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Method For Identification Of A Deficient Brca1 Function

Abstract: The present invention is related to an in vitro method for identifying deficient BRCA1 function in a test biological sample obtained from a human individual said method comprising the steps of:  Assaying the test sample to determine an expression profile of at least BRCA1 gene and ID4 gene; and  Establishing the ratio of BRCA1 to ID4 gene expression; Wherein a BRCA1/ID4 ratio lower than a threshold value is used as positive criterion for identification of the deficient BRCA1 function in the tested sample.

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Notices, Deadlines & Correspondence

Patent Information

Application #
Filing Date
14 November 2017
Publication Number
47/2017
Publication Type
INA
Invention Field
BIO-CHEMISTRY
Status
Email
Parent Application

Applicants

NADATHUR ESTATES PVT. LTD.
2010, Nadathur Place, 3rd Floor, Plot no 23, 8th Main Road, 3rd Block, Jayanagar, Bangalore-560011, Karnataka, India.
SRIDHAR, T.S
601 B, STERLING RESIDENCY, RMV II STAGE, BANGALORE

Inventors

1. SRIDHAR T.S.
601 B Sterling Residency RMV II Stage BANGALORE 560094 Bangalore,Karnataka India-560094.
2. PRABHU, Jyothi S
A-406, Gopalan Jewels, Kanakapura Main Road, Doddakallasandra, BANGALORE 560062
3. KORLIMARLA, Aruna
941, Ist G Maind Road, Girinagar 2nd Phase, BANGALORE - 560085, Karnataka, India
4. REMACLE, Jose
125 Rue Mazy bte 40, 5100 JAMBES, BELGIUM

Specification

We Claim:
1. An in vitro method for identifying
deficient BRCA1 function in a test biological sample
obtained from a human individual, said method
comprising the steps of:
- Assaying the test sample to determine an expression profile of at least BRCA1 gene and ID4 gene; and
- Establishing the ratio of BRCA1 to ID4 gene expression;
Wherein a BRCA1/ID4 ratio lower than a threshold value is used as positive criterion for identification of the deficient BRCA1 function in the tested sample.
2. The method of claim 1, wherein the threshold value for the BRCA1/ID4 ratio corresponds to the median value of a cohort of Triple Negative Breast Cancers (TNBC) samples.
3. The method of claim 1 or 2, wherein the threshold value for the BRCA1/ID4 ratio is the value of said ratio separating a reference breast cancer population into a low and high ratio range wherein less than 50% of the population is in the low ratio range, preferably less than 32%, better less than 16% and even better less than 10%.
4. The method of claims 1 or 2, wherein the BRCA1/ID4 ratio is lower than 1 and better lower than 0.9 and even better lower than 0.8, when the BRCA1 and ID4 gene expressions are calculated according to the same log scale.
5. The method of any one of the preceding claims, which further comprises the step of assaying the test sample to determine a percentage of cell nucleus positive for BRCA1 protein by immunohistochemistry, wherein a percentage lower than 20% and even lower than 10% and even lower than 5% is

used as positive criterion for identification of a deficient BRCA1 function.
6. The method of any one of the preceding claims, which further comprises the step of assaying the test sample to determine the expression level of MIR182 microRNA, wherein an expression value higher than a threshold value is used as positive criterion for identification of a deficient BRCA1 function in the tested sample.
7. The method according to any of the preceding claims, wherein the criterion for identification of a deficient BRCA1 function further comprises:
- the expression value of MIR182 microRNA higher than a
threshold value as in claim 6 and the percentage of
cell nucleus positive for BRCA1 protein as in claim 5;
wherein the presence of at least two positive criteria among the said three criteria is used for identification of a deficient BRCA1 function in the tested sample.
8. The method according to any of the
preceding claims, wherein the criterion for
identification of a deficient BRCA1 function further
comprises:
- the expression value of MIR182 microRNA higher than a threshold value as in claim 6;
- the percentage of cell nucleus positive for BRCA1 protein as in claim 5;
- the expression value of BRCA1 lower than a threshold value;
- the expression of ID4 higher than a threshold value; and
- the methylation level of the BRCA1 promoter being higher than a threshold value;

