DNA Repair Gene Variants Associated with Benign Breast Disease in High Cancer Risk Women

Department of Radiation Medicine, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia, USA.
Cancer Epidemiology Biomarkers & Prevention (Impact Factor: 4.13). 02/2009; 18(1):346-50. DOI: 10.1158/1055-9965.EPI-08-0659
Source: PubMed


Benign breast disease (BBD) is a risk factor for breast cancer and may have a heritable component. Deficient DNA repair has been implicated in breast cancer etiology and may exert its effect before BBD, a known precursor. The association between allelic variants in DNA repair genes and BBD was examined in a cohort of women in Washington County, Maryland. BBD was defined by two criteria: (a) a physician diagnosis of BBD or fibrocystic disease and/or (b) a benign breast biopsy. 3,212 women without BBD at baseline were genotyped for 12 candidate single nucleotide polymorphisms in seven DNA repair genes. Of these women, 482 subsequently reported a diagnosis of BBD. The Cox model was used to calculate hazard ratios (HR). Variant alleles of XRCC1 Arg(194)Trp (rs1799782) and ERCC4 Arg(415)Gln (rs1800067) were significantly associated with BBD [HR, 1.36; 95% confidence interval (95% CI), 1.06-1.74 and HR, 1.39; 95% CI, 1.09-1.76, respectively]. Similar estimates were also observed for each of the BBD criterion used. The BBD association for ERCC4 was even stronger among women with a family history of breast cancer (HR, 2.68; 95% CI, 1.52-4.66; P(interaction) = 0.02). This study suggests that variant alleles in DNA repair genes may modify BBD risk, a potential intermediate marker of breast cancer risk, particularly among high-risk subgroups.

