XRCC1 Genotype and Breast Cancer: Functional Studies and Epidemiologic Data Show Interactions between XRCC1 Codon 280 His and Smoking

Abstract

Tobacco smoke produces oxidative and alkylative DNA damage that necessitates repair by base excision repair coordinated by X-ray cross-complementing gene 1 (XRCC1). We investigated whether polymorphisms in XRCC1 alter DNA repair capacity and modify breast cancer risk associated with smoking. To show the functionality of the 280His variant, we evaluated single-strand break (SSB) repair capacity of isogenic Chinese hamster ovary cells expressing human forms of XRCC1 after exposure to hydrogen peroxide (H 2 O 2 ), methyl methanesulfonate (MMS), or camptothecin by monitoring NAD(P)H. We used data from the Carolina Breast Cancer Study (CBCS), a population-based, case-control study that included 2,077 cases (786 African Americans and 1,281 Whites) and 1,818 controls (681 African Americans and 1,137 Whites), to examine associations among XRCC1 codon 194, 280, and 399 genotypes, breast cancer, and smoking. Odds ratios and 95% confidence intervals (95% CI) were calculated by unconditional logistic regression. Only cells expressing the 280His protein accumulated SSB, indicated by NAD(P)H depletion, from both H 2 O 2 and MMS exposures. In the CBCS, positive associations were observed between breast cancer and smoking dose for participants with XRCC1 codon 194 Arg/ Arg (P trend = 0.046), 399 Arg/Arg (P trend = 0.012), and 280 His/His or His/Arg (P trend = 0.047) genotypes. The 280His allele was in strong linkage disequilibrium with 194Arg (Lewontin's D V= 1.0) and 399Arg (D V= 1.0). These data suggest that less common, functional polymorphisms may lie within common haplotypes and drive gene-environment interactions. (Cancer Res 2006; 66(5): 2860-8)

Cigarette smoke condensate-induced level of adenomatous polyposis coli blocks long-patch base excision repair in breast epithelial cells

“…The results show either a positive or null association between long-term smoking and N-acetyltransferase (NAT-2), CYP1A1, glutathione S-transferase, sulfotransferase 1A1 genes (Terry and Goodman, 2006). Studies of the BER enzyme, XRCC1, have shown a positive association of long-term smoking with breast cancer risk (Duell et al, 2001;Terry and Rohan, 2002;Patel et al, 2005;Pachkowski et al, 2006). Thus, mutations in the XRCC1 gene may influence the BER activity and reduce the repair of nonbulky DNA adducts generated by cigarette smoke constituents.…”

Dietary and genetic modulation of DNA repair in healthy human adults

“…In addition, the Gln allele of the ERCC2 Lys751Gln SNP has been associated with both reduced NER capacity (Spitz et al 2001;Qiao et al 2002b) and increased prevalence of adducts (Palli et al 2001;Hou et al 2002;Tang et al 2002). Similar effects are seen in other repair systems, with variants of the BER proteins 8-oxoguanine DNA glycosylase 1 and X-ray cross-complementing group 1 showing reduced activity (Pachkowski et al 2006;Sokhansanj & Wilson, 2006). The same polymorphisms that appear to modulate repair capacity have been associated with cancer risk.…”

Prevalence of BER gene polymorphisms in sporadic breast cancer

“…Previous studies indicated that the XRCC1 399Gln allele is a BER gene polymorphism frequently inherited by American white women (allele frequency, 0.34-0.37) (14,15,20,21,(26)(27)(28)(29)40). Other ethnic groups have not been as well-studied.…”

“…Other studies did not find a similar risk. For example, XRCC1 399Gln was not associated with breast cancer in Chinese (19) and USA women (North Carolina) (20,21), but a protective effect was suggested for Portuguese women with no family history of breast cancer (22). Even though the epidemiological results are not uniform, mechanistic studies indicate that XRCC1 399Gln is detrimental to the cell.…”

“…It affects BER activity (23) and increases mutagenesis in smokers (24,25). On the other hand, it is inherited more frequently (up to 37%) than the incidence rate (~13%) of breast cancer (21,(26)(27)(28)(29)(30). Therefore, XRCC1 399Gln may be a low-penetrance variant that requires additional factors to exert its deleterious effects.…”