823]
　On the other hand, as shown in Table 3 and Table 6 of Example 1 and Example 2 above, all of a polynucleotide comprising the nucleotide sequence represented by SEQ ID NOs: 226, existing early pancreatic cancer or pancreatic 1 showing a more sensitive cancer precursor lesions markers, two or more of a plurality of combinations exist, it can be said to be an excellent diagnostic marker.
[0824]
[Comparative Example 2]

　For the validation sample group learning sample group obtained in the above Reference Example, pancreatic cancer patients the are described as being specifically identifiable from other cancer patients groups in Patent Document 2 hsa-miR-6075, hsa -miR-4294, hsa-miR-6836-3p, hsa-miR-4530, and, in the hsa-miR-6880-5p, hsa- miR-4294 ( SEQ ID NO: 125) included in the present invention, hsa-miR-6836-3p (SEQ ID NO: 231), and, hsa-miR-6880- the combination of one or more miRNA selected from 5p (SEQ ID NO: 219), were evaluated discrimination performance for early pancreatic cancer or pancreatic cancer precursor lesions. For example, SEQ ID NO: 219,125, and the nucleotide sequence or a combination of the polynucleotide consisting of the complementary sequence represented by 231, showed an excellent accuracy of precision 93% in both the learning sample group and validation sample group but 50% sensitivity learning sample group is, specificity 94.7% sensitivity 72.7% of the validation sample group, adjacent specificity of 93.8%, a difference in sensitivity between the verification sample group learning sample group tends to occur is observed (Table 11).
[0825]
[Table 11]

[0826]
　On the other hand, as shown in Table 9-1 through 9-9 in Example 4, SEQ ID NO: 119,12,28,105,137,121,109,87,5,140,106,2,175,90, 237, and at least one polynucleotide selected from the group consisting of a polynucleotide consisting of the nucleotide sequence, or its complementary sequence represented by 247, for example, when measured using a combination of three polynucleotide, 100% in the learning sample group sensitivity at maximum 88.7% in the lowest, specificity 93.2% up at 88.8% in the lowest, 100% in the verification sample group sensitivity is the highest, the lowest 84. 6%, a specificity of 94.2% up, the next 85.3% lowest showed comparable high sensitivity and specificity in the validation sample group learning sample group. Thus, SEQ ID NO: 119,12,28,105,137,121,109,87,5,140,106,2,175,90,237, and the base sequence or its complementary sequence represented by 247 two or more comprising at least one polynucleotide selected from the group consisting of a polynucleotide consisting of, preferably three or more, the combination of more preferably 4 or more, or five or more polynucleotides existing pancreatic cancer shows high discrimination performance in excess of the combination of blood miRNA markers can be said to be excellent diagnostic marker.
[0827]
[Comparative Example 3]

　statistically significant expression between healthy body group and IPMN patient group in Patent Document 5 among the top 30 one miRNA there was amount difference, Fold Change of gene expression of pancreatic cancer precursor lesions patients and healthy body group gene expression levels is 3.0 or more hsa-miR-145-5p (SEQ ID NO: 813), hsa-let-7f -5p ( SEQ ID NO: 814), hsa-miR-146a -5p ( SEQ ID NO: 815), hsa-let-7d -5p ( SEQ ID NO: 816), hsa-let-7a select -5p (SEQ ID NO: 817), the learning sample and validation sample group group obtained in the above reference example was evaluated discrimination performance for early pancreatic cancer or pancreatic cancer precursor lesions. Combination of the nucleotide sequence or a polynucleotide consisting of a complementary sequence thereof is represented by SEQ ID NO: 813 to 817, the sensitivity 63.6% in the learning sample group, specificity 74.5%, sensitivity 54.5% in the verification sample group It became specificity 74.7% (Table 12).
[0828]
[Table 12]

[0829]
　On the other hand, as shown in Table 9-1 to 9-9 of Examples 4, SEQ ID NO: 119,12,28,105,137,121,109,87,5,140,106,2,175, 90,237, and at least one polynucleotide selected from the group consisting of a polynucleotide consisting of the nucleotide sequence, or its complementary sequence represented by 247, for example, was determined using a combination of five of the polynucleotide If 100% in the learning sample group sensitivity at maximum 94.3% in the lowest, specificity 98.6% at the highest 96.9% in the minimum sensitivity at the verification sample group is 100% at the highest, the lowest 92.3%, a specificity of 100% at the highest, showed 92.3% in minimum. Thus, SEQ ID NO: 119,12,28,105,137,121,109,87,5,140,106,2,175,90,237, and the base sequence or its complementary sequence represented by 247 two or more comprising at least one polynucleotide selected from the group consisting of a polynucleotide consisting of, preferably three or more, the combination of more preferably 4 or more, or five or more polynucleotides existing pancreatic cancer and shows high discrimination performance in excess of the combination of blood miRNA marker of pancreatic cancer precursor lesions, it can be said to be excellent diagnostic marker.
[0830]
　Above embodiments, as shown in Comparative Examples, according to the kit and method of the present invention, since the early pancreatic cancer or pancreatic cancer precursor lesions can sensitively and specifically detect than existing tumor markers, early treatment, as well as early determination of resection embodiment the cancer part surgical becomes possible, as a result, improvement of the 5-year survival rate, it is possible to lower the recurrence rate.
Industrial Applicability
[0831]
　The present invention, as compared with the conventional method, significantly higher sensitivity for early pancreatic cancer or pancreatic cancer precursor lesions in a subject, it is possible to detect with specificity and accuracy, early pancreatic cancer or pancreatic cancer precursor early detection of lesions, it is possible to diagnosis and treatment. Further, the present invention allows detection of early pancreatic cancer or pancreatic cancer precursor lesions minimally invasively using a subject's blood, early pancreatic cancer or pancreatic cancer precursor lesions simple, quickly and inexpensively determine it becomes possible to.
[0832]
　All publications cited herein shall be incorporated herein patents and patent applications as reference.
