Letter | Published:

Joint analysis of three genome-wide association studies of esophageal squamous cell carcinoma in Chinese populations

Nature Genetics volume 46, pages 10011006 (2014) | Download Citation

Abstract

We conducted a joint (pooled) analysis of three genome-wide association studies (GWAS)1,2,3 of esophageal squamous cell carcinoma (ESCC) in individuals of Chinese ancestry (5,337 ESCC cases and 5,787 controls) with 9,654 ESCC cases and 10,058 controls for follow-up. In a logistic regression model adjusted for age, sex, study and two eigenvectors, two new loci achieved genome-wide significance, marked by rs7447927 at 5q31.2 (per-allele odds ratio (OR) = 0.85, 95% confidence interval (CI) = 0.82–0.88; P = 7.72 × 10−20) and rs1642764 at 17p13.1 (per-allele OR = 0.88, 95% CI = 0.85–0.91; P = 3.10 × 10−13). rs7447927 is a synonymous SNP in TMEM173, and rs1642764 is an intronic SNP in ATP1B2, near TP53. Furthermore, a locus in the HLA class II region at 6p21.32 (rs35597309) achieved genome-wide significance in the two populations at highest risk for ESSC (OR = 1.33, 95% CI = 1.22–1.46; P = 1.99 × 10−10). Our joint analysis identifies new ESCC susceptibility loci overall as well as a new locus unique to the population in the Taihang Mountain region at high risk of ESCC.

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Acknowledgements

This work was funded by the National High-Tech Research and Development Program of China (2009AA022706 to D.L.), the National Basic Research Program of China (2011CB504303 to D.L. and W.T.) and the National Natural Science Foundation of China (30721001 to D.L., Q.Z. and Z.L.).

We thank all the subjects and their family members whose contributions made this work possible; medical students from Zhengzhou University, Xinxiang Medical University, Zhengzhou Medical School and the Henan University of Science and Technology for sample and data collections; Q.C. Kan (The First Affiliated Hospital of Zhengzhou University) and Y. Xing (Xinxiang Medical University) for organizing field work for sample collection and finding financial support for the study; the Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, China, for genotyping; and W. Huang (Health Department of Henan Province) for field work organization.

This work was supported by the Invitation Team of the Ministry of Education (2008IRTSTHN010), the National Natural Science Foundation of China (81071783), 863 High-Tech Key Projects (2012AA02A209, 2012AA02A503 and 2012AA02A201), Innovation Scientists and Technicians Troop Construction Projects of Henan Province (3047), the Key Disciplines Revitalization Plan of Zhengzhou University (20132016) and the Collaborative Innovation Center for Esophageal Cancer Research of Henan Province (20132016).

The Shanghai Men's Health Study (SMHS) was supported by NCI extramural research grant R01 CA82729. The Shanghai Women's Health Study (SWHS) was supported by NCI extramural research grant R37 CA70837 and, in part, for biological sample collection, by NCI intramural research program contract NO2-CP-11010 with Vanderbilt University. The studies would not be possible without continuing support and devotion from the study participants and the staff of SMHS and SWHS.

The Singapore Chinese Health Study (SCHS) was supported by NCI extramural research grants R01 CA55069, R35 CA53890, R01 CA80205 and R01 CA144034. We are indebted to the contributions of M.C. Yu and H.-P. Lee in the establishment of this cohort. The study would not be possible without the assistance in identifying cancer cases through database linkage provided by the Ministry of Health in Singapore. We are indebted to the study subjects for their continuing participation and to the staff of SCHS for their support.

The Shanxi Upper Gastrointestinal Cancer Genetics Project was supported by NCI intramural research program contract NO2-SC-66211 with the Shanxi Cancer Hospital and Institute.

The Nutrition Intervention Trials (NIT) was supported by NCI intramural research program contracts NO1-SC-91030 and HHSN261200477001C with the Cancer Institute and Hospital of the Chinese Academy of Medical Sciences.

This research was supported in part by the intramural research program of the US NIH/NCI, the Division of Cancer Epidemiology and Genetics, and the Center for Cancer Research.

This project was funded in part with federal funds from the US NIH/NCI under contract HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the US Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US government.

Author information

Author notes

    • Chen Wu
    • , Zhaoming Wang
    • , Xin Song
    • , Xiao-Shan Feng
    • , Christian C Abnet
    • , Jie He
    • , Nan Hu
    • , Xian-Bo Zuo
    •  & Wen Tan

    These authors contributed equally to this work.

