[1]National Cancer Institute, Division of Cancer Epidemiology and Genetics,Bethesda,United States
[2]Nanjing Medical University, Department of Biostatistics and Epidemiology,Nanjing,China
[3]The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Department of Cancer Biotherapy Center,Kunming,China
[4]Nantong University, Eye Institute,Nantong,China
[5]Anyang Cancer Hospital, Department of Radiation Oncology,,China
[6]Cixian Hospital, Department of Pathology and Thoracic Surgery,,China
[7]Vanderbilt Ingram Cancer Center, Department of Medicine,Nashville,United States
[8]University of Pittsburgh Cancer Institute, Division of Cancer Control and Population Sciences,Pittsburgh,United States
[9]National Cancer Institute,Bethesda,United States
[10]National Cancer Institute, Center for Cancer Research,Bethesda,United States
[11]Shanxi Cancer Hospital,Taiyuan,China
[12]Cancer Institute and Hospital, Chinese Academy of Medical Sciences, Department of Epidemiology,Beijing,China
[13]Medical Center of Fudan University, Shanghai Cancer Institute,Shanghai,China
[14]National University Health System, Saw Swee Hock School of Public Health,Singapore City,Singapore
[15]Renji Hospital, Department of Epidemiology,Shanghai,China
[16]Johns Hopkins Bloomberg School of Public Health,Baltimore,United States
[17]Cancer Institute and Hospital, Chinese Academy of Medical Sciences, Department of Cancer Epidemiology,Beijing,China
[18]Information Management Services, Inc.,Silver Spring,United States
[19]SAIC-Frederick, Division of Cancer Epidemiology and Genetics,Frederick,United States
[20]Leidos Biomedical Research, Inc., Cancer Genomics Research Laboratory,Frederick,United States
[21]University Medicine Greifswald, Interfaculty Institute for Genetics and Functional Genomics,Greifswald,Germany
[22]INFORMATION MANAGEMENT SERVICES, INC.,Calverton,United States
[23]National Cancer Institute, Radiation Epidemiology Branch,Bethesda,United States
[24]University of Texas M. D. Anderson Cancer Center, Department of Epidemiology,Houston,United States
[25]First Affiliated Hospital of Zhengzhou University, Henan Key Laboratory for Esophageal Cancer Research,Zhengzhou,China
[26]First Affiliated Hospital of Zhengzhou University,Zhengzhou,China
[27]Anhui Medical University, Institute of Dermatology and Department of Dermatology,Hefei,China
[28]Changzhi Medical College, Department of Hematology,Changzhi,China
[29]Guangxi Medical University, Department of Research,Nanning,China
[30]Sichuan University, Department of Urology,Chengdu,China
[31]Zhejiang University School of Medicine, Collaborative Innovation Center for Brain Science,Hangzhou,China
[32]Zhejiang University School of Medicine, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases,Hangzhou,China
[33]Hebei Provincial Cixian Hospital, Department of Pathology and Thoracic Surgery,,China
[34]Linzhou Cancer Hospital,,China
[35]Sun Yat-Sen University, Laboratory of Molecular Medicine,Guangzhou,China
[36]Xinxiang Medical College, 1] Department of Pathology,Xinxiang,China
[37]Yibin University, Department of Mathematics,Yibin,China
[38]Zhengzhou University, Henan Key Laboratory for Esophageal Cancer Research of The First Affiliated Hospital,Zhengzhou,China
[39]an University of Science and Technology, School of Materials Science and Engineering,Xian,China
[40]First Affiliated Hospital of Zhengzhou University, Department of Endocrinology,Zhengzhou,China
[41]Sun Yat-Sen University, Department of Pathology,Guangzhou,China
[42]an Jiaotong University, Department of Cardiology,Xian,China
[43]Southern Medical University, School of Biomedical Engineering,TongHe,China
[44]Changzhi Medical College, Central Laboratory,Changzhi,China
[45]Anyang Tumor Hospital,,China
[46]Nanyang Medical College, Department of Pathology,,China
[47]s Hospital of Hebi, Department of Oncology,,China
[48]Hebi City Public Health Bureau, Department of Biostatistics,,China
[49]Zhengzhou University, Department of Pathology,Zhengzhou,China
[50]Xinxiang Medical College, Center for Cancer Research,Xinxiang,China
[51]Qixian Commerce Bureau,,China
[52]First Affiliated Hospital of Zhengzhou University, Department of Nephrology,Zhengzhou,China
[53]Henan University of Science and Technology, Department of Oncology,Luoyang,China
[54]Zhengzhou University, Henan Key Laboratory for Esophageal Cancer Research,Zhengzhou,China
[55]Education Department of Heilongjiang Province,,China