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Available from: Kathy Helzlsouer, Jul 30, 2014
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    • "Earlier, Shen and colleagues [19] had identified three polymorphisms in the coding region of XRCC1, i.e., at codon 194 (Arg to Trp; UniProt ID: VAR_013400), at codon 280 (Arg to His; UniProt ID: VAR_013401), and at codon 399 (Arg to Gln; UniProt ID: VAR_011487). Studies have associated these three polymorphisms with breast cancer [20] and lung cancer [21,22]. To our knowledge, however, apart from the studies on Iranian population, attempts have not been made to explore the possible association of XRCC1 with schizophrenia in any other population. "
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    ABSTRACT: This paper depicts the first report from an Indian population on the association between the variant Arg399Gln of XRCC1 locus in the DNA repair system and schizophrenia, the debilitating disease that affects 1% of the world population. Genotypic analysis of a total of 523 subjects (260 patients and 263 controls) revealed an overwhelming presence of Gln399Gln in the case subjects against the controls (P < 0.0068), indicating significant level of association of this nsSNP with schizophrenia; the Gln399 allele frequency was also perceptibly more in cases than in controls (p < 0.003; OR=1.448). The results of the genotypic studies were further validated using pathogenicity and stability prediction analysis employing computational tools [I-Mutant Suite, iStable, PolyPhen2, SNAP, and PROVEAN], with a view to assess the magnitude of deleteriousness of the mutation. The pathogenicity analysis reveals that the nsSNP could be deleterious inasmuch as it could affect the functionality of the gene, and interfere with protein function. Molecular dynamics simulation of 60ns was performed using GROMACS to analyse structural change due to a mutation (Arg399Gln) that was never examined before. RMSD, RMSF, hydrogen bonds, radius of gyration and SASA analysis showed the existence of a significant difference between the native and the mutant protein. The present study gives a strong indication that the XRCC1 locus deserves serious attention, as it could be a potential candidate contributing to the etiopathogenesis of the disease.
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    ABSTRACT: X-ray repair cross-complementing group 1 (XRCC1) plays an important role in base excision and single-strand break repair, as a scaffold protein that brings together proteins of the DNA repair complex, and appears to be a candidate for cancer risk. However, studies on the association between polymorphisms in this protein and cancer have yielded conflicting results. We performed a meta-analysis to investigate the association between the breast cancer and the XRCC1 polymorphisms Arg194Trp (9411 cases and 9783 controls), Arg399Gln (22 481 cases and 23 905 controls) and Arg280His (6062 cases and 5864 controls) in different inheritance models. Our analysis suggested that Arg399Gln was associated with a trend of increased breast cancer risk when using both dominant [odds ratio (OR) = 1.06, 95% confidence interval (CI): 1.00–1.13] and recessive models (OR = 1.12, 95% CI: 1.02–1.23) to analyse the data. In ethnic subgroups and using recessive model analysis: Arg399Gln increased breast cancer risk in Asians (OR = 1.26, 95% CI: 0.96–1.64) and Africans (OR = 1.80, 95% CI: 0.97–3.32), and also while only slightly increasing the breast cancer risk in Caucasians (OR = 1.08, 95% CI: 0.95–1.22). However, Arg194Trp (recessive model, OR = 0.95, 95% CI: 0.75–1.20) and Arg280His (recessive model, OR = 1.28, 95% CI: 0.64–2.55) did not appear to be risk factors for breast cancer. Larger scale primary studies are required to further evaluate the interaction of XRCC1 polymorphisms and breast cancer risk in specific populations.
    Preview · Article · Jun 2009 · Mutagenesis
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    ABSTRACT: The possible role for DNA repair deficiencies in cancer development, namely in breast cancer has been the subject of increasing interest since it has been reported that breast cancer patients might be deficient in the repair of DNA damage. Exposure to ionizing radiation has been pointed out as a risk factor for breast cancer, and the type of DNA lesions induced by this carcinogen can be repaired by homologous recombination DNA repair (HRR) pathway. To evaluate the potential modifying role of some single nucleotide polymorphisms (SNP) in HRR involved genes on the individual susceptibility to breast cancer we carried out a hospital based case–control study in a Caucasian Portuguese population (289 histological confirmed breast cancer patients and 548 control individuals). We genotyped 4 SNPs in 4 different HRR pathway genes, XRCC2 (Ex3 + 442G > A, R188H, rs3218536), XRCC3 (Ex8-5C > T, T241M, rs861539), NBS1 (Ex5-32C > G, E185Q, rs1805794) and RAD51 5′UTR (Ex1-59G > T, rs1801321), tagging 41 SNPs in these genes. The frequency of the different polymorphisms in the Portuguese control population is similar to the ones reported for other Caucasian populations, and the deviation of the Hardy–Weinberg equilibrium was only observed for the XRCC2 (Ex3 + 442G > A, R188H, rs3218536) polymorphism in the control population. The results obtained, after logistic regression analysis, did not reveal a major role of these polymorphisms on breast cancer susceptibility. However, when the population was stratified according to breast feeding (women that breast fed and women that never breast fed) it is observed, in women that never breast fed, that the heterozygous individuals for the XRCC2 (Ex3 + 442G > A, R188H, rs3218536) polymorphism have a decreased risk for breast cancer [adjusted OR = 0.45; 95% CI = 0.22–0.92] (P = 0.03). Additionally, after stratification according to menopausal status, our results suggest that post-menopausal women carrying at least one variant allele for the XRCC3 (Ex8-5C > T, T241M, rs861539) polymorphism have a lower risk for breast cancer [adjusted OR = 0.67; 95% CI, 0.47–0.94] (P = 0.03). Most of the studies suggest that breastfeeding may be responsible for 2/3 of the estimate reduction of breast cancer. The longer the duration of breastfeeding the lower the potential risk associated with breast cancer. Therefore, in our study the potential protective role of the variant allele of XRCC2 (Ex3 + 442G > A, R188H, rs3218536), in never breast fed women, might be related with a more efficient DNA repair activity.
    No preview · Article · Feb 2010
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