Breast cancer is the most common cancer and the second leading cause of cancer death among women in the United States. Epidemiological studies have shown that familial breast cancer constitutes only about 5–10% of total breast cancer, and only 15–20% of the observed familial clustering of breast cancer is attributable to strongly predisposing BRCA1 and BRCA2 mutations [1
]. Most of the genetic variants that contribute to the risk of developing sporadic breast cancer remain unknown [2
Deficient DNA repair capacity has been suggested as a predisposing factor in familial and sporadic breast cancer [2
]. Reduced DNA repair capacity among breast cancer cases has been observed in mutagen (X-rays, bleomycin, and BPDE [benzopyrene dihydrodiol epoxide]) sensitivity assays conducted in human peripheral blood lymphocytes [5
] and in host cell reactivation assays with BPDE- or UV-induced damage [10
]. The wide range of carcinogens used in these assays suggests that defects in global DNA repair capacity, rather than a single substrate-specific DNA repair pathway, underlie cancer risk. The spectrum of p53 gene mutations in breast cancer suggests the involvement of multiple genotoxic compounds and DNA repair abnormalities in breast cell mutagenesis [12
]. The importance of DNA repair in breast cancer development is further supported by the involvement of BRCA1 and BRCA2 in many critical cellular processes including multiple DNA repair pathways and apoptosis through protein-protein interactions and transcriptional regulation. One mechanism that may lead to inter-individual variation in DNA repair capacity is germline variation in DNA repair genes [14
]. Even though a variety of factors modulate the path from genotype to phenotype, there are substantial correlations between DNA repair gene variants and DNA repair capacity [17
]. A deficient DNA repair capacity may be attributable to multiple polymorphisms in multiple DNA repair pathways.
Breast cancer in premenopausal women is more aggressive, with a poorer prognosis than postmenopausal breast cancer. The etiology for premenopausal breast cancer may differ from that for postmenopausal women, and involve a relatively stronger component of inherited predisposition. In this study of 239 cases and 477 matched controls among premenopausal predominantly Caucasian women in a nested case-control study within the Nurses’ Health Study II, we comprehensively and systematically evaluated genetic variation in 60 DNA repair genes in relation to breast cancer risk. These pathways/genes included direct reversion repair (MGMT), base excision repair (BER) (APE1, LIG3, NEIL1, NEIL2, OGG1, PARP1, XRCC1, FEN1), nucleotide excision repair (NER) (XPA, ERCC3, XPC, ERCC2, ERCC4, ERCC5, ERCC1, LIG1, ERCC6, ERCC8, RPA1, RPA2, RPA3), double-strand break (DSB) repair via a) homologous recombination (HR) (RAD50, RAD51, RAD52, XRCC2, XRCC3, NBN, MRE11A, ATM, ATR) or b) non-homologous end-joining (NHEJ) (XRCC4, XRCC5, XRCC6, ARTEMIS, PRKDC, LIG4), mismatch repair (MMR) (MSH2, MSH3, MSH6, MLH1, MLH3, PMS1, PMS2), DNA polymerases (POLB, POLD1, POLE, POLI, POLK), Fanconi Anemia complementation groups (FANCA, FANCC, FANCD2, FANCE, FANCF, FANCG), and other related genes (CHEK1, CHEK2, TP53, PCNA, BLM).