ERCC4 Associated with Breast Cancer Risk: A Two-Stage Case-Control Study Using High-throughput Genotyping

Abstract

The failure of linkage studies to identify further highpenetrance susceptibility genes for breast cancer points to a polygenic model, with more common variants having modest effects on risk, as the most likely candidate. We have carried out a two-stage case-control study in two European populations to identify low-penetrance genes for breast cancer using high-throughput genotyping. Single-nucleotide polymorphisms (SNPs) were selected across preselected cancer-related genes, choosing tagSNPs and functional variants where possible. In stage 1, genotype frequencies for 640 SNPs in 111 genes were compared between 864 breast cancer cases and 845 controls from the Spanish population. In stage 2, candidate SNPs identified in stage 1 (nominal P < 0.01) were tested in a Finnish series of 884 cases and 1,104 controls. Of the 10 candidate SNPs in seven genes identified in stage 1, one (rs744154) on intron 1 of ERCC4, a gene belonging to the nucleotide excision repair pathway, was associated with recessive protection from breast cancer after adjustment for multiple testing in stage 2 (odds ratio, 0.57; Bonferroniadjusted P = 0.04). After considering potential functional SNPs in the region of high linkage disequilibrium that extends across the entire gene and upstream into the promoter region, we concluded that rs744154 itself could be causal. Although intronic, it is located on the first intron, in a region that is highly conserved across species, and could therefore be functionally important. This study suggests that common intronic variation in ERCC4 is associated with protection from breast cancer. (Cancer Res 2006; 66(19): 9420-7)

Evaluation of a candidate breast cancer associated SNP in ERCC4 as a risk modifier in BRCA1 and BRCA2 mutation carriers. Results from the Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA)

“…We observed a marginally significant association of the G allele in ERCC4-rs744154 with breast cancer risk for both BRCA1 (HR: 0.78, 95% CI: 0.60 -1.00, P ¼ 0.05) and BRCA2 (HR: 0.68, 95% CI: 0.45 -1.02, P ¼ 0.06) mutation carriers. As this result was consistent with our previously reported protective association in the general population (Milne et al, 2006), we genotyped this SNP in subjects from the remaining CIMBA studies and repeated the analysis in the combined series of 9408 BRCA1 and 5632 BRCA2 mutation carriers (see Table 2). However, when the whole CIMBA series was analysed (stage II), there was no longer evidence of an association with breast cancer risk for either BRCA1 (HR: 0.98, 95% CI: 0.93 - 1.04, P ¼ 0.5) or BRCA2 (HR: 0.97, 95% CI: 0.89 -1.06, P ¼ 0.5) mutation carriers.…”

“…This has been confirmed in a recent report from CIMBA in which minor alleles in three SNPs in the FGFR2, TNRC9 and MAP3K1 genes, previously found to be associated with increased breast cancer risk in the general population , were found to increase breast cancer risk in BRCA1 and/or BRCA2 mutation carriers as well . We therefore aimed to investigate the role of the rs744154 SNP in ERCC4 as a potential BRCA1/BRCA2 risk modifier, based on our earlier finding that the minor G allele was associated with breast cancer protection in the general population (OR under a recessive model 0.61; P ¼ 0.0002) (Milne et al, 2006).…”

“…We previously reported that the minor G allele in a SNP on intron 1 of ERCC4 (rs744154) was associated with protection from breast cancer in the general population (OR under a recessive model 0.61; P ¼ 0.0002) (Milne et al, 2006). On the basis of this finding, we aimed to assess ERCC4-rs744154 as a breast cancer risk modifier in BRCA1 and BRCA2 mutation carriers.…”

Common variations in ERCC2 are associated with response to cisplatin chemotherapy and clinical outcome in osteosarcoma patients

“…We only observed a tendency towards an increased risk of poor tumor response and reduced EFS in patients carriers of the polymorphic alleles for ERCC1 Lys504Gln and ERCC1 Asn118Asn polymorphisms, but without reaching the statistical significance in none of the cases. The rest of variants analyzed in XPA, ERCC5 and ERCC4 genes were included in this study since previously described as cancer risk related variants 24,30,31 that could be an indication of the implication of these variants in DNA repair efficiency. Despite so, we have not found any evidence of association with cisplatin response.…”

“…All these SNPs have been related to platinum and radiotherapy response and/or risk of cancer in other type of tumors. [9][10][11][12]24,30,31 Genotypes were determined by TaqMan SNP Genotyping Assays (Applied Biosystems, Foster City, CA, USA) for all SNPs, except rs1800975 (or which the KASPar SNP genotyping system was used (KBioscience, Hoddesdon, UK). Allelic discrimination was carried out using the ABI PRISM 7900 Sequence Detection System (Applied Biosystems).…”