A genome-wide association study identifies colorectal cancer susceptibility loci on chromosomes 10p14 and 8q23.3

Lü

Molecular Cancer Research

et al. 2012

To identify the genetic determinants of colon tumorigenesis, 268 male mice from 33 inbred strains derived from different genealogies were treated with azoxymethane (AOM; 10 mg/kg) once a week for six weeks to induce colon tumors. Tumors were localized exclusively within the distal colon in each of the strains examined. Inbred mouse strains exhibit a large variability in genetic susceptibility to AOM-induced colon tumorigenesis. The mean colon tumor multiplicity ranged from 0 to 38.6 (mean ¼ 6.5 AE 8.6) and tumor volume ranged from 0 to 706.5 mm 3 (mean ¼ 87.4 AE 181.9) at 24 weeks after the first dose of AOM. AOM-induced colon tumor phenotypes are highly heritable in inbred mice, and 68.8% and 71.3% of total phenotypic variation in colon tumor multiplicity and tumor volume, respectively, are attributable to strain-dependent genetic background. Using 97,854 single-nucleotide polymorphisms, we carried out a genome-wide association study (GWAS) of AOM-induced colon tumorigenesis and identified a novel susceptibility locus on chromosome 15 (rs32359607, P ¼ 6.31 Â 10 -6 ). Subsequent fine mapping confirmed five (Scc3, Scc2, Scc12, Scc8, and Ccs1) of 16 linkage regions previously found to be associated with colon tumor susceptibility. These five loci were refined to less than 1 Mb genomic regions of interest. Major candidates in these loci are Sema5a, Fmn2, Grem2, Fap, Gsg1l, Xpo6, Rabep2, Eif3c, Unc5d, and Gpr65. In particular, the refined Scc3 locus shows high concordance with the human GWAS locus that underlies hereditary mixed polyposis syndrome. These findings increase our understanding of the complex genetics of colon tumorigenesis, and provide important insights into the pathways of colorectal cancer development and might ultimately lead to more effective individually targeted cancer prevention strategies. Mol Cancer Res; 10(1); 66-74. Ó2011 AACR.

Section: Introductionmentioning

confidence: 99%

Genome-Wide Association and Fine Mapping of Genetic Loci Predisposing to Colon Carcinogenesis in Mice

Lü

Molecular Cancer Research

et al. 2012

“…4 Loss of MMR frequently involves MLH1 gene promoter silencing and concomitant loss of protein expression, which gives rise to CRC predominantly in the proximal colon. In addition to rare constitutional mutations, MMR genes also contain common single nucleotide polymorphisms (SNP) which can predispose to nonfamilial CRC with low to moderate penetrance, [5][6][7] suggesting an important contribution of common genetic variants to the burden of CRC in the general population.…”

mentioning

confidence: 99%

MLH1 −93G>A promoter polymorphism and risk of mismatch repair deficient colorectal cancer

Allan

Shorto

Adlard

et al. 2008

Intl Journal of Cancer

Rare inherited mutations in the mutL homolog 1 (MLH1) DNA mismatch repair gene can confer an increased susceptibility to colorectal cancer (CRC) with high penetrance where disease frequently develops in the proximal colon. The core promoter of MLH1 contains a common single nucleotide polymorphism (SNP) (293G>A, dbSNP ID:rs1800734) located in a region essential for maximum transcriptional activity. We used logistic regression analysis to examine the association between this variant and risk of CRC in patients in the United Kingdom. All statistical tests were 2 sided. In an analysis of 1,518 patients with CRC, homozygosity for the MLH1 293A variant was associated with a significantly increased 3-fold risk of CRC negative for MLH1 protein by immunohistochemistry (odds ratio (OR): AA vs GG 5 3.30, 95% CI 1.46-7.47, n 5 1392, p 5 0.004, MLH1 negative vs MLH1 positive CRC) and with a 68% excess of proximal CRC (OR: AA vs GG51.68, 95% confidence interval (CI) 1.00-2.83, n 5 1,518, p 5 0.05, proximal vs distal CRC). These findings suggest that the MLH1 293G>A polymorphism defines a low penetrance risk allele for CRC. ' 2008 Wiley-Liss, Inc.Key words: MLH1; mismatch repair; colorectal; polymorphism; proximal; promoter; dna repair; cancer MLH1 and MSH2 are components of the DNA mismatch repair (MMR) system, which recognises and repairs mismatches in DNA that occur during replication. 1 Rare constitutional mutations in MLH1, MSH2 and other genes are responsible for the autosomal dominant disorder hereditary nonpolyposis colorectal cancer (HNPCC), 2,3 where loss of MMR predisposes to colorectal cancer (CRC) with high penetrance. Loss of MMR can also develop somatically and occurs in 15-20% of all CRC. 4 Loss of MMR frequently involves MLH1 gene promoter silencing and concomitant loss of protein expression, which gives rise to CRC predominantly in the proximal colon. In addition to rare constitutional mutations, MMR genes also contain common single nucleotide polymorphisms (SNP) which can predispose to nonfamilial CRC with low to moderate penetrance, 5-7 suggesting an important contribution of common genetic variants to the burden of CRC in the general population.In view of the importance of MLH1 in colorectal carcinogenesis, we examined the association between a potentially functional SNP in MLH1 (dbSNP ID:rs1800734) and risk of CRC. The MLH1 293G>A polymorphism is located in the core promoter of MLH1, 93 bases upstream of the transcription start site in a region that is required for maximal transcriptional activity. 8,9 Polymorphic variation in this region is predicted to affect MLH1 protein expression. Indeed, site-directed mutagenesis of the adenine residue 2 bases downstream of the 293G>A polmorphism (position-91) reduces promoter activity by 75%. 9 These observations suggest that the MLH1 293G>A polymorphism might affect risk of CRC. Consistent with this hypothesis, the MLH1 293A variant has been associated with an increased risk of developing hyperplastic colonic polyps in smokers, 10

“…One additional gene for colorectal cancer was confirmed other than the 8q24 locus, the SMAD7 gene is involved in TGF-b and Wnt signaling, and abnormalities in these pathways are well established in the pathogenesis of this cancer. [85][86][87] For lung cancer, the first convincing genetic locus also emerged, 15q25, which contained several genes encoding for nicotinic acetylcholine receptors. [88][89][90] The combination of three GWAS further identified additional susceptibility loci for this common cancer, 75 where one of the loci (5p15.33) was also identified by another GWAS.…”

Section: The Recent 2 Years: 2008 and 2009mentioning

confidence: 99%

The pursuit of genome-wide association studies: where are we now?

et al. 2010

It is now 5 years since the first genome-wide association studies (GWAS), published in 2005, identified a common risk allele with large effect size for age-related macular degeneration in a small sample set. Following this exciting finding, researchers have become optimistic about the prospect of the genome-wide association approach. However, most of the risk alleles identified in the subsequent GWAS for various complex diseases are common with small effect sizes (odds ratio o1.5). So far, more than 450 GWAS have been published and the associations of greater than 2000 single nucleotide polymorphisms (SNPs) or genetic loci were reported. The aim of this review paper is to give an overview of the evolving field of GWAS, discuss the progress that has been made by GWAS and some of the interesting findings, and summarize what we have learned over the past 5 years about the genetic basis of human complex diseases. This review will focus on GWAS of SNPs association for complex diseases but not studies of copy number variations.