Breast cancer is the most common type of cancer and the second leading cause of cancer death among women in the United States. While family history of breast cancer is an established predisposing factor, epidemiological studies suggest that only 5–10% of breast cancer cases are familial and the remaining proportion is sporadic [1
]. The majority of genetic variants that influence susceptibility to sporadic breast cancer are unknown [2
]. Common variants may explain a greater proportion of breast cancer morbidity and mortality than rare highly penetrant mutations, such as those in BRCA1 and BRCA2 which account for only 15–20% of familial breast cancer cases[1
DNA repair plays an essential role in the maintenance of DNA integrity. Failure of DNA repair mechanisms can lead to sustained damage, potentially resulting in the malfunction of cellular systems and checkpoints, and the ability of a cell to over-proliferate or evade apoptosis. Deficient DNA repair capacity has been suggested as a predisposing factor in familial and sporadic breast cancer [3
]. Substantial correlations have been found between DNA repair gene variants and DNA repair capacity[6
]. Several studies have observed a low nucleotide excision repair capacity and direct reversion repair capacity of breast tissue [7
] and suggest that the breast epithelium may uniquely lack redundant systems of double-strand break repair that are present in other tissues [10
]. If true, this suggests common genetic variation in DNA repair genes would have greater impact in breast tissues than other tissues with more extensive DNA repair redundancy.
Despite the relevance of DNA repair to carcinogenesis, the impact of common genetic variation on postmenopausal breast cancer susceptibility is not fully understood. In this case-control study of 2,287 postmenopausal women of European ancestry (1,145 cases and 1,142 controls matched on age and postmenopausal hormone use) nested within the Nurses’ Health Study (NHS), we comprehensively and systematically evaluated genetic variation in the coding and non-coding regions of 68 DNA repair genes in relation to invasive postmenopausal breast cancer risk. The association between breast cancer risk and each of these markers individually was assessed as part of the Cancer Genetic Markers of Susceptibility (CGEMS) Project, although none reached conventional genome-wide significance in the initial scan [12
] and only one reached genome-wide significance (rs999737 within RAD51L1) after extensive follow-up [13
]. Here we present the results for these markers adjusted for multiple testing at the gene, rather than the genome-wide level. We also explore the possibility that markers in DNA repair pathways may be collectively associated with risk of breast cancer even though the association between breast cancer and any particular marker is too weak to detect. To this end, we conduct a test that aggregates evidence for association across multiple markers (the Admixture Maximum Likelihood test (AML)) and a test that explicitly allows for non-additive interactions among markers in the same pathway (the Kernel Machine test).
These pathways/genes included direct reversion repair (MGMT), base excision repair (BER) (ADPRT, APEX1, FEN1, LIG1, LIG3, NEIL1, NEIL2, OGG1, PCNA, UNG2, XRCC1), nucleotide excision repair (NER) (CKN1, ERCC1, ERCC2, ERCC3, ERCC4, ERCC5, ERCC6, RAD23a, RAD23b, RPA1, RPA2, RPA3, XPA, XPC), double-strand break (DSB) repair via (a) homologous recombination (HR) (BRCA1, BRCA2, MRE11A, NBS1, RAD50, RAD51, RAD51c, RAD51L1, RAD51L3, RAD52, RAD54L, XRCC2, XRCC3), or (b) non-homologous end-joining (NH) (DCLRE1C, G22P1, LIG4, PRKDC, XRCC4, XRCC5), mismatch repair (MMR) (MLH1, MLH3, MSH2, MSH3, MSH6, PMS1, PMS2), DNA polymerases (POL) (POLB, POLD1, POLE, POLI, POLK), Fanconi Anemia complementation groups (FAN) (FANCA, FANCC, FANCD2, FANCE, FANCF, FANCG), and DNA damage recognition and response (REG)(ATM, ATR, CHEK1, CHEK2, TP53).
Breast cancer tumors are heterogeneous across ER and PR status with respect to tumor characteristics, response to treatment, and risk profiles [14
]. In this study we investigate overall breast cancer susceptibility as well as ER and PR subtype specific susceptibility. Preliminary reports suggest that categorization into ER and PR subtypes may be particularly useful when studying the etiology of breast cancer with respect to DNA repair [18