wherein the presence of at least two and better three and even better four positive criteria among the said criteria is used for identification of a deficient BRCA1 function in the tested sample.
9. The method according to claim 8,
wherein the threshold value for MIR182 and/or ID4
expression is the value of said expression separating a
reference breast cancer population into a low and high
expression range wherein more than 50% of the
population is in the high expression range, preferably
more than 60%, better more than 70% and even better
more than 84%.
10. The method according to any one of the preceding claims, wherein a value is attributed to the criterion(a) used for identification of deficient BRCA1 function and the tumor is defined as deficient BRCA1 function if the score calculated on said value(s) by using a classifier algorithm reaches a threshold.
11. The method of any one of the preceding claims, wherein the in vitro test biological sample comprises cancer cells preferably selected from the group consisting of breast cancer, ovarian cancer, early onset breast cancer, early onset ovarian cancer, sporadic breast cancer and sporadic ovarian cancer.
12. The method according to any of the claims 1 to 11, which further comprises the step of selecting patient(s) with deficient BRCA1 function and the step of determining therapeutic agent(s) comprising chemical or physical DNA damaging agent and/or PARP inhibitor, which would be suitable for treatment of said patient(s).
13. The method according to claim 12, wherein the therapeutic agent(s) are selected from the group consisting of platinum salt(s), alkylating

agents, antitumoral compounds especially
anthracyclines, such as doxorubicin, bleomycin, cyclophosphamide, PARP inhibitor and irradiation agent or a combination thereof.
14. The method according to claim 12 or 13, which further comprises the step of assaying the test sample to determine the presence of mutated P53 protein, wherein the presence of mutated P53 protein is considered as a positive criterion for treatment of patients from which the test sample is obtained.
15. The method of claim 1 to 11, wherein the threshold value for the positive criterion is determined to include more than 30% and better more than 50% and better more than 75% and even better more than 90% of patients selected according to claims 12 to 14 who responded positively to chemical or physical therapeutic agent comprising DNA damaging agent and/or PARP inhibitor.

Documents

Application Documents

# Name Date
1 201747040542-STATEMENT OF UNDERTAKING (FORM 3) [14-11-2017(online)].pdf 2017-11-14
1 Correspondence by Agent_Power of Attorney_16-07-2018.pdf 2018-07-16
2 201747040542-FORM-26 [27-06-2018(online)].pdf 2018-06-27
2 201747040542-PRIORITY DOCUMENTS [14-11-2017(online)].pdf 2017-11-14
3 201747040542-Proof of Right (MANDATORY) [27-06-2018(online)].pdf 2018-06-27
3 201747040542-FORM 1 [14-11-2017(online)].pdf 2017-11-14
4 Correspondence by Agent_Form 5_20-11-2017.pdf 2017-11-20
4 201747040542-DRAWINGS [14-11-2017(online)].pdf 2017-11-14
5 201747040542-DECLARATION OF INVENTORSHIP (FORM 5) [14-11-2017(online)].pdf 2017-11-14
5 201747040542.pdf 2017-11-16
6 201747040542-COMPLETE SPECIFICATION [14-11-2017(online)].pdf 2017-11-14
7 201747040542-DECLARATION OF INVENTORSHIP (FORM 5) [14-11-2017(online)].pdf 2017-11-14
7 201747040542.pdf 2017-11-16
8 201747040542-DRAWINGS [14-11-2017(online)].pdf 2017-11-14
8 Correspondence by Agent_Form 5_20-11-2017.pdf 2017-11-20
9 201747040542-FORM 1 [14-11-2017(online)].pdf 2017-11-14
9 201747040542-Proof of Right (MANDATORY) [27-06-2018(online)].pdf 2018-06-27
10 201747040542-PRIORITY DOCUMENTS [14-11-2017(online)].pdf 2017-11-14
10 201747040542-FORM-26 [27-06-2018(online)].pdf 2018-06-27
11 Correspondence by Agent_Power of Attorney_16-07-2018.pdf 2018-07-16
11 201747040542-STATEMENT OF UNDERTAKING (FORM 3) [14-11-2017(online)].pdf 2017-11-14