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Genotypic variants at 2q33 and risk of esophageal squamous cell carcinoma in China: a meta-analysis of genome-wide association studies.

ABSTRACT: Genome-wide association studies have identified susceptibility loci for esophageal squamous cell carcinoma (ESCC). We conducted a meta-analysis of all single-nucleotide polymorphisms (SNPs) that showed nominally significant P-values in two previously published genome-wide scans that included a total of 2961 ESCC cases and 3400 controls. The meta-analysis revealed five SNPs at 2q33 with P< 5 × 10(-8), and the strongest signal was rs13016963, with a combined odds ratio (95% confidence interval) of 1.29 (1.19-1.40) and P= 7.63 × 10(-10). An imputation analysis of 4304 SNPs at 2q33 suggested a single association signal, and the strongest imputed SNP associations were similar to those from the genotyped SNPs. We conducted an ancestral recombination graph analysis with 53 SNPs to identify one or more haplotypes that harbor the variants directly responsible for the detected association signal. This showed that the five SNPs exist in a single haplotype along with 45 imputed SNPs in strong linkage disequilibrium, and the strongest candidate was rs10201587, one of the genotyped SNPs. Our meta-analysis found genome-wide significant SNPs at 2q33 that map to the CASP8/ALS2CR12/TRAK2 gene region. Variants in CASP8 have been extensively studied across a spectrum of cancers with mixed results. The locus we identified appears to be distinct from the widely studied rs3834129 and rs1045485 SNPs in CASP8. Future studies of esophageal and other cancers should focus on comprehensive sequencing of this 2q33 locus and functional analysis of rs13016963 and rs10201587 and other strongly correlated variants.

SUBMITTER: Abnet CC

PROVIDER: S-EPMC3315211 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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Genotypic variants at 2q33 and risk of esophageal squamous cell carcinoma in China: a meta-analysis of genome-wide association studies.

Abnet Christian C CC Wang Zhaoming Z Song Xin X Hu Nan N Zhou Fu-You FY Freedman Neal D ND Li Xue-Min XM Yu Kai K Shu Xiao-Ou XO Yuan Jian-Min JM Zheng Wei W Dawsey Sanford M SM Liao Linda M LM Lee Maxwell P MP Ding Ti T Qiao You-Lin YL Gao Yu-Tang YT Koh Woon-Puay WP Xiang Yong-Bing YB Tang Ze-Zhong ZZ Fan Jin-Hu JH Chung Charles C CC Wang Chaoyu C Wheeler William W Yeager Meredith M Yuenger Jeff J Hutchinson Amy A Jacobs Kevin B KB Giffen Carol A CA Burdett Laurie L Fraumeni Joseph F JF Tucker Margaret A MA Chow Wong-Ho WH Zhao Xue-Ke XK Li Jiang-Man JM Li Ai-Li AL Sun Liang-Dan LD Wei Wu W Li Ji-Lin JL Zhang Peng P Li Hong-Lei HL Cui Wen-Yan WY Wang Wei-Peng WP Liu Zhi-Cai ZC Yang Xia X Fu Wen-Jing WJ Cui Ji-Li JL Lin Hong-Li HL Zhu Wen-Liang WL Liu Min M Chen Xi X Chen Jie J Guo Li L Han Jing-Jing JJ Zhou Sheng-Li SL Huang Jia J Wu Yue Y Yuan Chao C Huang Jing J Ji Ai-Fang AF Kul Jian-Wei JW Fan Zhong-Min ZM Wang Jian-Po JP Zhang Dong-Yun DY Zhang Lian-Qun LQ Zhang Wei W Chen Yuan-Fang YF Ren Jing-Li JL Li Xiu-Min XM Dong Jin-Cheng JC Xing Guo-Lan GL Guo Zhi-Gang ZG Yang Jian-Xue JX Mao Yi-Ming YM Yuan Yuan Y Guo Er-Tao ET Zhang Wei W Hou Zhi-Chao ZC Liu Jing J Li Yan Y Tang Sa S Chang Jia J Peng Xiu-Qin XQ Han Min M Yin Wan-Li WL Liu Ya-Li YL Hu Yan-Long YL Liu Yu Y Yang Liu-Qin LQ Zhu Fu-Guo FG Yang Xiu-Feng XF Feng Xiao-Shan XS Wang Zhou Z Li Yin Y Gao She-Gan SG Liu Hai-Lin HL Yuan Ling L Jin Yan Y Zhang Yan-Rui YR Sheyhidin Ilyar I Li Feng F Chen Bao-Ping BP Ren Shu-Wei SW Liu Bin B Li Dan D Zhang Gao-Fu GF Yue Wen-Bin WB Feng Chang-Wei CW Qige Qirenwang Q Zhao Jian-Ting JT Yang Wen-Jun WJ Lei Guang-Yan GY Chen Long-Qi LQ Li En-Min EM Xu Li-Yan LY Wu Zhi-Yong ZY Bao Zhi-Qin ZQ Chen Ji-Li JL Li Xian-Chang XC Zhuang Xiang X Zhou Ying-Fa YF Zuo Xian-Bo XB Dong Zi-Ming ZM Wang Lu-Wen LW Fan Xue-Pin XP Wang Jin J Zhou Qi Q Ma Guo-Shun GS Zhang Qin-Xian QX Liu Hai H Jian Xin-Ying XY Lian Sin-Yong SY Wang Jin-Sheng JS Chang Fu-Bao FB Lu Chang-Dong CD Miao Jian-Jun JJ Chen Zhi-Guo ZG Wang Ran R Guo Ming M Fan Zeng-Lin ZL Tao Ping P Liu Tai-Jing TJ Wei Jin-Chang JC Kong Qing-Peng QP Fan Lei L Wang Xian-Zeng XZ Gao Fu-Sheng FS Wang Tian-Yun TY Xie Dong D Wang Li L Chen Shu-Qing SQ Yang Wan-Cai WC Hong Jun-Yan JY Wang Liang L Qiu Song-Liang SL Goldstein Alisa M AM Yuan Zhi-Qing ZQ Chanock Stephen J SJ Zhang Xue-Jun XJ Taylor Philip R PR Wang Li-Dong LD