Affiliations

  1. State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

    • Chen Wu
    • , Wen Tan
    • , Qimin Zhan
    • , Zhihua Liu
    • , Yu Liu
    • , Dianke Yu
    • , Jiang Chang
    • , Lixuan Wei
    • , Ying Huang
    • , Chunling Liu
    • , Kan Zhai
    • , Yan Qiao
    •  & Dongxin Lin
  2. Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institutes of Health, Bethesda, Maryland, USA.

    • Zhaoming Wang
    • , Christian C Abnet
    • , Nan Hu
    • , Kai Yu
    • , Sanford M Dawsey
    • , Linda Liao
    • , Chaoyu Wang
    • , Mitchell Gail
    • , Meredith Yeager
    • , Jeff Yuenger
    • , Amy Hutchinson
    • , Kevin Jacobs
    • , Laurie Burdette
    • , Joseph F Fraumeni Jr
    • , Charles C Chung
    • , Margaret A Tucker
    • , Neal D Freedman
    • , Alisa M Goldstein
    • , Philip R Taylor
    •  & Stephen J Chanock
  3. Cancer Genome Research Laboratory, Division of Cancer Epidemiology and Genetics, Advanced Technology Program, SAIC-Frederick, Inc., NCI-Frederick, Frederick, Maryland, USA.

    • Zhaoming Wang
    • , Meredith Yeager
    • , Jeff Yuenger
    • , Amy Hutchinson
    • , Kevin Jacobs
    • , Laurie Burdette
    •  & Charles C Chung
  4. Department of Pathology, Cancer Research Center, Basic Medical College, Xinxiang Medical University, Xinxiang, China.

    • Xin Song
    • , Zhi-Qing Yuan
    • , Ji-Li Cui
    • , Hong-Li Lin
    • , Ya-Li Liu
    • , Yan-Long Hu
    • , Li Wang
    • , Guo Yuan
    • , Li-Sha Chen
    • , Xiu-Min Li
    • , Wei-Xing Zhao
    • , Wan-Cai Yang
    • , Liang Wang
    •  & Li-Dong Wang
  5. Henan Key Laboratory for Esophageal Cancer Research of The First Affiliated Hospital, Zhengzhou University, Zhengzhou, China.

    • Xin Song
    • , Xue-Ke Zhao
    • , Zong-Min Fan
    • , Ji-Li Cui
    • , Hong-Li Lin
    • , Xue-Na Han
    • , Bei Li
    • , Xi Chen
    • , Jing-Jing Han
    • , Sheng-Li Zhou
    • , Peng Zhang
    • , Dong-Yun Zhang
    • , Yuan Yuan
    • , Er-Tao Guo
    • , Ai-Li Li
    • , Wei Zhang
    • , Yan Li
    • , Sa Tang
    • , Xiu-Qing Peng
    • , Jing Liu
    • , Zhi-Chao Hou
    • , Ya-Li Liu
    • , Yan-Long Hu
    • , Yu Liu
    • , Guo Yuan
    • , Li-Sha Chen
    • , Xiao Liu
    • , Teng Ma
    • , Hui Meng
    • , Li Sun
    • , Xin-Min Li
    • , Jian-Wei Ku
    • , Ying-Fa Zhou
    • , Wen-Bin Yue
    • , Ran Wang
    • , Lu-Wen Wang
    • , Xue-Ping Fan
    • , Mei Zhang
    • , Guo-Lan Xing
    • , Jin Wang
    •  & Li-Dong Wang
  6. Department of Oncology, Pathology, Clinical Laboratory and Respiratory Medicine, The First Affiliated Hospital, Henan University of Science and Technology, Luoyang, China.

    • Xiao-Shan Feng
    • , She-Gan Gao
    • , Xiu-Qing Peng
    •  & Yi-Min Mao
  7. Department of Thoracic Surgery, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

    • Jie He
  8. Key Laboratory of Dermatology, Anhui Medical University, Anhui, China.

    • Xian-Bo Zuo
    • , Liang-Dan Sun
    •  & Xue-Jun Zhang
  9. Department of Epidemiology and Biostatistics, Cancer Center, Nanjing Medical University, Nanjing, China.