The scope of the claims
[Requested item 1]
　An early pancreatic cancer or pancreatic cancer precursor lesions marker, miR-6784-5p, miR-1181, miR-671-5p, miR-6857-5p, miR-4276, miR-1914-3p, miR-149- 3p, miR-937-5p, miR-4675, miR-6795-5p, miR-4731-5p, miR-5090, miR-3620-5p, miR-1343-5p, miR-6717-5p, miR-6825- 5p, miR-6738-5p, miR-6769a-5p, miR-4728-5p, miR-652-5p, miR-4257, miR-6785-5p, miR-7110-5p, miR-6887-5p, miR- 887-3p, miR-1228-5p, miR-5572, miR-6782- p, miR-4298, miR-6786-5p, miR-5010-5p, miR-6087, miR-6765-5p, miR-6732-5p, miR-6787-5p, miR-6737-5p, miR-128- 2-5p, miR-4270, miR-6861-5p, miR-6756-5p, miR-1229-5p, miR-6891-5p, miR-6848-5p, miR-1237-5p, miR-30c-1- 3p, miR-1233-5p, miR-211-3p, miR-4758-5p, miR-614, miR-6746-5p, miR-1915-5p, miR-4688, miR-3917, miR-5787, miR- 4632-5p, miR-6126, miR-135a-3p, miR-80 3, miR-5698, miR-6089, miR-498, miR-296-3p, miR-4419b, miR-6802-5p, miR-6829-5p, miR-6803-5p, miR-1199-5p, miR- 6840-3p, miR-6752-5p, miR-6798-5p, miR-6131, miR-4667-5p, miR-6510-5p, miR-4690-5p, miR-920, miR-23
[Requested item 2]
　miR-6784-5p is hsa-miR-6784-5p, miR-1181 is hsa-miR-1181, miR-671-5p is hsa-miR-671-5p, is miR-6857-5p is hsa-miR-6857-5p, miR-4276 is hsa-miR-4276, miR-1914-3p is hsa-miR-1914-3p, miR-149-3p is hsa-miR-149- is a 3p, miR-937-5p is hsa-miR-937-5p, miR-4675 is hsa-miR-4675, miR-6795-5p is hsa-miR-6795-5p, miR- 4731-5p is hsa-miR-4731-5p, miR-5090 is hsa-miR Is 5090, miR-3620-5p is hsa-miR-3620-5p, miR-1343-5p is hsa-miR-1343-5p, miR-6717-5p is in hsa-miR-6717-5p Yes, miR-6825-5p is hsa-miR-6825-5p, miR-6738-5p is hsa-miR-6738-5p, miR-6769a-5p is hsa-miR-6769a-5p, miR-4728-5p is hsa-miR-4728-5p, miR-652-5p is hsa-miR-652-5p, miR-4257 is hsa-miR-4257, is miR-6785-5p is hsa-miR-6785-5p, miR-7110-5p is hsa-miR- Is a 110-5p, miR-6887-5p is hsa-miR-6887-5p, miR-887-3p is hsa-miR-887-3p, miR-1228-5p is hsa-miR-1228- is 5p, miR-5572 is hsa-miR-5572, miR-6782-5p is hsa-miR-6782-5p, miR-4298 is hsa-miR-4298, miR-6786-5 p is hsa-miR-6786-5p, miR-5010-5p is hsa-miR-5010-5p, miR-6087 is hsa-miR-6087, miR-6765-5p is hsa-miR- is a 6765-5p, miR-6732-5p is hsa-miR-6732-5p, miR-6787-5p is hsa-miR-6787-5p, miR-6737-5p is hsa-miR-6737- is 5p, miR-128-2-5p is hsa-miR-128-2-5p, miR-4270 is hsa-miR-4270, miR-6861-5p is in hsa-miR-6861-5p Yes, miR-6756-5p is hsa-miR-6756-5p, is miR-1229-5p Is a sa-miR-1229-5p, miR-6891-5p is hsa-miR-6891-5p, miR-6848-5p is hsa-miR-6848-5p, is miR-1237-5p hsa- is a miR-1237-5p, miR-30c-1-3p is hsa-miR-30c-1-3p, miR-1233-5p is hsa-miR-1233-5p, is miR-211-3p a hsa-miR-211-3p, miR-4758-5p is hsa-miR-4758-5p, miR-614 is hsa-miR-614, miR-6746-5p is hsa-miR-6746- is 5p, miR-1915-5p is hsa-miR-1915-5p, miR-4688 is hsa Is a miR-4688, miR-3917 is hsa-miR-3917, miR-5787 is hsa-miR-5787, miR-4632-5p is hsa-miR-4632-5p, is miR-6126 a hsa-miR-6126, miR-135a-3p is hsa-miR-135a-3p, miR-8063 is hsa-miR-8063, miR-5698 is hsa-miR-56 Is 98, miR-6089 is hsa-miR-6089, miR-498 is hsa-miR-498, miR-296-3p is hsa-miR-296-3p, is miR-4419b hsa- is a miR-4419b, miR-6802-5p is hsa-miR-6802-5p, miR-6829-5p is hsa-miR-6829-5p, miR-6803-5p is hsa-miR-6803- is 5p, miR-1199-5p is hsa-miR-1199-5p, miR-6840-3p is hsa-miR-6840-3p, miR-6752-5p is in hsa-miR-6752-5p Yes, miR-6798-5p is hsa-miR-6798-5p, miR-61 1 is hsa-miR-6131, miR-4667-5p is hsa-miR-4667-5p, miR-6510-5p is hsa-miR-6510-5p, the miR-4690-5p hsa- is a miR-4690-5p, miR-920 is hsa-miR-920, miR-23b-3p is hsa-miR-23b-3p, miR-4448 is hsa-miR-4448, miR- 2110 is hsa-miR-2110, miR-4706 is hsa-miR-4706, miR-7845-5p is hsa-miR-7845-5p, miR-6808-5p is hsa-miR-6808- is 5p, miR-4447 is hsa-miR-4447, miR-686 -5p is hsa-miR-6869-5p, miR-6794-5p is hsa-miR-6794-5p, miR-6511a-5p is hsa-miR-6511a-5p, miR-6824-5p There is a hsa-miR-6824-5p, miR-6766-3p is hsa-miR-6766-3p, miR-6511a-5p is hsa-miR-6511a-5p, miR-6749-5p
[Requested item 3]
　Said nucleic acid, a polynucleotide shown in any one of the following (a) -
(e): (a) SEQ ID NO: 1 ~ 83,227 ~ 229,246,248, and nucleotide sequence or represented by any one of the 250 the base polynucleotide consisting of the nucleotide sequence u is t in the sequence, a variant thereof, a fragment comprising the derivative, or 15 or more continuous
nucleotides, (b) SEQ ID NO: 1 ~ 83,227 ~ 229,246, 248, and a polynucleotide comprising the nucleotide sequence shown in any of the
250, the base sequence or the base sequence represented by any one of (c) SEQ ID NO: 1 ~ 83,227 ~ 229,246,248, and 250 As u comprises a polynucleotide comprising a nucleotide sequence complementary to the nucleotide sequence which is t, a variant thereof, a derivative thereof, or 15 or more contiguous bases in Pieces,
including a nucleotide sequence complementary to the nucleotide sequence u is t in the nucleotide sequence or the nucleotide sequence represented by any one of (d) SEQ ID NO: 1 ~ 83,227 ~ 229,246,248, and 250 polynucleotides, and
(e) wherein (a) ~ any polynucleotide and a polynucleotide hybridizing under stringent conditions (d),
a polynucleotide selected from the group consisting of, claim 1 or 2 the kit according to.
