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Title: Genotypic variants at 2q33 and risk of esophageal squamous cell carcinoma in China: a meta-analysis of genome-wide association studies.
Authors: Abnet CC,  Wang Z,  Song X,  Hu N,  Zhou FY,  Freedman ND,  Li XM,  Yu K,  Shu XO,  Yuan JM,  Zheng W,  Dawsey SM,  Liao LM,  Lee MP,  Ding T,  Qiao YL,  Gao YT,  Koh WP,  Xiang YB,  Tang ZZ,  Fan JH,  Chung CC,  Wang C,  Wheeler W,  Yeager M,  Yuenger J,  Hutchinson A,  Jacobs KB,  Giffen CA,  Burdett L,  Fraumeni JF Jr,  Tucker MA,  Chow WH,  Zhao XK,  Li JM,  Li AL,  Sun LD,  Wei W,  Li JL,  Zhang P,  Li HL,  Cui WY,  Wang WP,  Liu ZC,  Yang X,  Fu WJ,  Cui JL,  Lin HL,  Zhu WL,  Liu M,  Chen X,  Chen J,  Guo L,  Han JJ,  Zhou SL,  Huang J,  Wu Y,  Yuan C,  Huang J,  Ji AF,  Kul JW,  Fan ZM,  Wang JP,  Zhang DY,  Zhang LQ,  Zhang W,  Chen YF,  Ren JL,  Li XM,  Dong JC,  Xing GL,  Guo ZG,  Yang JX,  Mao YM,  Yuan Y,  Guo ET,  Zhang W,  Hou ZC,  Liu J,  Li Y,  Tang S,  Chang J,  Peng XQ,  Han M,  Yin WL,  Liu YL,  Hu YL,  Liu Y,  Yang LQ,  Zhu FG,  Yang XF,  Feng XS,  Wang Z,  Li Y,  Gao SG,  Liu HL,  Yuan L,  Jin Y,  Zhang YR,  Sheyhidin I,  Li F,  Chen BP,  Ren SW,  Liu B,  Li D,  Zhang GF,  Yue WB,  Feng CW,  Qige Q,  Zhao JT,  Yang WJ,  Lei GY,  Chen LQ,  Li EM,  Xu LY,  Wu ZY,  Bao ZQ,  Chen JL,  Li XC,  Zhuang X,  Zhou YF,  Zuo XB,  Dong ZM,  Wang LW,  Fan XP,  Wang J,  Zhou Q,  Ma GS,  Zhang QX,  Liu H,  Jian XY,  Lian SY,  Wang JS,  Chang FB,  Lu CD,  Miao JJ,  Chen ZG,  Wang R,  Guo M,  Fan ZL,  Tao P,  Liu TJ,  Wei JC,  Kong QP,  Fan L,  Wang XZ,  Gao FS,  Wang TY,  Xie D,  Wang L,  Chen SQ,  Yang WC,  Hong JY,  Wang L,  Qiu SL,  Goldstein AM,  Yuan ZQ,  Chanock SJ,  Zhang XJ,  Taylor PR,  Wang LD
Journal: Hum Mol Genet
Date: 2012 May 1
PubMed ID: 22323360
PMC ID: PMC3315211
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.