Letter | Published:

Genome-wide association study of esophageal squamous cell carcinoma in Chinese subjects identifies a susceptibility locus at PLCE1

Nature Genetics volume 42, pages 759763 (2010) | Download Citation

  • A Corrigendum to this article was published on 27 August 2014

This article has been updated

Abstract

We performed a genome-wide association study of esophageal squamous cell carcinoma (ESCC) by genotyping 1,077 individuals with ESCC and 1,733 control subjects of Chinese Han descent. We selected 18 promising SNPs for replication in an additional 7,673 cases of ESCC and 11,013 control subjects of Chinese Han descent and 303 cases of ESCC and 537 control subjects of Chinese Uygur-Kazakh descent. We identified a previously unknown susceptibility locus for ESCC: PLCE1 at 10q23 (PHan combined for ESCC = 7.46 × 10−56, odds ratio (OR) = 1.43; PUygur-Kazakh for ESCC = 5.70 × 10−4, OR = 1.53). We also confirmed association in 2,766 cases of gastric cardia adenocarcinoma and the same 11,013 control subjects (PLCE1, PHan for GCA = 1.74 × 10−39, OR = 1.55. PLCE1 has important biological implications for both ESCC and GCA. PLCE1 might regulate cell growth, differentiation, apoptosis and angiogenesis.

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Change history

  • 27 August 2014

    In contrast to the version of this article initially published, the authors now find no evidence to support association with esophageal squamous cell carcinoma susceptibility for rs13042395[T] at 20p13 in their original data, in two independent sets of cases and controls collected in other Chinese populations or in the joint analysis of these three studies.   The original signal at the C20orf54 locus (rs13042395) in the published Henan genome-wide association study (GWAS) was based on the scan of a total of 2,810 subjects (1,077 cases and 1,733 controls) with a per-allele odds ratio (OR) of 0.66 (95% confidence interval (CI) = 0.58–0.74; P =1.51 × 10−11), and P < 5 × 10−6 was reported for a genetically matched subset of 937 cases and 692 controls.   A new analysis by the authors (see Supplementary Table 8 in Nat. Genet.  46, 1001–1006, 2014) included a distinct genetically matched subset of the original genotypes (1,789 total subjects: 1,076 cases and 713 controls; OR = 0.80 (95% CI = 0.65–0.98); P = 0.03) and subjects scanned after publication of the initial Henan data (669 new subjects: 229 cases and 370 controls; OR = 1.06 (95% CI = 0.82–1.38); P = 0.63). The combination of the genetically matched and new subjects (n = 2,458 subjects in total: 1,375 cases and 1,083 controls) yielded OR = 0.88 (95% CI = 0.76–1.02; P = 9.12 × 10−2).   Thus, the original Henan scan is the only result that showed a significant association for rs13042395. None of the three new analyses performed confirmed a significant association for rs13042395. Moreover, this SNP was not significant in the National Cancer Institute GWAS (OR = 0.95, 95% CI = 0.86–1.05; P = 3.04 × 10−1), Beijing GWAS (OR = 1.07, 95% CI = 0.93–1.23; P = 3.34 × 10−1) or combined data (OR = 0.96, 95% CI = 0.90–1.03; P = 3.02 × 10−1; see Supplementary Table 8 in Nat. Genet.  46, 1001–1006, 2014).   In summary, the published association for rs13042395 did not replicate in additional analyses of data from Henan. Nor did it replicate in a GWAS from a similar high-risk population (National Cancer Institute) or in a GWAS from a low-risk population (Beijing). Thus, the original finding was likely the result of inadequate control for population stratification using the genetically unmatched subjects or, less likely, could have been due to chance alone.   The error has been corrected in the HTML and PDF versions of the article. In addition, Supplementary Figures 1–4 and Supplementary Table 1 have been corrected.

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Acknowledgements

We thank all the patients and their family members whose contributions made this work possible; medical students from Xinxiang Medical University for sample and data collections; Y. Xing (Xinxiang Medical University) for organizing field work for sample collections and finding financial support for this study; the genotyping at Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, China, Hefei, Anhui for genotyping and statistical and bioinformatic analyses; B.G. Ma (Henan Provincial People's Hospital), W. Huang (Health Department of Henan Province), S.Y. Lian (Tumor Hospital of Linzhou), Z. Wang (Anyang Tumor Hospital), W. Zhang and J.T. Zhao (both People's Hospital of Heibi) for field work organization; J.H. Bian (Shantou University), J.J. Liu (Human Genetics, Genome Institute of Singapore) and I. Ding (National Cancer Institute, NIH) for discussions about the manuscript. Supported by Xinxiang Medical University Key Scientific Program (2009-5), the National Natural Science Foundations (30670956, 30971133), 863 HighTech Key Projects (2006AA02A403, 2007AA02Z161), China Key Program on Basic Research (2007CB516812), Special Scientific Programs from Science and Technology Department (2009-8), Health Department (2009-10) and Education Department (2008-7) of Henan Province and Anhui Provincial Special Scientific Program (2007-7).

Author information

Author notes

    • Wan-Cai Yang
    •  & Jun-Yan Hong

    Present addresses: Department of Pathology, University of Illinois at Chicago, Chicago, Illinois, USA (W.-C.Y.); Department of Environment and Occupational Health, School of Public Health, University of Medicine and Dentistry of New Jersey, Piscataway, New Jersey, USA (J.-Y.H.).

Affiliations

  1. Cancer Research Center, Xinxiang Medical University, Xinxiang, Henan, China.

    • Li-Dong Wang
    • , Xin Song
    • , Yan Jin
    • , Jiang-Man Li
    • , Lian-Qun Zhang
    • , Ji-Lin Li
    • , Dan Li
    • , Sheng-Li Zhou
    • , Zhi-Gang Guo
    • , Xue-Ke Zhao
    • , Na Liu
    • , Yong-Hong Ai
    • , Fang-Fang Shen
    • , Wen-Yan Cui
    • , Yi Yuan
    • , Hai-Yan Wang
    • , Peng Zhang
    • , Xiu-Min Li
    • , