Assessing tumor mutations to gain insight into base excision repair sequence polymorphisms and smoking in colon cancer.
DNA repair enzymes function in major pathways to reverse DNA damage, including base excision repair (BER). Missense polymorphisms in BER repair genes may contribute to differences in DNA repair capacity, specific mutations, and susceptibility to cancer in the presence of exposure to carcinogens such as cigarette smoking. In a study of 1,604 incident colon cancer cases and 1,969 matched population-based controls genotyped for BER variants OGG1 (S326C) and XRCC1 (R194W, R280H, and R399Q), we found no associations with colon cancer overall. However, a 2-fold increased risk of BRAF V600E tumor mutation was observed in current and former cigarette smokers homozygous for the OGG1 polymorphism (odds ratio, 2.2; 95% confidence interval, 1.02-4.9, recessive model); similar associations were not observed for microsatellite instability, CpG island methylator phenotype, KRAS2 mutations, or TP53 mutations. The XRCC1 R194W polymorphism was associated with a modest increased risk of TP53 tumor mutations in those who regularly smoked cigarettes (odds ratio, 1.4; 95% confidence interval, 1.02-1.9). These findings point to the importance of studying tumor mutations when examining DNA repair polymorphisms and cigarette smoke exposure to identify potentially relevant associations with colorectal cancer.
Curtin
Karen
K
Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City, 84132, USA. karen.curtin@hsc.utah.edu
Samowitz
Wade S
WS
Wolff
Roger K
RK
Ulrich
Cornelia M
CM
Caan
Bette J
BJ
Potter
John D
JD
Slattery
Martha L
ML
D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D003110:Colonic Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D018899:CpG Islands; D045647:DNA Glycosylases / Q000235:genetics; D019175:DNA Methylation; D004260:DNA Repair / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D011110:Polymorphism, Genetic / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D012307:Risk Factors; D012907:Smoking / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D000076105:X-ray Repair Cross Complementing Protein 1; D018631:ras Proteins / Q000235:genetics
D004268:DNA-Binding Proteins; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D000076105:X-ray Repair Cross Complementing Protein 1; C000619371:XRCC1 protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D045647:DNA Glycosylases; C479058:oxoguanine glycosylase 1, human; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D045643:DNA Repair Enzymes