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Common genetic variants in the 9p21 region and their associations with multiple tumours.

ABSTRACT: The chromosome 9p21.3 region has been implicated in the pathogenesis of multiple cancers.We systematically examined up to 203 tagging SNPs of 22 genes on 9p21.3 (19.9-32.8?Mb) in eight case-control studies: thyroid cancer, endometrial cancer (EC), renal cell carcinoma, colorectal cancer (CRC), colorectal adenoma (CA), oesophageal squamous cell carcinoma (ESCC), gastric cardia adenocarcinoma and osteosarcoma (OS). We used logistic regression to perform single SNP analyses for each study separately, adjusting for study-specific covariates. We combined SNP results across studies by fixed-effect meta-analyses and a newly developed subset-based statistical approach (ASSET). Gene-based P-values were obtained by the minP method using the Adaptive Rank Truncated Product program. We adjusted for multiple comparisons by Bonferroni correction.Rs3731239 in cyclin-dependent kinase inhibitors 2A (CDKN2A) was significantly associated with ESCC (P=7 × 10(-6)). The CDKN2A-ESCC association was further supported by gene-based analyses (Pgene=0.0001). In the meta-analyses by ASSET, four SNPs (rs3731239 in CDKN2A, rs615552 and rs573687 in CDKN2B and rs564398 in CDKN2BAS) showed significant associations with ESCC and EC (P<2.46 × 10(-4)). One SNP in MTAP (methylthioadenosine phosphorylase) (rs7023329) that was previously associated with melanoma and nevi in multiple genome-wide association studies was associated with CRC, CA and OS by ASSET (P=0.007).Our data indicate that genetic variants in CDKN2A, and possibly nearby genes, may be associated with ESCC and several other tumours, further highlighting the importance of 9p21.3 genetic variants in carcinogenesis.

SUBMITTER: Gu F

PROVIDER: S-EPMC3619272 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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Common genetic variants in the 9p21 region and their associations with multiple tumours.

Gu F F Pfeiffer R M RM Bhattacharjee S S Han S S SS Taylor P R PR Berndt S S Yang H H Sigurdson A J AJ Toro J J Mirabello L L Greene M H MH Freedman N D ND Abnet C C CC Dawsey S M SM Hu N N Qiao Y-L YL Ding T T Brenner A V AV Garcia-Closas M M Hayes R R Brinton L A LA Lissowska J J Wentzensen N N Kratz C C Moore L E LE Ziegler R G RG Chow W-H WH Savage S A SA Burdette L L Yeager M M Chanock S J SJ Chatterjee N N Tucker M A MA Goldstein A M AM Yang X R XR

British journal of cancer 20130129 6

<h4>Background</h4>The chromosome 9p21.3 region has been implicated in the pathogenesis of multiple cancers.<h4>Methods</h4>We systematically examined up to 203 tagging SNPs of 22 genes on 9p21.3 (19.9-32.8 Mb) in eight case-control studies: thyroid cancer, endometrial cancer (EC), renal cell carcinoma, colorectal cancer (CRC), colorectal adenoma (CA), oesophageal squamous cell carcinoma (ESCC), gastric cardia adenocarcinoma and osteosarcoma (OS). We used logistic regression to perform single SN ...[more]

PMID: 23361049

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Project description:Approximately 10% of patients undergoing cardiac surgery have perioperative myocardial injury. A recent genome-wide association study identified an association between myocardial infarction in nonsurgical populations and common genetic variants on chromosome 9p21. We hypothesized that these variants are also associated with perioperative myocardial injury after isolated primary coronary artery bypass graft surgery.In a prospective observational study of 846 Caucasian patients undergoing primary coronary bypass surgery at 2 US centers, we genotyped 61 linkage-disequilibrium tagging single nucleotide polymorphisms, encompassing 436 kbp of the 9p21 region. A multivariable logistic model was used to adjust for previously identified clinical covariates of perioperative myocardial injury. Perioperative myocardial injury was defined as a postoperative day 1 cardiac troponin I in the top 10th percentile (>9.13 microg/L) of the cohort. Multiple testing of single nucleotide polymorphisms was corrected for with family-wise errors.Prior myocardial infarction and longer cardiopulmonary bypass time were significant independent predictors of perioperative myocardial injury. Levels of postoperative cardiac troponin I were incrementally increased for each additional copy of the risk alleles of 3 single nucleotide polymorphisms: rs10116277, rs6475606, and rs2383207. Adjusted additive odds ratios ranged between 1.64 and 1.79 (asymptotic P value between 3.7 x 10(-3) and 6 x 10(-4)) and remained significantly associated with perioperative myocardial injury even after accounting for clinical covariates including severity of coronary disease, and multiple comparisons.We have now demonstrated that common genetic variants in the same 9p21 locus, previously known to be associated with myocardial infarction in nonsurgical populations, are also associated with perioperative myocardial injury after coronary artery bypass grafting. Further investigation is warranted to elucidate functional mechanisms.

Dataset Information

Common genetic variants in the 9p21 region and their associations with multiple tumours.

Publications

Common genetic variants in the 9p21 region and their associations with multiple tumours.

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