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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; Pχ2 = 0.0006) versus controls, with the largest risk found for female rectal cases (odds ratio, 3.1; 95% confidence interval, 1.6-6.1; Pχ2 = 0.0006). This difference was significantly different to that for proximal and distal colon cancers (Pχ2 = 0.02). Our investigation supports a role for XRCC2 in colorectal cancer tumorigenesis, conferring susceptibility to rectal tumors. (Cancer Epidemiol Biomarkers Prev 2009;18(9):2476–84)

Background: Genome-wide association studies of colorectal cancer (CRC) have identified genetic variants that reproducibly associate with CRC. Associations of 12 single nucleotide polymorphisms at 8q24, 9p24, and 18q21 (SMAD7) and CRC were investigated in a three-center collaborative study including two U.K. case-control cohorts (Sheffield and Leeds) and a U.S. case-control study of CRC cases from high-risk Utah pedigrees. Methods: Our combined resource included 1,092 CRC case subjects and 1,060 age- and sex-matched controls. Meta statistics and Monte Carlo significance testing using Genie software provided a valid combined analysis of our mixed independent and related case-control resource. We also evaluated whether these associations differed by sex, age at diagnosis, family history, or tumor site. Results: At 8q24, we observed two independent significant associations at single nucleotide polymorphisms located in two different risk regions of 8q24: rs6983267 in region 3 [Ptrend = 0.01; per allele odds ratio (OR), 1.17; 95% confidence intervals (95% CI), 1.03-1.32] and rs10090154 in region 5 (Ptrend = 0.05; per allele OR, 1.24; 95% CI, 1.01-1.51). At 18q21, associations were observed in distal colon tumors but not in proximal or rectal cancers: rs4939827 (Ptrend = 0.007; per allele OR, 0.77; 95% CI, 0.64-0.93; case-case pdiff = 0.03) and rs12953717 (Ptrend = 0.01; per allele OR, 1.27; 95% CI, 1.06-1.52). We were unable to detect any associations at 9p24 with CRC. Conclusions: Our investigation confirms that variants across multiple risk regions of 8q24 are associated with CRC, and that associations at 18q21 differ by tumor site. (Cancer Epidemiol Biomarkers Prev 2009;18(2):616–21)

Evidence of genotype specific selection at the BRCA2 polymorphism N372H was originally reported by Healey et al.1 These workers found significant evidence of a heterozygous excess in women control samples when studying the polymorphism for breast cancer association. They then genotyped a large series of newborn boys and girls to examine if this effect was also seen at birth. The newborn girls were consistent with the women but the newborn boys were significantly different. The genotypes in the boys appeared to demonstrate a significant deficit of heterozygotes. Healey et al suggested that sex differential viabilities resulted in a stable allele frequency, but this was not formally investigated. We wanted to explore further this apparent sex specific selection in two ways; to refine the estimates of fitness, and we examined the mathematical properties of the sex specific selection model to determine if the data were consistent with a stable equilibrium. Three control populations were available for additional genotyping. These were blood donors, colon cancer controls, and mammography screening control women. Anonymous blood donors were recruited from the Sheffield Blood Transfusion Service in 1996, and their ages and sexes were recorded. Blood DNA samples were obtained for the mammography screening series of controls from white women attending for routine mammography screening at the Sheffield Breast Screening Service between September 2000 and August 2002. Women’s DNA samples were included in the study if the mammogram showed no evidence of a breast lesion. All women resident in Sheffield and on the Community Health Index, who are between the ages of 50 and 65, are invited to attend for screening every three years, and the uptake in Sheffield is 81.2%. Ethical approval for this study was obtained from the South Sheffield Research Ethics Committee and informed written consent was obtained from all subjects. Colon …