[Requested item 4]
　The kit is another early pancreatic cancer or pancreatic cancer precursor lesions marker, miR-1908-5p, miR-6729-5p, miR-5195-3p, miR-638, miR-6125, miR-3178, miR-3196, miR-8069, miR-4723-5p, miR-4746-3p, miR-4689, miR-6816-5p, miR-6757-5p, miR-7109-5p, miR-6724-5p, miR- 1225-3p, miR-6875-5p, miR-7108-5p, miR-4508, miR-6085, miR-6779-5p, miR-642a-3p, miR-4695-5p, miR-7847-3p, miR- 3197, miR-6769b-5p, miR-7641, miR-187- p, miR-3185, miR-2861, miR-3940-5p, miR-1203, miR-615-5p, miR-4787-5p, miR-1343-3p, miR-6813-5p, miR-1225-5p, miR-602, miR-4488, miR-125a-3p, miR-5100, miR-4294, miR-1231, miR-6765-3p, miR-4442, miR-718, miR-6780b-5p, miR-6090, miR-6845-5p, miR-4741, miR-4467, miR-4707-5p, miR-4271, miR-4673, miR-3184-5p, miR-1469, miR-4640-5p, miR-663a, miR- 6791-5p, miR-6826-5p miR-4433b-3p, miR-1915-3p, miR-4417, miR-4449, miR-4707-3p, miR-3180-3p, miR-5585-3p, miR-1268a, miR-8072, miR-296- 5p, miR-204-3p, miR-4454, miR-6722-3p, miR-1290, miR-3622a-5p, miR-939-5p, miR-675-5p, miR-313 1, miR-4648, miR-1268b, miR-6741-5p, miR-6893-5p, miR-3162-5p, miR-642b-3p, miR-4734, miR-150-3p, miR-8089, miR 6805-3p, miR-7113-3p, miR-6850-5p, miR-6799-5p, miR-6768-5p, miR-92b-5p, miR-3679-5p, miR-4792, miR-3656, miR 92a-2-5p, miR-4466, miR-4513, miR-6781-5p, miR-4649-5p, miR-6775-5p, miR-4651, miR-3195, miR-6726-5p, miR-6872- 3p, miR-371a-5p, miR-6777-5p, m R-6789-5p, miR-7975, miR-6821-5p, miR-4534, miR-619-5p, miR-7107-5p, miR-1228-3p, miR-6774-5p, miR-6805-5p, miR-23a-3p, miR-4665-5p, miR-4505, miR-4638-5p, miR-24-3p, miR-3135b, miR-4745-5p, miR-128-1-5p, miR-4476, miR-4687-3p, miR-3665, miR-6806-5p, miR-3937, miR-711, miR-3141, miR-3188, miR-4281, miR-5196-5p, miR-6880-5p, miR 3960, miR-3648, miR-6721-5p, miR 492, miR-744-5p, miR-7704, miR-4749-5p, miR-762, miR-6836-3p, miR-6727-5p, miR-4739, miR-7977, miR-4484, miR-6515- 3p, miR-373-5p, miR-4258, miR-4674, miR-3180, miR-6076, miR-1238-5p, miR-4463, miR-4486, miR-4730,
[Requested item 5]
　miR-1908-5p is hsa-miR-1908-5p, miR-6729-5p is hsa-miR-6729-5p, miR-5195-3p is hsa-miR-5195-3p, miR- 638 is hsa-miR-638, miR-6125 is hsa-miR-6125, miR-3178 is hsa-miR-3178, miR-3196 is hsa-miR-3196, is miR-8069 is hsa-miR-8069, miR-4723-5p is hsa-miR-4723-5p, miR-4746-3p is hsa-miR-4746-3p, miR-4689 is in hsa-miR-4689 Yes, miR-6816-5p is located in hsa-miR-6816-5p miR-6757-5p is hsa-miR-6757-5p, miR-7109-5p is hsa-miR-7109-5p, miR-6724-5p is hsa-miR-6724-5p, miR- 1225-3p is hsa-miR-1225-3p, miR-6875-5p is hsa-miR-6875-5p, miR-7108-5p is hsa-miR-7108-5p, is miR-4508 is hsa-miR-4508, miR-6085 is hsa-miR-6085, miR-6779-5p is hsa-miR-6779-5p, miR-642a-3p is in hsa-miR-642a-3p Yes, miR-4695-5p is hsa-miR-4695-5p, miR 7847-3p is hsa-miR-7847-3p, miR-3197 is hsa-miR-3197, miR-6769b-5p is hsa-miR-6769b-5p, miR-7641 is hsa-miR- is 7641, miR-187-5p is hsa-miR-187-5p, miR-3185 is hsa-miR-3185, miR-2861 is hsa-miR-2861, miR -3940-5p is hsa-miR-3940-5p, miR-1203 is hsa-miR-1203, miR-615-5p is hsa-miR-615-5p, miR-4787-5p is hsa is a -miR-4787-5p, miR-1343-3p is hsa-miR-1343-3p, miR-6813-5p is hsa-miR-6813-5p, miR-1225-5p is hsa-miR a -1225-5p, miR-602 is hsa-miR-602, miR-4488 is hsa-miR-4488, miR-125a-3p is hsa-miR-125a-3p, miR-5100 There is a hsa-miR-5100, miR-4294 is hsa-miR-4294 der , MiR-1231 is hsa-miR-1231, miR-6765-3p is hsa-miR-6765-3p, miR-4442 is hsa-miR-4442, miR-718 is hsa-miR-718 in it, miR-6780b-5p is hsa-miR-6780b-5p, miR-6090 is hsa-miR-6090, miR-6845-5p is hsa-miR-6845-5p, miR-4741 There is a hsa-miR-4741, miR-4467 is hsa-miR-4467, miR-4707-5p is hsa-miR-4707-5p, miR-4271 is hsa-miR-4271, miR -4673 is hsa-miR-4673, miR-318 -5p is hsa-miR-3184-5p, miR-1469 is hsa-miR-1469, miR-4640-5p is hsa-miR-4640-5p, miR-663a is hsa-miR-663a in it, miR-6791-5p is hsa-miR-6791-5p, miR-6826-5p is hsa-miR-6826-5p, miR-4433b-3p