[56]s Hospital, Department of Gastroenterology and Thoracic Surgery,Shangqiu,China
[57]Cancer Institute and Hospital, Chinese Academy of Medical Sciences, Department of Etiology and Carcinogenesis,Beijing,China
[58]Xinxiang Central Hospital, Department of Radiotherapy,Xinxiang,China
[59]Anhui Medical University, Department of Biostatistics and Epidemiology,Hefei,China
[60]Hong Kong University of Science and Technology, Oncology Department of the First Affiliated Hospital of Henan,Hong Kong,China
[61]Shandong Provincial Hospital, Department of Thoracic Surgery,Jinan,China
[62]Zhengzhou University, Department of Thoracic Surgery,Zhengzhou,China
[63]Henan University of Science and Technology, Henan Key Laboratory of Cancer Epigenetics,Luoyang,China
[64]Zhengzhou University, Department of Radiotherapy,Zhengzhou,China
[65]The Fourth Military Medical University, Research and Development Center for Tissue Engineering,Xian,China
[66]s Hospital, Central Laboratory,Zhengzhou,China
[67]Xinjiang Medical University, Department of Thoracic Surgery,Urumqi,China
[68]Harbin University of Science and Technology, School of Materials Science and Engineering,Harbin,China
[69]Henan University, Department of Nephrology,Kaifeng,China
[70]Xinyang Central Hospital, Department of Oncology,Xinyang,China
[71]Kansas State University, Department of Chemical Engineering,Manhattan,United States
[72]The Red Cross Hospital of Huojia, Department of Surgery,Xinxiang,China
[73]The General Hospital of Puyang Oil Field, Department of Medical Oncology,,China
[74]Zhengzhou University, Department of Gastroenterology,Zhengzhou,China
[75]Inner Mongolia Medical College, Department of Internal Mongolia Medicine,Hohhot,China
[76]Ningxia Medical College, College of Public Health,Yinchuan,China
[77]an Jiaotong University, School of Medicine, Department of Thoracic Surgery,Xian,China
[78]Sichuan University, Department of Thoracic Surgery,Chengdu,China
[79]Shantou University, Medical College (SUMC), The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area,Shantou,China
[80]Key Laboratory of Molecular Biology for High Cancer Incidence in the Coastal Chaoshan Area,,China
[81]Sun Yat-Sen University, Department of Oncology Surgery,Guangzhou,China
[82]Zhengzhou University, Department of Pathophysiology,Zhengzhou,China
[83]Liverpool John Moores University, Offshore and Marine (LOOM) Research Institute,Liverpool,United Kingdom
[84]Soochow University, Department of Tumor Biological Treatment,Suzhou,China
[85]Neihuang Public Health Bureau, Department of Biostatistics,,China
[86]Zhengzhou University, Department of Histology and Embryology,Zhengzhou,China
[87]s Hospital of Yunnan Province, Department of Gastroenterology,Kunming,China
[88]Linzhou Esophageal Cancer Hospital, Department of Pathology,,China
[89]Tumor Hospital of Linzhou, Department of Thoracic Surgery,,China
[90]Changzhi Medical College, Department of Pathology,Changzhi,China
[91]Linzhou Central Hospital, Department of Thoracic Surgery,,China
[92]Anyang Cancer Hospital,,China
[93]Sun Yat-Sen University, Department of Gastrointestinal-Pancreatic Surgery,Guangzhou,China
[94]Zhengzhou University,Zhengzhou,China
[95]s Hospital, Department of Oncologic Pathology,,China
[96]Linzhou Esophageal Cancer Hospital, Department of Thoracic Surgery,,China
[97]Kunming Institute of Zoology Chinese Academy of Sciences, State Key Laboratory of Genetic Resources and Evolution,Kunming,China
[98]s Hospital, Department of Thoracic Surgery,,China
[99]Capital Medical University China, Department of Gastroenterology,Beijing,China
[100]Xinxiang Medical College, Department of Biochemistry and Molecular Biology,Xinxiang,China
[101]Tongji University, Department of Thoracic Surgery,Shanghai,China
[102]Peking Union Medical College, Department of Pathology,Beijing,China
[103]Zhejiang University, College of Pharmaceutical Sciences,Hangzhou,China
[104]Jining Medical University, Department of Pathology and Institute of Precision Medicine,,China
[105]University of Medicine and Dentistry of New Jersey, Department of Occupational and Environmental Health,Newark,United States
[106]Medical College of Wisconsin,Milwaukee,United States
[107]Xinxiang Medical College, Department of Pathology,Xinxiang,China
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. Published by Oxford University Press 2012.
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