Interindividual Variation in Nucleotide Excision Repair Genes and Risk of Endometrial Cancer

Abstract

Exposure to estrogens is a likely cause of endometrial cancer, but the means by which estrogens exert this effect are not entirely clear. One hypothesis is that certain estrogen metabolites bind to the DNA, forming bulky adducts that damage the DNA and initiate carcinogenesis. A woman's reduced capacity to repair such damage may increase her risk of endometrial cancer. We conducted a population-based case-control study in western Washington State to address the role of variation in nucleotide excision repair genes on the risk of endometrial cancer. Case women (n = 371), ages 50 to 69 years, were diagnosed with invasive endometrial cancer between 1994 and 1999. Control women (n = 420) were selected using random-digit dialing (ages 50-65 years) and by random selection from Health Care Financing Administration data files (ages 66-69 years). Genotyping assays were done for ERCC1, ERCC2 (XPD), ERCC4 (XPF), ERCC5 (XPG), XPA, and XPC. No appreciable differences between cases and controls were observed in the genotype distributions of ERCC1 (c8092a and c19007t), ERCC2 (D312N, K751Q, and c22541a), ERCC4 (R415Q and t30028c), or ERCC5 (D1104H). Carriage of at least one variant allele for XPA G23A was associated with decreased risk of endometrial cancer [odds ratio (OR), 0.70; 95% confidence interval (95% CI), 0.53-0.93]. Carriage of at least one XPC A499V variant allele was associated with a modest decrease in risk (OR, 0.79; 95% CI, 0.59-1.05). Women with variant alleles at both XPC A499V and K939Q had 58% of the risk of women with no XPC variant alleles (OR, 0.58; 95% CI, 0.35-0.96). Our data suggest that interindividual variation in XPA and XPC influences a woman's risk of endometrial cancer. (Cancer Epidemiol Biomarkers Prev 2005;14(11):2524 -30)

Modulation of DNA damage/DNA repair capacity by XPC polymorphisms

“…We found a decreased risk of bladder cancer in subjects carrying the variant allele of this polymorphism [38]. In an endometrial cancer study, Weiss et al [15] observed a borderline protective effect of the variant T allele. Huang et al [16] also reported a protective effect of the variant allele on the risk of advanced colorectal cancer.…”

“…In our previous study [38], the haplotype "T-A" was borderline protective against bladder cancer. Weiss et al [15] found a marginally reduced risk of endometrial cancer in subjects with the variant allele (T) of Ala499Val and the wild-type allele (A) of the Lys939Gln. Huang et al [16] reported that ever smokers carrying the 499T and 939A alleles exhibited a decreased colorectal cancer risk.…”

“…AC090645). More than a hundred polymorphic variants in the XPC gene have been identified and the three most common polymorphisms are Ala499Val (C→T), PAT (-/+), and Lys939Gln (A→C), which have been associated with risks of many human malignancies, including cancers of lung, bladder, breast, esophagus, skin, oral cavity, and head and neck [8][9][10][11][12][13][14][15][16]. The PAT+ polymorphism was associated with increased risks of skin [8,9], head and neck [11], and esophageal cancer [17].…”

“…The variant allele of Lys939Gln (A→C) was also associated with increased risks of skin [9], breast [14], and bladder cancers [12,18]. Although the variant allele of Ala499Val was reported to be a risk allele for lung cancer [19], it was found to be protective against cancers of colorectum [16] and endometrium [15]. A potential rationale behind these gene-cancer risk associations is that these genetic variants may result in alterations in phenotypes like DNA repair capacity (DRC).…”

Xeroderma pigmentosum complementation group C single‐nucleotide polymorphisms in the nucleotide excision repair pathway correlate with prolonged progression‐free survival in advanced ovarian cancer

“…The resultant gap is filled in by DNA polymerase using the intact strand as a template. 16 Each step in the NER pathway has the potential for genetic variation through SNPs causing alteration in DNA repair activity.…”