is hsa-miR-4433b- Is a 3p, miR-1915-3p is hsa-miR-1915-3p, miR-4417 is hsa-miR-4417, miR-4449 is hsa-miR-4449, is miR-4707-3p is hsa-miR-4707-3p, miR-3180-3p is hsa-miR-3180-3p, miR-5585-3p is hsa-miR-5585-3p, miR-1268a is hsa-miR- is a 1268a, miR-8072 is hsa-miR-8072, miR-296-5p is hsa-miR-296-5p, miR-204-3p is hsa-miR-204-3p, miR- 4454 is hsa-miR-4454, miR-6722-3p is hsa-mi Is a -6722-3p, miR-1290 is hsa-miR-1290, miR-3622a-5p is hsa-miR-3622a-5p, miR-939-5p is located in hsa-miR-939-5p , miR-675-5p is hsa-miR-675-5p, miR-3131 is hsa-miR-3131, miR-4648 is hsa-miR-4648, miR-1268b is hsa-miR-1268b in it, miR-6741-5p is hsa-miR-6741-5p, miR-6893-5p is hsa-miR-6893-5p, miR-3162-5p is located in hsa-miR-3162-5p , miR-642b-3p is hsa-miR-642b-3p, miR 4734 is hsa-miR-4734, miR-150-3p is hsa-miR-150-3p, miR-8089 is hsa-miR-8089, miR-6805-3p is hsa-miR-6805- is a 3p, miR-7113-3p is hsa-miR-7113-3p, miR-6850-5p is hsa-miR-6850-5p, miR-6799-5p is hsa-miR-6799- Is 5p, miR-6768-5p is hsa-miR-6768-5p, miR-92b-5p is hsa-miR-92b-5p, miR-3679-5p is in hsa-miR-3679-5p Yes, miR-4792 is hsa-miR-4792, miR-3656 is hsa-miR-3656, miR-92a-2-5p is hsa-miR-92a-2-5p, is miR-4466 is hsa-miR-4466, miR-4513 is hsa-miR-4513, miR-6781-5p is hsa-miR-6781-5p, miR-4649-5p is in hsa-miR-4649-5p Yes, miR-6775-5p is hsa-miR-6775-5p, miR-4651 is h Is a a-miR-4651, miR-3195 is hsa-miR-3195, miR-6726-5p is hsa-miR-6726-5p, miR-6872-3p is in hsa-miR-6872-3p Yes, miR-371a-5p is hsa-miR-371a-5p, miR-6777-5p is hsa-miR-6777-5p, miR-6789-5p is hsa-miR-6789-5p, miR-7975 is hsa-miR-7975, miR-6821-5p is hsa-miR-6821-5p, miR-4534 is hsa-miR-4534, miR-619-5p is hsa-miR- is a 619-5p, miR-7107-5p is in hsa-miR-7107-5p Ri, miR-1228-3p is hsa-miR-1228-3p, miR-6774-5p is hsa-miR-6774-5p, miR-6805-5p is hsa-miR-6805-5p, miR-23a-3p is hsa-miR-23a-3p, miR-4665-5p is hsa-miR-4665-5p, miR-4505 is hsa-miR-4505, is miR-4638-5p h Is a sa-miR-4638-5p, miR-24-3p is a hsa-miR-24-3p, miR-3135b is a hsa-miR-3135b, miR-4745-5p the hsa-miR-4745- is 5p, miR-128-1-5p is hsa-miR-128-1-5p, miR-4476 is hsa-miR-4476, miR-4687-3p is in hsa-miR-4687-3p There, miR-3665 is hsa-miR-3665, miR-6806-5p is hsa-miR-6806-5p, miR-3937 is hsa-miR-3937, miR-711 is hsa-miR is 711, miR-3141 is hsa-miR-3141, miR-3188 is hsa Is a miR-3188, miR-4281 is hsa-miR-4281, miR-5196-5p is hsa-miR-5196-5p, miR-6880-5p is hsa-miR-6880-5p, miR-3960 is hsa-miR-3960, miR-3648 is hsa-miR-3648, miR-6721-5p is hsa-miR-6721-5p, miR-4492 is in hsa-miR-4492 Yes, miR-744-5p is hsa-miR-744-5p, miR-7704 is hsa-miR-7704, miR-4749-5p is hsa-miR-4749-5p, miR-762 is is hsa-miR-762, miR-6836-3p is hsa-miR Is a 6836-3p, miR-6727-5p is hsa-miR-6727-5p, miR-4739 is hsa-miR-4739, miR-7977 is hsa-miR-7977, is miR-4484 is hsa-miR-4484, miR-6515-3p is hsa-miR-6515-3p, miR-373-5p is hsa-miR-373-5p, miR-4258 is hsa-miR
[Requested item 6]
　Said nucleic acid, a polynucleotide shown in any one of the following (f) -
(j): (f) SEQ ID NO: 84 ~ 226, 230 ~ 245, 247, and 249 nucleotide sequence or the base represented by any one of a polynucleotide consisting of the nucleotide sequence u is t in the sequence, a variant thereof, a fragment comprising the derivative, or 15 or more continuous
nucleotides, (g) SEQ ID NO: 84 ~ 226, 230 ~ 245, 247, and 249
polynucleotides the u in the nucleotide sequence or the nucleotide sequence represented by any one of (h) SEQ ID NO: 84 ~ 226, 230 ~ 245, 247, and 249 is t polynucleotides, a variant thereof comprising a nucleotide sequence complementary to the nucleotide sequence, the fragment comprising the derivative, or 15 or more continuous nucleotides,
(i) SEQ ID NO 84 to 226, 230 ~ 245, 247, and polynucleotides comprising a nucleotide sequence complementary to the nucleotide sequence u is t in the nucleotide sequence or the nucleotide sequence shown in any of 249, and
