Common genetic variants at the CRAC1 (HMPS) locus on chromosome 15q13.3 influence colorectal cancer risk

Jaeger, Emma; Webb, Emily L.; Howarth, Kimberley; Carvajal‐Carmona, Luis G.; Rowan, Andrew; Broderick, Peter; Walther, Axel; Spain, Sarah L.; Pittman, Alan; Kemp, Zoe; Sullivan, Kate; Heinimann, Karl; Lubbe, Steven; Domingo, Enric; Barclay, Ella; Martin, Lynn; Gorman, Maggie; Chandler, Ian; Vijayakrishnan, Jayaram; Wood, Wendy; Papaemmanuil, Elli; Penegar, Steven; Qureshi, Mobshra; Farrington, Susan M.; Tenesa, Albert; Cazier, Jean‐Baptiste; Kerr, David; Gray, Richard; Peto, Julian; Dunlop, Malcolm G.; Campbell, Harry; Thomas, Huw; Houlston, Richard S.; Tomlinson, Ian

doi:10.1038/ng.2007.41

Cited by 269 publications

(157 citation statements)

References 14 publications

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“…Three GWA studies of CRC have so far been reported and 10 independent loci shown conclusively to be associated with CRC risk: 8q24.21, 11q23, 18q21.1 (SMAD7), 8q23.1 (EIF3H), 15q (GREM1), 19q13.1 (RHPN2), 20q12.3, 14q22.2 (BMP4), 16q22.1 (CDH1) and 10p14 (Tomlinson et al, 2005Broderick et al, 2007;Zanke et al, 2007;Houlston et al, 2008;Jaeger et al, 2008;Tenesa et al, 2008). Risks associated with each of the common variants at each of these loci are modest (ORs 1.1 -1.3; Table 2) and there is little evidence of interactive effects.…”

Section: Characteristics Of Low-penetrance Variantsmentioning

confidence: 99%

“…This assertion has recently been vindicated by genome-wide association (GWA) studies, which have provided robust evidence for several common low-risk variants influencing CRC risk (Tomlinson et al, 2005Broderick et al, 2007;Zanke et al, 2007;Houlston et al, 2008;Jaeger et al, 2008;Tenesa et al, 2008). Although the risk of CRC associated with each of these common variants is individually modest, they make a significant contribution to the overall disease burden by virtue of their high frequencies in the population.…”

Section: Introductionmentioning

confidence: 99%

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COGENT (COlorectal cancer GENeTics): an international consortium to study the role of polymorphic variation on the risk of colorectal cancer

Tomlinson¹,

Dunlop²,

Campbell³

et al. 2009

Br J Cancer

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It is now recognised that a part of the inherited risk of colorectal cancer (CRC) can be explained by the co-inheritance of low-penetrance genetic variants. The accumulated experience to date in identifying these variants has served to highlight difficulties in conducting statistically and methodologically rigorous studies and follow-up analyses. The COGENT (COlorectal cancer GENeTics) consortium includes 20 research groups in Europe, Australia, the Americas, China and Japan. The overarching goal of COGENT is to identify and characterise low-penetrance susceptibility variants for CRC through association-based analyses. In this study, we review the rationale for identifying low-penetrance variants for CRC and our proposed strategy for establishing COGENT.

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Section: Characteristics Of Low-penetrance Variantsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

COGENT (COlorectal cancer GENeTics): an international consortium to study the role of polymorphic variation on the risk of colorectal cancer

Tomlinson¹,

Dunlop²,

Campbell³

et al. 2009

Br J Cancer

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“…Grem2 mRNA expression was significantly repressed in both Apc Min/þ and AOM-induced colon tumors, although we did not observe significant changes in Fmn2 expression. A recent GWAS identified common genetic variants at CRAC1 (HMPS) locus on human chromosome 15q13.3 that confers colorectal cancer risk in the Ashkenazi population (9). The CRAC1 locus was initially …”

Section: Discussionmentioning

confidence: 99%

“…Direct evidence for common variants for colorectal cancer is highlighted by recent genome-wide association studies (GWAS). These GWAS on colorectal cancer have identified 10 independent loci that confer risk of colorectal cancer, including those on chromosomes 8q24.21, 11q23, 18q21.1, 8q23.1 15q, 19q13.1, 20q12.3, 14q22.2, 16q22.1, and 10p14 (4)(5)(6)(7)(8)(9)(10). However, risk associated with these common variants is modest and only a small proportion of colorectal cancer risk can be explained by currently identified loci.…”

Section: Introductionmentioning

confidence: 99%

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

Liu

Lü

Liu

et al. 2012

Molecular Cancer Research

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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.

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“…Much of the heritable risk of CRC is now thought to be the consequence of the co-inheritance of multiple low-risk variants. Such an assertion is supported by recent genome-wide association studies (GWASs) of CRC Tomlinson et al, 2007Tomlinson et al, , 2008Zanke et al, 2007;Houlston et al, 2008Houlston et al, , 2010Jaeger et al, 2008;Tenesa et al, 2008).…”

Section: Introductionmentioning

confidence: 54%

The 14q22.2 colorectal cancer variant rs4444235 shows cis-acting regulation of BMP4

et al. 2011

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Common genetic variation at human 14q22.2 tagged by rs4444235 is significantly associated with colorectal cancer (CRC) risk. Re-sequencing was used to comprehensively annotate the 17kb region of strong linkage disequilibrium encompassing rs4444235. Through bioinformatic analyses using H3K4Me1, H3K4Me3, and DNase-I hypersensitivity chromatin signatures and evolutionary conservation we identified seven candidate disease-causing single-nucleotide polymorphisms mapping to six regions within the 17-kb region predicted to have regulatory potential. Reporter gene studies of these regions demonstrated that the element to which rs4444235 maps acts as an allele-specific transcriptional enhancer. Allele-specific expression studies in CRC cell lines heterozygous for rs4444235 showed significantly increased expression of bone morphogenetic protein-4 (BMP4) associated with the risk allele (Po0.001). These data provide evidence for a functional basis for the noncoding risk variant rs4444235 at 14q22.2 and emphasizes the importance of genetic variation in the BMP pathway genes as determinants of CRC risk.

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Common genetic variants at the CRAC1 (HMPS) locus on chromosome 15q13.3 influence colorectal cancer risk

Cited by 269 publications

References 14 publications

COGENT (COlorectal cancer GENeTics): an international consortium to study the role of polymorphic variation on the risk of colorectal cancer

COGENT (COlorectal cancer GENeTics): an international consortium to study the role of polymorphic variation on the risk of colorectal cancer

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

The 14q22.2 colorectal cancer variant rs4444235 shows cis-acting regulation of BMP4

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