A potential role for the XRCC2 R188H polymorphic site in DNA-damage repair and breast cancer

Abstract

An acquired genetic instability, resulting from the loss of some types of DNA repair, is an early event in the development of a subset of human cancers. The involvement of BRCA1 and BRCA2 in the homologous recombination repair (HRR) of double-strand breaks in DNA implicates this pathway in the suppression of breast cancer. A family of proteins related to human RAD51, including XRCC2, are essential components of this repair pathway. Using site-directed mutagenesis of XRCC2, we show that non-conservative substitution or deletion of amino acid 188 of XRCC2 can significantly affect cellular sensitivity to DNA damage, and that a polymorphic variant at this site (R188H ), present on 6% of chromosomes in the population, has a weak effect on damage sensitivity. We tested the hypothesis that the R188H polymorphism could be a low-penetrance susceptibility factor for breast cancer, by genotyping 521 women with breast cancer and a total of 895 control women. Carriage of the rare allele of XRCC2 R188H was associated with breast cancer overall [odds ratio 1.3; 95% confidence interval (CI) ¼ (1.0, 1.8)] and when younger-onset cases with a positive family history were compared with older controls with no family history [odds ratio 1.9; 95% CI ¼ (1.0, 3.8)]. These results support the hypothesis that subtle variation in DNA repair capacity may influence cancer susceptibility in the population.

Genetic Polymorphisms in the DNA Double-Strand Break Repair Genes XRCC3, XRCC2, and NBS1 Are Not Associated with Acute Side Effects of Radiotherapy in Breast Cancer Patients

“…Frequencies of rare alleles were 0.41, 0.07, and 0.32 for XRCC3 241 Met, XRCC2 188 His, and NBS1 185 Gln, respectively, consistent with published reports (0.39, XRCC3; 0.06, XRCC2; and 0.32, NBS1) in European populations (8,12,14). All genotype distributions were in Hardy-Weinberg equilibrium.…”

Influence of VEGF‐A gene variation and protein levels in breast cancer susceptibility and severity

“…We 15,16 have previously described the design and methodology of this case control study. Briefly, recruitment commenced in November 1998 and is ongoing.…”

“…15,16 Briefly, the case and control groups were all female Caucasians. Table II shows the demographic characteristics of the population under study.…”

Xrcc2 Modulates Spontaneous and Radiation-Induced Tumorigenesis in Apcmin/+ Mice

“…Very recently, analyses of germline mutations of RAD51C in breast and ovarian cancer pedigrees have established this HR repair gene as a cancer susceptibility gene (18). A marginally significant association of breast cancer susceptibility has also been found with a rare variant of XRCC2 (19,20), as well as a potential link to ionizing radiation exposure (21). Earlier studies using Brca1 heterozygous knockout mice showed small increases in incidence of mammary tumors when Trp53 was also compromised, and this was further increased by irradiation (22).…”