(j) wherein (f) any of the polynucleotides under stringent conditions with a polynucleotide hybridizing of ~ (i),
a polynucleotide selected from the group consisting of a kit according to claim 4 or 5.
[Requested item 7]
　An early pancreatic cancer or pancreatic cancer precursor lesions marker, miR-6784-5p, miR-1181, miR-671-5p, miR-6857-5p, miR-4276, miR-1914-3p, miR-149- 3p, miR-937-5p, miR-4675, miR-6795-5p, miR-4731-5p, miR-5090, miR-3620-5p, miR-1343-5p, miR-6717-5p, miR-6825- 5p, miR-6738-5p, miR-6769a-5p, miR-4728-5p, miR-652-5p, miR-4257, miR-6785-5p, miR-7110-5p, miR-6887-5p, miR- 887-3p, miR-1228-5p, miR-5572, miR-6782- p, miR-4298, miR-6786-5p, miR-5010-5p, miR-6087, miR-6765-5p, miR-6732-5p, miR-6787-5p, miR-6737-5p, miR-128- 2-5p, miR-4270, miR-6861-5p, miR-6756-5p, miR-1229-5p, miR-6891-5p, miR-6848-5p, miR-1237-5p, miR-30c-1- 3p, miR-1233-5p, miR-211-3p, miR-4758-5p, miR-614, miR-6746-5p, miR-1915-5p, miR-4688, miR-3917, miR-5787, miR- 4632-5p, miR-6126, miR-135a-3p, miR-80 3, miR-5698, miR-6089, miR-498, miR-296-3p, miR-4419b, miR-6802-5p, miR-6829-5p, miR-6803-5p, miR-1199-5p, miR- 6840-3p, miR-6752-5p, miR-6798-5p, miR-6131, miR-4667-5p, miR-6510-5p, miR-4690-5p, miR-920, miR-23
[Requested item 8]
　miR-6784-5p is hsa-miR-6784-5p, miR-1181 is hsa-miR-1181, miR-671-5p is hsa-miR-671-5p, is miR-6857-5p is hsa-miR-6857-5p, miR-4276 is hsa-miR-4276, miR-1914-3p is hsa-miR-1914-3p, miR-149-3p is hsa-miR-149- is a 3p, miR-937-5p is hsa-miR-937-5p, miR-4675 is hsa-miR-4675, miR-6795-5p is hsa-miR-6795-5p, miR- 4731-5p is hsa-miR-4731-5p, miR-5090 is hsa-miR Is 5090, miR-3620-5p is hsa-miR-3620-5p, miR-1343-5p is hsa-miR-1343-5p, miR-6717-5p is in hsa-miR-6717-5p Yes, miR-6825-5p is hsa-miR-6825-5p, miR-6738-5p is hsa-miR-6738-5p, miR-6769a-5p is hsa-miR-6769a-5p, miR-4728-5p is hsa-miR-4728-5p, miR-652-5p is hsa-miR-652-5p, miR-4257 is hsa-miR-4257, is miR-6785-5p is hsa-miR-6785-5p, miR-7110-5p is hsa-miR- Is a 110-5p, miR-6887-5p is hsa-miR-6887-5p, miR-887-3p is hsa-miR-887-3p, miR-1228-5p is hsa-miR-1228- is 5p, miR-5572 is hsa-miR-5572, miR-6782-5p is hsa-miR-6782-5p, miR-4298 is hsa-miR-4298, miR-6786-5 p is hsa-miR-6786-5p, miR-5010-5p is hsa-miR-5010-5p, miR-6087 is hsa-miR-6087, miR-6765-5p is hsa-miR- is a 6765-5p, miR-6732-5p is hsa-miR-6732-5p, miR-6787-5p is hsa-miR-6787-5p, miR-6737-5p is hsa-miR-6737- is 5p, miR-128-2-5p is hsa-miR-128-2-5p, miR-4270 is hsa-miR-4270, miR-6861-5p is in hsa-miR-6861-5p Yes, miR-6756-5p is hsa-miR-6756-5p, is miR-1229-5p Is a sa-miR-1229-5p, miR-6891-5p is hsa-miR-6891-5p, miR-6848-5p is hsa-miR-6848-5p, is miR-1237-5p hsa- is a miR-1237-5p, miR-30c-1-3p is hsa-miR-30c-1-3p, miR-1233-5p is hsa-miR-1233-5p, is miR-211-3p a hsa-miR-211-3p, miR-4758-5p is hsa-miR-4758-5p, miR-614 is hsa-miR-614, miR-6746-5p is hsa-miR-6746- is 5p, miR-1915-5p is hsa-miR-1915-5p, miR-4688 is hsa Is a miR-4688, miR-3917 is hsa-miR-3917, miR-5787 is hsa-miR-5787, miR-4632-5p is hsa-miR-4632-5p, is miR-6126 a hsa-miR-6126, miR-135a-3p is hsa-miR-135a-3p, miR-8063 is hsa-miR-8063, miR-5698 is hsa-miR-56 Is 98, miR-6089 is hsa-miR-6089, miR-498 is hsa-miR-498, miR-296-3p is hsa-miR-296-3p, is miR-4419b hsa- is a miR-4419b, miR-6802-5p is hsa-miR-6802-5p, miR-6829-5p is hsa-miR-6829-5p, miR-6803-5p is hsa-miR-6803- is 5p, miR-1199-5p is hsa-miR-1199-5p, miR-6840-3p is hsa-miR-6840-3p, miR-6752-5p is in hsa-miR-6752-5p Yes, miR-6798-5p is hsa-miR-6798-5p, miR-61 1 is hsa-miR-6131, miR-4667-5p is hsa-miR-4667-5p, miR-6510-5p is hsa-miR-6510-5p, the miR-4690-5p hsa- is a miR-4690-5p, miR-920 is hsa-miR-920, miR-23b-3p is hsa-miR-23b-3p, miR-4448 is hsa-miR-4448, miR- 2110 is hsa-miR-2110, miR-4706 is hsa-miR-4706, miR-7845-5p is hsa-miR-7845-5p, miR-6808-5p is hsa-miR-6808- is 5p, miR-4447 is hsa-miR-4447, miR-686 -5p is hsa-miR-6869-5p, miR-6794-5p is hsa-miR-6794-5p, miR-6511a-5p is hsa-miR-6511a-5p, miR-6824-5p There is a hsa-miR-6824-5p, miR-6766-3p is hsa-miR-6766-3p, miR-6511a-5p is hsa-miR-6511a-5p, miR-6749-5p
