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Common variation near CDKN1A, POLD3 and SHROOM2 influences colorectal cancer risk.

ABSTRACT: We performed a meta-analysis of five genome-wide association studies to identify common variants influencing colorectal cancer (CRC) risk comprising 8,682 cases and 9,649 controls. Replication analysis was performed in case-control sets totaling 21,096 cases and 19,555 controls. We identified three new CRC risk loci at 6p21 (rs1321311, near CDKN1A; P = 1.14 × 10(-10)), 11q13.4 (rs3824999, intronic to POLD3; P = 3.65 × 10(-10)) and Xp22.2 (rs5934683, near SHROOM2; P = 7.30 × 10(-10)) This brings the number of independent loci associated with CRC risk to 20 and provides further insight into the genetic architecture of inherited susceptibility to CRC.

SUBMITTER: Dunlop MG

PROVIDER: S-EPMC4747430 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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Common variation near CDKN1A, POLD3 and SHROOM2 influences colorectal cancer risk.

Dunlop Malcolm G MG Dobbins Sara E SE Farrington Susan Mary SM Jones Angela M AM Palles Claire C Whiffin Nicola N Tenesa Albert A Spain Sarah S Broderick Peter P Ooi Li-Yin LY Domingo Enric E Smillie Claire C Henrion Marc M Frampton Matthew M Martin Lynn L Grimes Graeme G Gorman Maggie M Semple Colin C Ma Yusanne P YP Barclay Ella E Prendergast James J Cazier Jean-Baptiste JB Olver Bianca B Penegar Steven S Lubbe Steven S Chander Ian I Carvajal-Carmona Luis G LG Ballereau Stephane S Lloyd Amy A Vijayakrishnan Jayaram J Zgaga Lina L Rudan Igor I Theodoratou Evropi E Starr John M JM Deary Ian I Kirac Iva I Kovacević Dujo D Aaltonen Lauri A LA Renkonen-Sinisalo Laura L Mecklin Jukka-Pekka JP Matsuda Koichi K Nakamura Yusuke Y Okada Yukinori Y Gallinger Steven S Duggan David J DJ Conti David D Newcomb Polly P Hopper John J Jenkins Mark A MA Schumacher Fredrick F Casey Graham G Easton Douglas D Shah Mitul M Pharoah Paul P Lindblom Annika A Liu Tao T Smith Christopher G CG West Hannah H Cheadle Jeremy P JP Midgley Rachel R Kerr David J DJ Kerr David J DJ Campbell Harry H Tomlinson Ian P IP Houlston Richard S RS

Nature genetics 20120527 7

We performed a meta-analysis of five genome-wide association studies to identify common variants influencing colorectal cancer (CRC) risk comprising 8,682 cases and 9,649 controls. Replication analysis was performed in case-control sets totaling 21,096 cases and 19,555 controls. We identified three new CRC risk loci at 6p21 (rs1321311, near CDKN1A; P = 1.14 × 10(-10)), 11q13.4 (rs3824999, intronic to POLD3; P = 3.65 × 10(-10)) and Xp22.2 (rs5934683, near SHROOM2; P = 7.30 × 10(-10)) This brings ...[more]

PMID: 22634755

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Project description:BackgroundColorectal cancer is the second cause of death by cancer around the world. Sporadic colorectal cancer is the most frequent (75%), and it is produced by the interaction of environmental, epigenetic, and genetic factors. The accumulation of single-nucleotide variants in genes associated with cell proliferation, DNA repair, and/or apoptosis could confer a risk to cancer. The aim of this study was to analyze the gene-gene interactions among CCND2 (rs3217901), CDKN1A (rs1059234 and rs1801270), and POLD3 (rs3824999) variants in Mexican patients with colorectal cancer.MethodsWe collected peripheral blood samples from 185 patients with sporadic colorectal cancer before treatment and from 185 unrelated blood donors as the reference group; all participants signed an informed consent form. DNA extraction was performed by Miller and Cetyltrimethylammonium bromide (CTAB)/ Dodecyltrimethylammonium bromide (DTAB) methods. Polymerase chain reaction- restriction fragment length polymorphism followed by polyacrylamide gel electrophoresis stained with AgNO3 methods were used to identify the variants rs3217901, rs1059234, rs1801270, and rs3824999. Odds ratio and single-nucleotide variant interaction were determined by single-locus analysis and Multifactorial Dimensionality Reduction software, respectively.ResultsNo association was found for CCND2 and CDKN1A variants; yet, a significant association for the GG genotype, G allele, and recessive and additive models for the POLD3 variant was observed (P < .05). The single-nucleotide variant-single-nucleotide variant interaction revealed the combination rs1059234, rs3217901, and rs3824999 as the best model and the comparison showed an increased risk (P < .05).ConclusionSingle-locus and gene-gene interaction analyses disclosed that both the rs3824999 (POLD3) variant and the combination of rs3217901 (CCND2), rs1059234 (CDKN1A), and rs3824999 (POLD3) genotypes increase the risk for colorectal cancer in Mexican population.

Dataset Information

Common variation near CDKN1A, POLD3 and SHROOM2 influences colorectal cancer risk.

Publications

Common variation near CDKN1A, POLD3 and SHROOM2 influences colorectal cancer risk.

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