    • Zhibin Hu
    • , Guangfu Jin
    •  & Hongbing Shen
  10. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University School of Oncology, Beijing Cancer Hospital and Institute, Beijing, China.

    • Zhonghu He
    • , Chuanhai Guo
    •  & Yang Ke
  11. State Key Laboratory of Oncology in Southern China, Sun Yat-Sen University Cancer Center, Guangzhou, China.

    • Weihua Jia
    • , Jianhua Fu
    •  & Yixin Zeng
  12. Department of Experimental Research, Sun Yat-Sen University Cancer Center, Guangzhou, China.

    • Weihua Jia
    • , Jianhua Fu
    •  & Yixin Zeng
  13. Laboratory of Cancer Molecular Genetics, Medical College of Soochow University, Suzhou, China.

    • Yifeng Zhou
  14. Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA.

    • Xiao-Ou Shu
    •  & Wei Zheng
  15. Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee, USA.

    • Xiao-Ou Shu
    •  & Wei Zheng
  16. University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, USA.

    • Jian-Min Yuan
  17. Anyang Tumor Hospital, Anyang, China.

    • Fu-You Zhou
    • , Changdong Lu
    •  & Haijun Yang
  18. Department of Basic Oncology and Pathology at the College of Medicine, Zhengzhou University, Zhengzhou, China.

    • Xi Chen
    •  & Jing-Jing Han
  19. Center for Cancer Research, National Cancer Institute, US National Institutes of Health, Bethesda, Maryland, USA.

    • Maxwell P Lee
  20. Shanxi Cancer Hospital, Taiyuan, China.

    • Ti Ding
    •  & Ze-Zhong Tang
  21. Department of Epidemiology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

    • You-Lin Qiao
    •  & Jin-Hu Fan
  22. Shanghai Cancer Institute, Shanghai, China.

    • Yu-Tang Gao
    •  & Yong-Bing Xiang
  23. Duke–National University of Singapore Graduate Medical School, Singapore.

    • Woon-Puay Koh
  24. Key Laboratory for Environment and Health (Ministry of Education), School of Public Health, Huazhong University of Sciences and Technology, Wuhan, China.

    • Xiaoping Miao
    •  & Tangchun Wu
  25. Information Management Services, Inc., Silver Spring, Maryland, USA.

    • William A Wheeler
    •  & Carol Giffen
  26. Department of Medical Oncology, Tumor Hospital of Linzhou, Linzhou, China.

    • Ai-Li Li
  27. Department of Pathology and Thoracic Surgery, Centre for Health Screening and Endoscopy, Cixian Hospital, Cixian, China.

    • Xue-Min Li
  28. Department of Gastroenterology, Henan Provincial People's Hospital, Zhengzhou, China.

    • Bao-Gen Ma
    •  & Yan-Rui Zhang
  29. Department of Hematology, Henan Provincial People's Hospital, Zhengzhou, China.

    • Bao-Gen Ma
    •  & Yan-Rui Zhang
  30. Central Laboratory, Henan Provincial People's Hospital, Zhengzhou, China.

    • Bao-Gen Ma
    •  & Yan-Rui Zhang
  31. Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA.

    • Peter Kraft
    •  & Ying-Fa Zhou
  32. Department of Basic Oncology, Pathology and Gastroenterology, The Second Affiliated Hospital, Zhengzhou University, Zhengzhou, China.

    • Li Wang
    • , Jing-Li Ren
    •  & Chang-Wei Feng
  33. Department of Oncology, The Second Affiliated Hospital of Nanyang Medical College, Nanyang, China.

    • Jian-Wei Ku
  34. Department of Radiotherapy, Pathology and Pediatrics, Central Hospital of Xinxiang, Xinxiang, China.

    • Liu-Qin Yang
    •  & Fang-Heng Zhu
  35. Department of Thoracic Surgery, Provincial Hospital affiliated to Shandong University, Jinan, China.

    • Zhou Wang
  36. Department of Thoracic Surgery and Radiotherapy, Cancer Hospital of Henan Province, Zhengzhou, China.

    • Yin Li
    •  & Ling Yuan
  37. Department of Internal Mongolia Medicine, The Affiliated Hospital, Inner Mongolia Medical College, Hohhot, China.

    • Qirenwang Qige
  38. Department of Biotechnology, Ningxia Medical University, Yinchuan, China.

    • Wen-Jun Yang
  39. Department of Thoracic Surgery, Tumor Hospital of Shaanxi Province, Xi'an, China.