[Requested item 9]
　Said nucleic acid, a polynucleotide shown in any one of the following (a) -
(e): (a) SEQ ID NO: 1 ~ 83,227 ~ 229,246,248, and nucleotide sequence or represented by any one of the 250 the base polynucleotide consisting of the nucleotide sequence u is t in the sequence, a variant thereof, a fragment comprising the derivative, or 15 or more continuous
nucleotides, (b) SEQ ID NO: 1 ~ 83,227 ~ 229,246, 248, and a polynucleotide comprising the nucleotide sequence shown in any of the
250, the base sequence or the base sequence represented by any one of (c) SEQ ID NO: 1 ~ 83,227 ~ 229,246,248, and 250 As u comprises a polynucleotide comprising a nucleotide sequence complementary to the nucleotide sequence which is t, a variant thereof, a derivative thereof, or 15 or more contiguous bases in Pieces,
including a nucleotide sequence complementary to the nucleotide sequence u is t in the nucleotide sequence or the nucleotide sequence represented by any one of (d) SEQ ID NO: 1 ~ 83,227 ~ 229,246,248, and 250 polynucleotides, and
(e) wherein (a) ~ any polynucleotide and a polynucleotide hybridizing under stringent conditions (d),
a polynucleotide selected from the group consisting of, claim 7 or 8 the device according to.
[Requested item 10]
　It said device is another early pancreatic cancer or pancreatic cancer precursor lesions marker, miR-1908-5p, miR-6729-5p, miR-5195-3p, miR-638, miR-6125, miR-3178, miR-3196, miR-8069, miR-4723-5p, miR-4746-3p, miR-4689, miR-6816-5p, miR-6757-5p, miR-7109-5p, miR-6724-5p, miR- 1225-3p, miR-6875-5p, miR-7108-5p, miR-4508, miR-6085, miR-6779-5p, miR-642a-3p, miR-4695-5p, miR-7847-3p, miR- 3197, miR-6769b-5p, miR-7641, miR-187 5p, miR-3185, miR-2861, miR-3940-5p, miR-1203, miR-615-5p, miR-4787-5p, miR-1343-3p, miR-6813-5p, miR-1225-5p, miR-602, miR-4488, miR-125a-3p, miR-5100, miR-4294, miR-1231, miR-6765-3p, miR-4442, miR-718, miR-6780b-5p, miR-6090, miR-6845-5p, miR-4741, miR-4467, miR-4707-5p, miR-4271, miR-4673, miR-3184-5p, miR-1469, miR-4640-5p, miR-663a, miR- 6791-5p, miR-6826-5 , MiR-4433b-3p, miR-1915-3p, miR-4417, miR-4449, miR-4707-3p, miR-3180-3p, miR-5585-3p, miR-1268a, miR-8072, miR-296 -5p, miR-204-3p, miR-4454, miR-6722-3p, miR-1290, miR-3622a-5p, miR-939-5p, miR-675-5p, miR-31 31, miR-4648, miR-1268b, miR-6741-5p, miR-6893-5p, miR-3162-5p, miR-642b-3p, miR-4734, miR-150-3p, miR-8089, miR 6805-3p, miR-7113-3p, miR-6850-5p, miR-6799-5p, miR-6768-5p, miR-92b-5p, miR-3679-5p, miR-4792, miR-3656, miR 92a-2-5p, miR-4466, miR-4513, miR-6781-5p, miR-4649-5p, miR-6775-5p, miR-4651, miR-3195, miR-6726-5p, miR-6872- 3p, miR-371a-5p, miR-6777-5p, iR 6789-5p, miR-7975, miR-6821-5p, miR-4534, miR-619-5p, miR-7107-5p, miR-1228-3p, miR-6774-5p, miR-6805-5p, miR-23a-3p, miR-4665-5p, miR-4505, miR-4638-5p, miR-24-3p, miR-3135b, miR-4745-5p, miR-128-1-5p, miR-4476, miR-4687-3p, miR-3665, miR-6806-5p, miR-3937, miR-711, miR-3141, miR-3188, miR-4281, miR-5196-5p, miR-6880-5p, miR 3960, miR-3648, miR-6721-5p, miR 4492, miR-744-5p, miR-7704, miR-4749-5p, miR-762, miR-6836-3p, miR-6727-5p, miR-4739, miR-7977, miR-4484, miR-6515- 3p, miR-373-5p, miR-4258, miR-4674, miR-3180, miR-6076, miR-1238-5p, miR-4463, miR-4486, miR-4730
[Requested item 11]
