A Role for XRCC4 in Age at Diagnosis and Breast Cancer Risk

Abstract

Genetic variants in DNA repair genes influence the ability to repair damaged DNA. Unrepaired or improperly repaired DNA may lead to genetic instability and carcinogenesis. We evaluated the role of four tagging single nucleotide polymorphisms (tSNP) in the DNA repair gene, XRCC4, and its association with breast cancer risk and age at diagnosis of breast cancer in 464 cases and 576 controls selected to be BRCA1/2 mutation negative from high-risk Utah pedigrees. We observed a significant association for two 4-locus tSNP haplotypes and age at diagnosis. Carriage of one haplotype was associated with later diagnosis (haplotype frequency, 0.039; mean age at diagnosis, 67.17 years; P = 0.001), and carriage of the other was associated with earlier diagnosis (haplotype frequency, 0.214; mean age at diagnosis, 54.04 years; P = 0.0085). For breast cancer risk, two 2-locus tSNP haplotypes explained the observed association as well as extended four-locus haplotypes. The two 2-locus haplotypes were nominally associated with breast cancer risk, one for reduced risk (odds ratio, 0.57; 95% confidence interval, 0.36-0.90; P = 0.014) and one for increased risk (odds ratio, 1.30; 95% confidence interval, 1.02-1.67; P = 0.033). Moreover, one of the tSNPs is in strong linkage disequilibrium (D ¶ = 1.00) with an XRCC4 SNP found to be significantly associated with breast cancer risk in Taiwan, hence, confirming their findings. Our results suggest that XRCC4 may play a role in the age at diagnosis and risk of breast cancer in non-BRCA1/2, heritable breast cancer cases. (Cancer Epidemiol Biomarkers Prev 2006;15(7):1306-10)

Genotype and Haplotype Analyses of TP53 Gene in Breast Cancer Patients: Association with Risk and Clinical Outcomes

“…To date, GWAS conducted for BC have identified more than 80 breast cancer susceptibility loci (all summarized in [ 3 ]). Although, several candidate gene association studies for BC have been conducted during the last decade [ 4 – 10 ], many of them were underpowered due to small sample size, resulting in inconsistent and not reproducible findings [ 11 , 12 ]. To date, only one polymorphism located in the coding region of CASP8 (rs1045485) has shown promise as a breast cancer predisposition risk factor [ 3 , 13 ].…”

A recessive variant of XRCC4 predisposes to non-BRCA1/2 breast cancer in chinese women and impairs the DNA damage response via dysregulated nuclear localization

“…Large studies on the role of XRCC4 single-nucleotide polymorphisms (SNPs) in cancer susceptibility have been performed in hepatocellular carcinoma [ 17 ], lung cancer [ 18 ], multiple myeloma [ 19 ], and oral cancer [ 20 ]. Notably, there have only been a few studies on the associations between genetic variants of XRCC4 and breast cancer susceptibility; these studies were performed regardless of the BRCA1/2 status, and the results were inconclusive [ 21 - 23 ]. Furthermore, the biological underpinnings of these genetic associations have not yet been well established.…”

DNA double-strand break repair genotype and phenotype and breast cancer risk within sisters from the New York site of the Breast Cancer Family Registry (BCFR)

“…A study conducted in Taiwan among Asian women found that carrying an increasing number of variant alleles in XRCC4 was associated with higher disease risk [8]. Another study found associations of XRCC4 haplotypes with age at diagnosis of BC and risk in non-BRCA1/2 heritable individuals [16]. In the current study, we examined six SNPs in XRCC4.…”