    • Guang-Yan Lei
  40. Department of Thoracic and Cardiovascular Surgery, West China Hospital, Sichuan University, Chengdu, China.

    • Long-Qi Chen
  41. Department of Oncologic Pathology, Medical College of Shantou University, Shantou, China.

    • En-Min Li
  42. Department of Biochemistry and Molecular Biology, Medical College of Shantou University, Shantou, China.

    • En-Min Li
  43. Department of Oncology, Puyang City Oil Field General Hospital, Puyang, China.

    • Wen-Bin Yue
  44. Department of Pathology and Thoracic Surgery, Linzhou Esophageal Cancer Hospital, Linzhou, China.

    • Ji-Lin Li
  45. Department of Gastroenterology and Thoracic Surgery, The First People's Hospital of Shangqiu, Shangqiu, China.

    • Min Han
  46. Department of Gastroenterology, Beijing Tongren Hospital affiliated to Capital Medical University, Beijing, China.

    • Bin Liu
  47. Department of Oncology, Xinyang Central Hospital, Xinyang, China.

    • Shu-Wei Ren
  48. State Key Laboratory of Genetic Resource and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China.

    • Qing-Peng Kong
  49. Department of Pathology, Shihezi University School of Medicine, Shihezi, China.

    • Feng Li
  50. Department of Thoracic Surgery, The First Affiliated Hospital, Xinjiang Medical University, Urumqi, China.

    • Ilyar Sheyhidin
  51. Medical Research Center, The First Affiliated Hospital, Xinjiang Medical University, Urumqi, China.

    • Ilyar Sheyhidin
  52. Institute of Hematologic Disease, Changzhi Medical University, Changzhi, China.

    • Wu Wei
  53. Department of Pathology, Changzhi Medical University, Changzhi, China.

    • Wu Wei
  54. Department of Surgery, Hebi Dahejian Hospital, Hebi, China.

    • Yu-Hua Yang
  55. Anyang District Hospital, Anyang, China.

    • Hong-Zhang Hao
    •  & Qi-De Bao
  56. Surgical Department of the Shanghai Public Health Clinical Center, Fudan University, Shanghai, China.

    • Bao-Chi Liu
  57. Department of Anatomy, the Second Military Medical University of the Chinese People's Liberation Army, Shanghai, China.

    • Ai-Qun Wu
  58. Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.

    • Dong Xie
  59. Medical College of Wisconsin, Cancer Research Center, Milwaukee, Wisconsin, USA.

    • Liang Wang
  60. National Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences, Beijing, China.

    • Xiao-Hang Zhao
  61. College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.

    • Shu-Qing Chen
    •  & Jun-Yan Hong
  62. Department of Environmental and Occupational Health, University of Medicine and Dentistry of New Jersey, Newark, New Jersey, USA.