　miR-1908-5p is hsa-miR-1908-5p, miR-6729-5p is hsa-miR-6729-5p, miR-5195-3p is hsa-miR-5195-3p, miR- 638 is hsa-miR-638, miR-6125 is hsa-miR-6125, miR-3178 is hsa-miR-3178, miR-3196 is hsa-miR-3196, is miR-8069 is hsa-miR-8069, miR-4723-5p is hsa-miR-4723-5p, miR-4746-3p is hsa-miR-4746-3p, miR-4689 is in hsa-miR-4689 Yes, miR-6816-5p is located in hsa-miR-6816-5p miR-6757-5p is hsa-miR-6757-5p, miR-7109-5p is hsa-miR-7109-5p, miR-6724-5p is hsa-miR-6724-5p, miR- 1225-3p is hsa-miR-1225-3p, miR-6875-5p is hsa-miR-6875-5p, miR-7108-5p is hsa-miR-7108-5p, is miR-4508 is hsa-miR-4508, miR-6085 is hsa-miR-6085, miR-6779-5p is hsa-miR-6779-5p, miR-642a-3p is in hsa-miR-642a-3p Yes, miR-4695-5p is hsa-miR-4695-5p, miR 7847-3p is hsa-miR-7847-3p, miR-3197 is hsa-miR-3197, miR-6769b-5p is hsa-miR-6769b-5p, miR-7641 is hsa-miR- is 7641, miR-187-5p is hsa-miR-187-5p, miR-3185 is hsa-miR-3185, miR-2861 is hsa-miR-2861, miR -3940-5p is hsa-miR-3940-5p, miR-1203 is hsa-miR-1203, miR-615-5p is hsa-miR-615-5p, miR-4787-5p is hsa is a -miR-4787-5p, miR-1343-3p is hsa-miR-1343-3p, miR-6813-5p is hsa-miR-6813-5p, miR-1225-5p is hsa-miR a -1225-5p, miR-602 is hsa-miR-602, miR-4488 is hsa-miR-4488, miR-125a-3p is hsa-miR-125a-3p, miR-5100 There is a hsa-miR-5100, miR-4294 is hsa-miR-4294 der , MiR-1231 is hsa-miR-1231, miR-6765-3p is hsa-miR-6765-3p, miR-4442 is hsa-miR-4442, miR-718 is hsa-miR-718 in it, miR-6780b-5p is hsa-miR-6780b-5p, miR-6090 is hsa-miR-6090, miR-6845-5p is hsa-miR-6845-5p, miR-4741 There is a hsa-miR-4741, miR-4467 is hsa-miR-4467, miR-4707-5p is hsa-miR-4707-5p, miR-4271 is hsa-miR-4271, miR -4673 is hsa-miR-4673, miR-318 -5p is hsa-miR-3184-5p, miR-1469 is hsa-miR-1469, miR-4640-5p is hsa-miR-4640-5p, miR-663a is hsa-miR-663a in it, miR-6791-5p is hsa-miR-6791-5p, miR-6826-5p is hsa-miR-6826-5p, miR-4433b-3p is hsa-miR-4433b- Is a 3p, miR-1915-3p is hsa-miR-1915-3p, miR-4417 is hsa-miR-4417, miR-4449 is hsa-miR-4449, is miR-4707-3p is hsa-miR-4707-3p, miR-3180-3p is hsa-miR-3180-3p, miR-5585-3p is hsa-miR-5585-3p, miR-1268a is hsa-miR- is a 1268a, miR-8072 is hsa-miR-8072, miR-296-5p is hsa-miR-296-5p, miR-204-3p is hsa-miR-204-3p, miR- 4454 is hsa-miR-4454, miR-6722-3p is hsa-mi Is a -6722-3p, miR-1290 is hsa-miR-1290, miR-3622a-5p is hsa-miR-3622a-5p, miR-939-5p is located in hsa-miR-939-5p , miR-675-5p is hsa-miR-675-5p, miR-3131 is hsa-miR-3131, miR-4648 is hsa-miR-4648, miR-1268b is hsa-miR-1268b in it, miR-6741-5p is hsa-miR-6741-5p, miR-6893-5p is hsa-miR-6893-5p, miR-3162-5p is located in hsa-miR-3162-5p , miR-642b-3p is hsa-miR-642b-3p, miR 4734 is hsa-miR-4734, miR-150-3p is hsa-miR-150-3p, miR-8089 is hsa-miR-8089, miR-6805-3p is hsa-miR-6805- is a 3p, miR-7113-3p is hsa-miR-7113-3p, miR-6850-5p is hsa-miR-6850-5p, miR-6799-5p is hsa-miR-6799- Is 5p, miR-6768-5p is hsa-miR-6768-5p, miR-92b-5p is hsa-miR-92b-5p, miR-3679-5p is in hsa-miR-3679-5p Yes, miR-4792 is hsa-miR-4792, miR-3656 is hsa-miR-3656, miR-92a-2-5p is hsa-miR-92a-2-5p, is miR-4466 is hsa-miR-4466, miR-4513 is hsa-miR-4513, miR-6781-5p is hsa-miR-6781-5p, miR-4649-5p is in hsa-miR-4649-5p Yes, miR-6775-5p is hsa-miR-6775-5p, miR-4651 is h Is a a-miR-4651, miR-3195 is hsa-miR-3195, miR-6726-5p is hsa-miR-6726-5p, miR-6872-3p is in hsa-miR-6872-3p Yes, miR-371a-5p is hsa-miR-371a-5p, miR-6777-5p is hsa-miR-6777-5p, miR-6789-5p is hsa-miR-6789-5p, miR-7975 is hsa-miR-7975, miR-6821-5p is hsa-miR-6821-5p, miR-4534 is hsa-miR-4534, miR-619-5p is hsa-miR- is a 619-5p, miR-7107-5p is in hsa-miR-7107-5p Ri, miR-1228-3p is hsa-miR-1228-3p, miR-6774-5p is hsa-miR-6774-5p, miR-6805-5p is hsa-miR-6805-5p, miR-23a-3p is hsa-miR-23a-3p, miR-4665-5p is hsa-miR-4665-5p, miR-4505 is hsa-miR-4505, is miR-4638-5p h Is a sa-miR-4638-5p, miR-24-3p is a hsa-miR-24-3p, miR-3135b is a hsa-miR-3135b, miR-4745-5p the hsa-miR-4745- is 5p, miR-128-1-5p is hsa-miR-128-1-5p, miR-4476 is hsa-miR-4476, miR-4687-3p is in hsa-miR-4687-3p There, miR-3665 is hsa-miR-3665, miR-6806-5p is hsa-miR-6806-5p, miR-3937 is hsa-miR-3937, miR-711 is hsa-miR is 711, miR-3141 is hsa-miR-3141, miR-3188 is hsa Is a miR-3188, miR-4281 is hsa-miR-4281, miR-5196-5p is hsa-miR-5196-5p, miR-6880-5p is hsa-miR-6880-5p, miR-3960 is hsa-miR-3960, miR-3648 is hsa-miR-3648, miR-6721-5p is hsa-miR-6721-5p, miR-4492 is in hsa-miR-4492 Yes, miR-744-5p is hsa-miR-744-5p, miR-7704 is hsa-miR-7704, miR-4749-5p is hsa-miR-4749-5p, miR-762 is is hsa-miR-762, miR-6836-3p is hsa-miR Is a 6836-3p, miR-6727-5p is hsa-miR-6727-5p, miR-4739 is hsa-miR-4739, miR-7977 is hsa-miR-7977, is miR-4484 is hsa-miR-4484, miR-6515-3p is hsa-miR-6515-3p, miR-373-5p is hsa-miR-373-5p, miR-4258 is hsa-miR