Human molecular genetics 20120208 9

Genome-wide association studies have identified susceptibility loci for esophageal squamous cell carcinoma (ESCC). We conducted a meta-analysis of all single-nucleotide polymorphisms (SNPs) that showed nominally significant P-values in two previously published genome-wide scans that included a total of 2961 ESCC cases and 3400 controls. The meta-analysis revealed five SNPs at 2q33 with P< 5 × 10(-8), and the strongest signal was rs13016963, with a combined odds ratio (95% confidence interval) of ...[more]

PMID: 22323360

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Project description:BackgroundCancers from lung and esophagus are the leading causes of cancer-related deaths in China and share many similarities in terms of histological type, risk factors and genetic variants. Recent genome-wide association studies (GWAS) in Chinese esophageal cancer patients have demonstrated six high-risk candidate single nucleotide polymorphisms (SNPs). Thus, the present study aimed to determine the risk of these SNPs predisposing to lung cancer in Chinese population.MethodsA total of 1170 lung cancer patients and 1530 normal subjects were enrolled in this study from high-incidence areas for esophageal cancer in Henan, northern China. Five milliliters of blood were collected from all subjects for genotyping. Genotyping of 20 high-risk SNP loci identified from genome-wide association studies (GWAS) on esophageal, lung and gastric cancers was performed using TaqMan allelic discrimination assays. Polymorphisms were examined for deviation from Hardy-Weinberg equilibrium (HWE) using Х2 test. Bonferroni correction was performed to correct the statistical significance of 20 SNPs with the risk of lung cancer. The Pearson's Х2 test was used to compare the distributions of gender, TNM stage, histopathological type, smoking and family history by lung susceptibility genotypes. Kaplan-Meier and Cox regression analyses were carried out to evaluate the associations between genetic variants and overall survival.ResultsFour of the 20 SNPs identified as high-risk SNPs in Chinese esophageal cancer showed increased risk for Chinese lung cancer, which included rs3769823 (OR = 1.26; 95% CI = 1.107-1.509; P = 0.02), rs10931936 (OR = 1.283; 95% CI = 1.100-1.495; P = 0.04), rs2244438 (OR = 1.294; 95% CI = 1.098-1.525; P = 0.04) and rs13016963 (OR = 1.268; 95% CI = 1.089-1.447; P = 0.04). All these SNPs were located at 2q33 region harboringgenes of CASP8, ALS2CR12 and TRAK2. However, none of these susceptibility SNPs was observed to be significantly associated with gender, TNM stage, histopathological type, smoking, family history and overall survival.ConclusionsThe present study identified four high-risk SNPs at 2q33 locus for Chinese lung cancer and demonstrated the shared susceptibility loci at 2q33 region for Chinese lung and esophageal cancers.

Dataset Information

Genotypic variants at 2q33 and risk of esophageal squamous cell carcinoma in China: a meta-analysis of genome-wide association studies.

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Genotypic variants at 2q33 and risk of esophageal squamous cell carcinoma in China: a meta-analysis of genome-wide association studies.

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