    • Jun-Yan Hong

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Contributions

C.C.A., S.J.C., N.D.F., A.M.G., N.H., D.L., X.S., P.R.T., L.-D.W., Zhaoming Wang and C. Wu organized and designed the study. L.B., S.J.C., A.H., D.L., X.S., P.R.T., L.-D.W., Zhaoming Wang, C. Wu, J.Y. and M.Y. conducted and supervised the genotyping of samples. C.C.A., S.J.C., N.D.F., A.M.G., M.G., D.L., N.H., P.R.T., L.-D.W., Zhaoming Wang and K.Y. contributed to the design and execution of statistical analysis. C.C.A., S.J.C., N.D.F., X.-S.F., A.M.G., J.H., N.H., D.L., X.S., P.R.T., W.T., L.-D.W., Zhaoming Wang, C. Wu and X.-B.Z. wrote the first draft of the manuscript. C. Wu, Zhaoming Wang, X.S., X.-S.F., C.C.A., J.H., N.H., X.-B.Z., W.T., Q.Z., Z. Hu, Z. He, W.J., Y. Zhou, K.Y., X.-O.S., J.-M.Y., W. Zheng, X.-K.Z., S.-G.G., Z.-Q.Y., F.-Y.Z., Z.-M.F., J.-L.C., H.-L.L., X.-N.H., B. Li, X.C., S.M.D., L.L., M.P.L., T.D., Y.-L.Q., Z.L., Yu Liu, D.Y., J.C., L. Wei, Y.-T.G., W.-P.K., Y.-B.X., Z.-Z.T., J.-H.F., J.-J.H., S.-L.Z., P.Z., D.-Y.Z., Y.Y., Y.H., C. Liu, K.Z., Y.Q., G.J., C. Guo, J.F., X.M., C. Lu, H.Y., C. Wang, W.A.W., M.G., M.Y., J.Y., E.-T.G., A.-L.L., W. Zhang, Xue-Min Li, L.-D.S., B.-G.M., Yan Li, S.T., X.-Q.P., J.L., A.H., K.J., C. Giffen, L.B., J.F.F., H.S., Y.K., Y. Zeng, T.W., P.K., C.C.C., M.A.T., Z.-C.H., Y.-L.L., Y.-L.H., Yu Liu, L.W., G.Y., L.-S.C., X.L., T.M., H.M., L.S., Xin-Min Li, Xiu-Min Li, J.-W.K., Y.-F.Z., L.-Q.Y., Zhou Wang, Yin Li, Q.Q., W.-J.Y., G.-Y.L., L.-Q.C., E.-M.L., L.Y., W.-B.Y., R.W., L.-W.W., X.-P.F., F.-H.Z., W.-X.Z., Y.-M.M., M.Z., G.-L.X., J.-L.L., M.H., J.-L.R., B. Liu, S.-W.R., Q.-P.K., F.L., I.S., W.W., Y.-R.Z., C.-W.F., J.W., Y.-H.Y., H.-Z.H., Q.-D.B., B.-C.L., A.-Q.W., D.X., W.-C.Y., L. Wang, X.-H.Z., S.-Q.C., J.-Y.H., X.-J.Z., N.D.F., A.M.G., D.L., P.R.T., L.-D.W. and S.J.C. contributed to the epidemiological studies or contributed samples to the GWAS or follow-up genotyping. C. Wu, Zhaoming Wang, X.S., X.-S.F., C.C.A., J.H., N.H., X.-B.Z., W.T., Q.Z., Z. Hu, Z. He, W.J., Y. Zhou, K.Y., X.-O.S., J.-M.Y., W. Zheng, X.-K.Z., S.-G.G., Z.-Q.Y., F.-Y.Z., Z.-M.F., J.-L.C., H.-L.L., X.-N.H., B. Li, X.C., S.M.D., L.L., M.P.L., T.D., Y.-L.Q., Z.L., Yu Liu, D.Y., J.C., L. Wei, Y.-T.G., W.-P.K., Y.-B.X., Z.-Z.T., J.-H.F., J.-J.H., S.-L.Z., P.Z., D.-Y.Z., Y.Y., Y.H., C. Liu, K.Z., Y.Q., G.J., C. Guo, J.F., X.M., C. Lu, H.Y., C. Wang, W.A.W., M.G., M.Y., J.Y., E.-T.G., A.-L.L., W. Zhang, Xue-Min Li, L.-D.S., B.-G.M., Yan Li, S.T., X.-Q.P., J.L., A.H., K.J., C. Giffen, L.B., J.F.F., H.S., Y.K., Y. Zeng, T.W., P.K., C.C.C., M.A.T., Z.-C.H., Y.-L.L., Y.-L.H., Yu Liu, L.W., G.Y., L.-S.C., X.L., T.M., H.M., L.S., Xin-Min Li, Xiu-Min Li, J.-W.K., Y.-F.Z., L.-Q.Y., Zhou Wang, Yin Li, Q.Q., W.-J.Y., G.-Y.L., L.-Q.C., E.-M.L., L.Y., W.-B.Y., R.W., L.-W.W., X.-P.F., F.-H.Z., W.-X.Z., Y.-M.M., M.Z., G.-L.X., J.-L.L., M.H., J.-L.R., B. Liu, S.-W.R., Q.-P.K., F.L., I.S., W.W., Y.-R.Z., C.-W.F., J.W., Y.-H.Y., H.-Z.H., Q.-D.B., B.-C.L., A.-Q.W., D.X., W.-C.Y., L. Wang, X.-H.Z., S.-Q.C., J.-Y.H., X.-J.Z., N.D.F., A.M.G., D.L., P.R.T., L.-D.W. and S.J.C. contributed to the writing of the manuscript.

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The authors declare no competing financial interests.

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Correspondence to Dongxin Lin or Philip R Taylor or Li-Dong Wang.

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https://doi.org/10.1038/ng.3064

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