DNA repair polymorphisms and risk of colorectal adenomatous or hyperplastic polyps.
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.
Bigler
Jeannette
J
Cancer Prevention Program, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, M5-A864, Seattle, WA 98109, USA. jbigler@fhcrc.org
Ulrich
Cornelia M
CM
Kawashima
Toana
T
Whitton
John
J
Potter
John D
JD
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
D002273:Carcinogens; D019853:O(6)-Methylguanine-DNA Methyltransferase; D051759:Xeroderma Pigmentosum Group D Protein; C497292:ERCC2 protein, human