Meta Association of Colorectal Cancer Confirms Risk Alleles at 8q24 and 18q21
ABSTRACT 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.
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.
At 8q24, we observed two independent significant associations at single nucleotide polymorphisms located in two different risk regions of 8q24: rs6983267 in region 3 [P(trend) = 0.01; per allele odds ratio (OR), 1.17; 95% confidence intervals (95% CI), 1.03-1.32] and rs10090154 in region 5 (P(trend) = 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 (P(trend) = 0.007; per allele OR, 0.77; 95% CI, 0.64-0.93; case-case p(diff) = 0.03) and rs12953717 (P(trend) = 0.01; per allele OR, 1.27; 95% CI, 1.06-1.52). We were unable to detect any associations at 9p24 with CRC.
Our investigation confirms that variants across multiple risk regions of 8q24 are associated with CRC, and that associations at 18q21 differ by tumor site.
Full-textDOI: · Available from: Lisa A Cannon-Albright, Jun 17, 2015
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ABSTRACT: A genome-wide association study (GWAS), which assessed multiple ethnicities, reported an association between single nucleotide polymorphisms in the 8q24 region and colorectal cancer risk. Although the association with the identified loci was strong, information on its impact in combination with lifestyle factors is limited. We conducted a case-control study in 481 patients with colorectal cancer (CRC) and 962 sex-age matched non-cancer controls. Data on lifestyle factors, including diet, were obtained by self-administered questionnaire. Two 8q24 loci, rs6983267 and rs10090154, were assessed by the TaqMan method. Associations were then assessed by multivariate logistic regression models that considered potential confounders. We found an increased risk of CRC with rs6983267 but not with rs10090154. An allelic OR was 1.22 (1.04-1.44, p for trend = 0.014), which remained significant after adjustment for confounders (OR = 1.25). No statistically significant interaction with potential confounding factors was observed. The polymorphism rs6983267 showed a significant association with CRC in a Japanese population. Further investigation of the biological mechanism of this association is warranted.BMC Cancer 10/2009; 9(1):379. DOI:10.1186/1471-2407-9-379 · 3.32 Impact Factor
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ABSTRACT: Recently, several genome-wide association studies (GWAS) have independently found numerous loci at which common single-nucleotide polymorphisms (SNPs) modestly influence the risk of developing colorectal cancer. The aim of this study was to test 11 loci, reported to be associated with an increased or decreased risk of colorectal cancer: 8q23.3 (rs16892766), 8q24.21 (rs6983267), 9p24 (rs719725), 10p14 (rs10795668), 11q23.1 (rs3802842), 14q22.2 (rs4444235), 15q13.3 (rs4779584), 16q22.1 (rs9929218), 18q21.1 (rs4939827), 19q13.1 (rs10411210) and 20p12.3 (rs961253), in a Swedish-based cohort. The cohort was composed of 1786 cases and 1749 controls that were genotyped and analysed statistically. Genotype-phenotype analysis, for all 11 SNPs and sex, age of onset, family history of CRC and tumour location, was performed. Of eleven loci, 5 showed statistically significant odds ratios similar to previously published findings: 8q23.3, 8q24.21, 10p14, 15q13.3 and 18q21.1. The remaining loci 11q23.1, 16q22.1, 19q13.1 and 20p12.3 showed weak trends but somehow similar to what was previously published. The loci 9p24 and 14q22.2 could not be confirmed. We show a higher number of risk alleles in affected individuals compared to controls. Four statistically significant genotype-phenotype associations were found; the G allele of rs6983267 was associated to older age, the G allele of rs1075668 was associated with a younger age and sporadic cases, and the T allele of rs10411210 was associated with younger age. Our study, using a Swedish population, supports most genetic variants published in GWAS. More studies are needed to validate the genotype-phenotype correlations.British Journal of Cancer 08/2010; 103(4):575-80. DOI:10.1038/sj.bjc.6605774 · 4.82 Impact Factor
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ABSTRACT: The SMAD7 gene was recently identified to be associated with colorectal cancer risk. Smad7 protein is a known inhibitor of TGF-β signalling pathway which has a prominent role in tumorigenesis. MGMT gene regulates the direct damage reversal repair pathway, preventing DNA damage and potential cancer development. This exploratory study aims to investigate the association between SMAD7 (rs4464148, rs4939827) and MGMT (rs12917, rs2308321) genotype variants, and all-cancer incidence. Our study population was a sub-cohort of the EPIC-Norfolk study, a prospective cohort of approximately 25,000 men and women aged 40-79. Between recruitment 1993-1997 and follow-up to 2006, 192 incident cases and 1155 non-cases with genotype data were identified. Baseline 7-day food diary and health/lifestyle questionnaire data were analysed. SMAD7 rs4464148 variant genotype was associated with increased cancer incidence [HR=1.34, 95%CI=1.00-1.80] but no overall association for SMAD7 rs4939827 or MGMT genotypes. Participants with variant genotypes in both SMAD7 SNPs had a higher cancer incidence compared to those without any (HR=2.74, 95%CI=1.10-6.79) (P=0.03; P(trend)=0.01). Amongst the younger age participants (<mean 62 years), SMAD7 rs4464148 variant genotype group had higher HR of 1.71 (95%CI=1.03-2.83) compared to the non-variant genotype group. These findings suggest that SMAD7 rs4464148 common variant genotype is associated with cancer incidence but not SMAD7 rs4939827, MGMT rs12917 or MGMT rs2308321. A combination of variants of the SMAD7 SNPs may be associated with increased cancer risk in this study population. However, these findings need to be replicated in larger studies and in studies of specific cancer sites.11/2010; 35(4):369-74. DOI:10.1016/j.canep.2010.09.011