Molecular diagnostic test for cancer
Methods and compositions are provided for the identification of a molecular diagnostic test for cancer. The test defines a novel DNA damage repair deficient molecular subtype and enables classification of a patient within this subtype. The present invention can be used to determine whether patients with cancer are clinically responsive or non-responsive to a therapeutic regimen prior to administration of any chemotherapy. This test may be used in different cancer types and with different drugs that directly or indirectly affect DNA damage or repair, such as many of the standard cytotoxic chemotherapeutic drugs currently in use. In particular, the present invention is directed to the use of certain combinations of predictive markers, wherein the expression of the predictive markers correlates with responsiveness or non-responsiveness to a therapeutic regimen.
1. A method of diagnosing and treating an individual as having a DNA damage response deficient (DDRD) cancer comprising;
a. measuring expression levels of at least two genes in a test sample of tumour cells obtained from the individual to determine a test score, wherein the at least two genes are selected from the group consisting of CXCL10, IDO1, CD2, GBP5, ITGAL, LRP4, APOL3, CDR1, FYB, TSPAN7, RAC2, KLHDC7B, GRB14, AC138128.1, KIF26A, CD274, CD109, ETV7, MFAP5, OLFM4, PI15, FOSB, FAM19A5, NLRC5, PRICKLE1, EGR1, CLDN10, ADAMTS4, SP140L, ANXA1, RSAD2, ESR1, IKZF3, OR2I1P, EGFR, NAT1, LATS2, CYP2B6, PTPRC, PPP1R1A, and AL137218.1; and
b. treating the individual with a DNA-damage therapeutic agent, wherein the individual is diagnosed as having the DDRD cancer because a test score of the test sample exceeds a threshold score, and said exceeding occurs if the test score, based on the expression levels of the at least two genes, exceeds a threshold score based on the same genes.
2. The method of claim 1 , wherein the at least two genes are selected from the group consisting of CXCL10, IDO1, CD2, GBP5, ITGAL, LRP4, and APOL3.
3. The method of claim 1 , wherein the cancer is selected from melanoma, colon cancer, breast cancer, and ovarian cancer.
4. The method of claim 3 , wherein the cancer is associated with one or more mutations in the Fanconi anemia/BRCA pathway.
5. The method of anyone of claims 1 - 4 , wherein the DNA-damage therapeutic agent comprises one or more substances selected from: a DNA damaging agent, a DNA repair targeted therapy, an inhibitor of DNA damage signalling, an inhibitor of DNA damage induced cell cycle arrest, a histone deacetylase inhibitor, and a heat shock protein inhibitor.
6. The method of claim 5 , wherein the DNA-damage therapeutic agent comprises doxorubicin, epirubicin, cyclophosphamide, ionising radiation, cisplatin, carboplatin, a PARP inhibitor, or a combination thereof.
7. The method of claim 6 , wherein the cancer is breast cancer.
8. The method of claim 5 , wherein the DNA-damage therapeutic agent comprises oxaliplatin, irinotecan, or a combination thereof.
9. The method of claim 8 , wherein the cancer is colorectal cancer.
10. The method of claim 5 , wherein the DNA-damage therapeutic agent comprises cisplatin, carboplatin, a PARP inhibitor, or a combination thereof.
11. The method of claim 10 , wherein the cancer is ovarian cancer.
12. A method of treating cancer, comprising administering a DNA-damage therapeutic agent to an individual, wherein:
a. the individual has been selected for the treatment because the combined expression level of at least two genes in a cancer sample from the individual is higher than an established threshold value, thereby diagnosing the individual as having a DDRD cancer; and
b. the combined expression level of the at least two genes is based on the expression of at least two genes selected from the group consisting of CXCL10, IDO1, CD2, GBP5, ITGAL, LRP4, APOL3, CDR1, FYB, TSPAN7, RAC2, KLHDC7B, GRB14, AC138128.1, KIF26A, CD274, CD109, ETV7, MFAP5, OLFM4, PI15, FOSB, FAM19A5, NLRC5, PRICKLE1, EGR1, CLDN10, ADAMTS4, SP140L, ANXA1, RSAD2, ESR1, IKZF3, OR2I1P, EGFR, NAT1, LATS2, CYP2B6, PTPRC, PPP1R1A, and AL137218.1.
13. The method of claim 12 , wherein the at least two genes are selected from the group consisting of CXCL10, IDO1, CD2, GBP5, ITGAL, LRP4, and APOL3.
14. The method of claim 12 , wherein the cancer is selected from melanoma, colon cancer, breast cancer, and ovarian cancer.
15. The method of claim 12 , wherein the cancer is associated with one or more mutations in the Fanconi anemia/BRCA pathway.
16. The method of anyone of claims 12 - 15 , wherein the DNA-damage therapeutic agent comprises one or more substances selected from: a DNA damaging agent, a DNA repair targeted therapy, an inhibitor of DNA damage signalling, an inhibitor of DNA damage induced cell cycle arrest, a histone deacetylase inhibitor, and a heat shock protein inhibitor.
17. The method of claim 12 , wherein the DNA-damage therapeutic agent comprises doxorubicin, epirubicin, cyclophosphamide, ionising radiation, cisplatin, carboplatin, a PARP inhibitor, or a combination thereof.
18. The method of claim 17 , wherein the cancer is breast cancer.
19. The method of claim 12 , wherein the DNA-damage therapeutic agent comprises oxaliplatin, irinotecan, or a combination thereof.
20. The method of claim 19 , wherein the cancer is colorectal cancer.
21. The method of claim 16 , wherein the DNA-damage therapeutic agent comprises cisplatin, carboplatin, a PARP inhibitor, or a combination thereof.
22. The method of claim 21 , wherein the cancer is ovarian cancer.
23. A method of treating cancer, comprising administering a modulator of DNA-damage-related immune signalling to an individual, wherein:
a. the individual has been selected for the treatment because the combined expression level of at least two genes in a cancer sample from the individual is higher than an established threshold value, thereby diagnosing the individual as having a DDRD cancer; and
b. the combined expression level of the at least two genes is based on the expression of at least two genes selected from the group consisting of CXCL10, IDO1, CD2, GBP5, ITGAL, LRP4, APOL3, CDR1, FYB, TSPAN7, RAC2, KLHDC7B, GRB14, AC138128.1, KIF26A, CD274, CD109, ETV7, MFAP5, OLFM4, PI15, FOSB, FAM19A5, NLRC5, PRICKLE1, EGR1, CLDN10, ADAMTS4, SP140L, ANXA1, RSAD2, ESR1, IKZF3, OR2I1P, EGFR, NAT1, LATS2, CYP2B6, PTPRC, PPP1R1A, and AL137218.1.
24. The method of claim 23 , wherein at least one of the at least two genes is selected from the group consisting of CXCL10, IDO1, CD2, GBP5, ITGAL, CDR1, CD274, CD109, FOSB, FAM19A5, NLRC5, ANXA1, RSAD2, and IKZF3.
25. The method of claim 23 , wherein at least one of the at least two genes is selected from the group consisting of CXCL10, IDO1, CD2, GBP5, CDR1, CD109, FOSB, FAM19A5, NLRC5, RSAD2, and IKZF3.
26. The method of claim 23 , wherein at least one of the at least two genes is selected from the group consisting of CXCL10, IDO1, GBP5, CD274, and IKZF3.
27. The method of any one of claims 23 - 26 , wherein the cancer is selected from melanoma, colon cancer, breast cancer, and ovarian cancer.
28. The method of claim 23 , wherein the cancer is associated with one or more mutations in the Fanconi anemia/BRCA pathway.