Selected polymorphisms of DNA repair genes and risk of pancreatic cancer.
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Bondy, Melissa L.
Hassan, Manal M.
Wolff, Robert A.
Evans, Douglas B.
Abbruzzese, James L.
MetadataShow full item record
AbstractBACKGROUND: Genetic variants of DNA repair genes may contribute to pancreatic carcinogenesis. O(6)-methylguanine-DNA methyltransferase (MGMT) is the major protein that removes alkylating DNA adducts, and apurinic/apyrimidinic endonuclease 1 (APE1) and X-ray repair cross-complementing group 1 (XRCC1) play important roles in the base excision repair pathway. METHODS: We investigated the association between polymorphisms of MGMT (Leu(84)Phe and Ile(143)Val), APE1 (Asp(148)Glu), and XRCC1 (Arg(194)Trp and Arg(399)Gln) and risk of pancreatic cancer in a case-control study. Exposure information from 384 patients with primary pancreatic ductal adenocarcinoma and 357 cancer-free healthy controls were collected and genomic DNAs were genotyped for five markers. Controls were frequency matched to patients by age at enrollment (+/-5 years), gender, and race. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) by using unconditional logistic regression models. RESULTS: There was no significant main effect or interaction with smoking of these genetic variants on the risk of pancreatic cancer. However, the XRCC1(194) polymorphism had a significant interaction with the APE1(148) (p=0.005) or MGMT(84) polymorphism (p=0.02) in modifying the risk of pancreatic cancer. CONCLUSIONS: This study suggests that polymorphisms of genes involved in the repair of alkylating DNA adduct and DNA base damage may play a role in modulating the risk of pancreatic cancer. Larger studies are required to validate these preliminary findings. The mechanism of the combined genotype effects remains to be elucidated.
CitationCancer Detect. Prev. 2006, 30 (3):284-291
JournalCancer Detection and Prevention
DescriptionBiomarkers of individual susceptibility: field studies. Biomarker : polymorphisms of MGMT [Leu(84)Phe and Ile(143)Val]; APE1 [Asp(148)Glu]; XRCC1 [Arg(194)Trp and Arg(399)Gln]Effect studied: pancreatic cancer risk. Tissue/biological material/sample size: blood. Method of analysis: MGMT143 polymorphism: PCR/SSCP; XRCC1399: PCR/RFLPStudy design: case-control study Study size: 384 cases and 357 controls. Impact on outcome (including dose-response): No significant main effect or interaction with smoking of any of the studied variants on cancer risk; however, significant gene-gene interactions were observed between XRCC1(194) and APE1(148) or MGMT(84): a) OR=4.98 (95% CI: 1.61-15.4) for individuals carrying at least one copy of the XRCC1194Trp allele and APE1 Asp148Asp relative to those carrying both the XRCC1 Arg194Arg and APE1 Asp148Asp wild type; b) OR=3.04 (95% CI: 1.14-7.87) for individuals carrying at least one copy of the XRCC1194Trp allele and at least one copy of the variant MGMT 84Phe allele relative to those carrying both the XRCC1 Arg194Arg and MGMT Leu84Leu wild type;Quality control: The SSCP results for MGMT143 were verified by direct DNA sequencing of 1% of the samples. KEYWORD-CLASSIFICATION: Adult;Aged;Alleles;analysis;biomarkers of individual susceptibility: field studies;blood;DNA Repair;Environment;Female;field studies;genetic;Genetic Predisposition to Disease;genetics;Humans;Male;Medical Oncology;metabolism;Middle Aged;O(6)-Methylguanine-DNA Methyltransferase;Pancreatic Neoplasms;Polymorphism,Genetic;Polymorphism,Single Nucleotide;Research;Risk;Smoking;