[Requested item 12]
　Said nucleic acid, a polynucleotide shown in any one of the following (f) -
(j): (f) SEQ ID NO: 84 ~ 226, 230 ~ 245, 247, and 249 nucleotide sequence or the base represented by any one of a polynucleotide consisting of the nucleotide sequence u is t in the sequence, a variant thereof, a fragment comprising the derivative, or 15 or more continuous
nucleotides, (g) SEQ ID NO: 84 ~ 226, 230 ~ 245, 247, and 249
polynucleotides the u in the nucleotide sequence or the nucleotide sequence represented by any one of (h) SEQ ID NO: 84 ~ 226, 230 ~ 245, 247, and 249 is t polynucleotides, a variant thereof comprising a nucleotide sequence complementary to the nucleotide sequence, the fragment comprising the derivative, or 15 or more continuous nucleotides,
(i) SEQ ID NO 84 to 226, 230 ~ 245, 247, and polynucleotides comprising a nucleotide sequence complementary to the nucleotide sequence u is t in the nucleotide sequence or the nucleotide sequence shown in any of 249, and
(j) wherein (f) any of the polynucleotides stringent polynucleotide hybridizing under conditions of ~ (i),
a polynucleotide selected from the group consisting of, according to claim 10 or 11 device.
[Requested item 13]
　It said device is a device for the measurement by hybridization techniques, according to any one of claims 7 to 12 devices.
[Requested item 14]
　The hybridization techniques, a nucleic acid array technology, according to claim 13 the device.
[Requested item 15]
　Measuring the expression level of target nucleic acid in a specimen of the subject using the device according to any one of claims 1 to kits or claims 7 to according to any one of 6 14 was the measurement by using the expression level, and the control expression level in healthy body that is measured in the same manner, that the subject is suffering from an early stage pancreatic cancer or pancreatic cancer precursor lesions or early pancreatic cancer or pancreatic cancer precursor that does not suffer from the lesion was evaluated in in vitro, thereby detecting the presence or absence of early pancreatic cancer or pancreatic cancer precursor lesions in a subject, early pancreatic cancer or pancreatic in a subject method for detecting cancer precursor lesions.
[Requested item 16]
　Using the device according to any one of claims 1 kit according to any one of 1-6 or claim 7 to 14 to measure the expression level of a target gene in a specimen of a subject, early pancreatic cancer or to have pancreatic cancer precursor lesions were created a gene expression amount of the specimen from gene expression level and healthy body sample from a subject known as teacher samples, and early pancreatic cancer or pancreatic cancer precursor the discriminant is possible to distinguish between lesions and healthy distinctively, by substituting the expression level of a target gene in a sample from said subject, whereby, early pancreatic cancer or pancreatic cancer precursor lesions and assessing the presence or absence, a method of detecting early pancreatic cancer or pancreatic cancer precursor lesions in a subject.
[Requested item 17]
　Wherein the subject is a human The method of claim 15 or 16.
[Requested item 18]
　Wherein the analyte is blood, serum or plasma, the method according to any one of claims 15-17.