BBD is a risk factor for breast cancer that persists for at least 25 years (5
) and is likely to have an inherited component (1
). The cumulative risk of breast cancer after a diagnosis of atypical hyperplasia may be as high as 18% at 25 years for a single focus and 40% for multiple foci (23
). Furthermore, BBD can be prevented by tamoxifen, a proven chemoprevention agent for breast cancer (24
). Therefore, identification of genetic risk factors associated with a diagnosis of BBD and its high risk subtypes may allow for the early introduction of prevention strategies that target BBD and, in turn, breast cancer.
Cellular DNA damage is thought to initiate carcinogenesis. Because BBD is an intermediate phenotype within the breast carcinogenesis pathway, deficiencies in DNA repair associated with breast cancer are likely to be associated with BBD as well. Our results support the contention that allelic variants in the nucleotide excision and base excision repair pathways (ERCC4 and XRCC1, respectively) may be linked to BBD. ERCC4 codes for a 5′-endonuclease in the nucleotide excision repair pathway, whereas XRCC1 codes for an important component in the base excision repair pathway (25
), suggesting that base damage repair pathways may be important in protecting against breast carcinogenesis. The 194 codon of XRCCI is located in a hydrophobic linker region between its DNA polymerase β domain and poly(ADP-ribose) polymerase-interacting domains, so the change from arginine to tryptophan could alter the interaction of XRCC1 with either or both of these DNA repair proteins within the base excision,repair complex. The functional role of codon 415 in ERCC4 is less clear, but some disease-related mutations in ERCC4 map close to Arg415
Gln within exon 8 suggesting functional significance. Our findings of a strong interaction between ERCC4 and family history of breast cancer is of particular interest. Having a falmily history of breast cancer is a major BBD and breast cancer risk factor (1
), but it is not clear what a family history of breast cancer reflects in terms of carcinogenic mechanisms. It could be related to differential estrogen metabolism. Estrogen metabolites have been shown to form base adducts in DNA (29
). These adducts can either be removed by the nucleotide excision repair pathway or spontaneously depurinate to produce apurinic sites that are then repaired by base excision repair. Thus, estrogens metabolites may directly produce many of the base lesions that ERCC4 and XRCC1 proteins repair. It has also been shown that estrogens can induce reactive oxygen species that are well-known base-damaging agents (30
). Alternatively, it could be that family history of breast cancer may partly reflect a heritable propensity to increased intracellular oxidative stress, which is known to produce base damage (34
), thus rendering these women vulnerable to deficiencies in base damage repair.
In this genotyped cohort, our ability to also evaluate the association between these two DNA repair SNPs and breast cancer was limited by the number of breast cancer cases accrued thus far (n
= 35). Longer follow-up is needed to evaluate the association between the SNPs and BBD progression to breast cancer within this population. However, nonstatistically significant positive associations were observed previously in an earlier case-control study within Clue II between these two DNA repair SNPs and breast cancer (13
). The variant alleles for both of these genes have also been reported previously to be breast cancer-associated, with marginal significance, in a hospital-based case-control study (36
). Furthermore, the ERCC4 gene has recently shown to be associated with premenopausal breast cancer in a nested case-control study within the Nurses’ Health Study II (37
). Taken together, these studies support the notion that DNA repair genes may have a common role in tlle etiology of both BBD and breast cancer.
Although the sample size of this prospective study is large, one limitation is the lack of information on histologic subtypes of BBD. Nevertheless, if the association reported here is restricted to proliferative BBD, which is a strong risk factor for invasive breast cancer, the magnitude of the association would be even larger than our observed overall point estimates. Subsequent investigations should explore potential differences in association by subtype.
In summary, variant ERCC4 and XRCC1 genotypes are statistically significantly associated with BBD in this population. For ERCC4, the risk is particularly increased in women with both the variant allele and a falmily history of breast cancer, suggesting that this subgroup of women is at much higher risk for DNA damage-induced BBD than the general population. Studying precursor lesions, such as BBD, which appear earlier than cancerous tumors, may also represent a powerful tool to explore potential associations between genotypes and cancer risk, particularly within high-risk subpopulations.