title: DNA repair polymorphisms and risk of colorectal adenomatous or hyperplastic polyps.
abstract: Genetic variability in DNA repair genes may contribute to differences in DNA repair capacity and susceptibility to cancer, especially in the presence of exposures such as smoking. In a Minnesota-based case-control study of cases with only adenomatous polyps (n = 384), only hyperplastic polyps (n = 191), or both types of polyps (n = 119) versus polyp-free controls (n = 601), we investigated the role of polymorphisms in the DNA repair genes O(6)-methylguanine methyltransferase (MGMT; p.L84F and p.I143V), XPD (p.D312N and p.K751Q), and XPG (p.D1104H). MGMT polymorphisms were not associated with polyp risk. Overall, a homozygous variant XPD-combined genotype was associated with an increased risk of adenomatous polyps [odds ratio (OR), 1.57; 95% confidence interval (95% CI), 1.04-2.38] and an XPGHH1104 genotype with a decreased risk of hyperplastic polyps (OR, 0.36; 95% CI, 0.13-0.98). However, age stratification showed that the XPD association was present only in subjects >/=60 years old (OR, 3.77; 95% CI, 1.94-7.35), whereas the XPG association was observed largely in subjects <60 years old (OR, 0.20; 95% CI, 0.05-0.91). Smokers did not have a significantly increased risk of adenomatous polyps in the absence of synchronous hyperplastic polyps, except for subjects with a homozygous variant XPD genotype or a homozygous wild-type XPG genotype (OR, 3.93; 95% CI, 1.68-9.21 and OR, 1.59; 95% CI, 1.01-2.50, respectively). Smoking was associated with a statistically significant 2.5- to 6-fold increased risk of hyperplastic polyps for individuals with most of the DNA repair genotypes. However, no substantial increase was observed among individuals who were homozygous variant for XPG (1104HH; OR, 1.38; 95% CI, 0.25-7.65). Our data suggest that polymorphisms in DNA repair genes may be risk factors for colorectal neoplasia and that they may exacerbate the effects of exposures to carcinogens.
authors.affiliation: Cancer Prevention Program, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, M5-A864, Seattle, WA 98109, USA. jbigler@fhcrc.org
authors.forename: Jeannette
authors.initials: J
authors.lastname: Bigler
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: Ulrich
authors.forename: Toana
authors.initials: T
authors.lastname: Kawashima
authors.forename: John
authors.initials: J
authors.lastname: Whitton
authors.forename: John D
authors.initials: JD
authors.lastname: Potter
mesh_terms: D000236:Adenoma / Q000150:complications / Q000209:etiology* / Q000235:genetics*; D000328:Adult; D000367:Age Factors; D000368:Aged; D002273:Carcinogens / Q000633:toxicity; D016022:Case-Control Studies; D003111:Colonic Polyps / Q000150:complications / Q000209:etiology* / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000209:etiology / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D006965:Hyperplasia; D008297:Male; D008875:Middle Aged; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000235:genetics; D011110:Polymorphism, Genetic; D012307:Risk Factors; D051759:Xeroderma Pigmentosum Group D Protein / Q000235:genetics
chemical_list: D002273:Carcinogens; D019853:O(6)-Methylguanine-DNA Methyltransferase; D051759:Xeroderma Pigmentosum Group D Protein; C497292:ERCC2 protein, human