title: Genetic variants in XRCC2: new insights into colorectal cancer tumorigenesis.
abstract: Polymorphisms in DNA double-strand break repair gene XRCC2 may play an important role in colorectal cancer etiology, specifically in disease subtypes. Associations of XRCC2 variants and colorectal cancer were investigated by tumor site and tumor instability status in a four-center collaboration including three U.K. case-control studies (Sheffield, Leeds, and Dundee) and a U.S. case-control study of cases from high-risk Utah pedigrees (total: 1,252 cases and 1,422 controls). The 14 variants studied were tagging single nucleotide polymorphisms (SNP) selected from National Institute of Environmental Health Sciences/HapMap data supplemented with SNPs identified from sequencing of 125 cases chosen to represent multiple colorectal cancer groups (familial, metastatic disease, and tumor subsite). Monte Carlo significance testing using Genie software provided valid meta-analyses of the total resource that includes family-based data. Similar to reports of colorectal cancer and other cancer sites, the rs3218536 R188H allele was not associated with increased risk. However, we observed a novel, highly significant association of a common SNP, rs3218499G>C, with increased risk of rectal tumors (odds ratio, 2.1; 95% confidence interval, 1.3-3.3; P(chi2) = 0.0006) versus controls, with the largest risk found for female rectal cases (odds ratio, 3.1; 95% confidence interval, 1.6-6.1; P(chi2) = 0.0006). This difference was significantly different to that for proximal and distal colon cancers (P(chi2) = 0.02). Our investigation supports a role for XRCC2 in colorectal cancer tumorigenesis, conferring susceptibility to rectal tumors.
authors.affiliation: Genetic Epidemiology, University of Utah School of Medicine, 391 Chipeta Way Suite D2, Salt Lake City, UT 84108, USA. karen.curtin@hsc.utah.edu
authors.forename: Karen
authors.initials: K
authors.lastname: Curtin
authors.forename: Wei-Yu
authors.initials: WY
authors.lastname: Lin
authors.forename: Rina
authors.initials: R
authors.lastname: George
authors.forename: Mark
authors.initials: M
authors.lastname: Katory
authors.forename: Jennifer
authors.initials: J
authors.lastname: Shorto
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Cannon-Albright
authors.forename: Gillian
authors.initials: G
authors.lastname: Smith
authors.forename: D Timothy
authors.initials: DT
authors.lastname: Bishop
authors.forename: Angela
authors.initials: A
authors.lastname: Cox
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Camp
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
chemical_list: D004268:DNA-Binding Proteins; C113187:XRCC2 protein, human
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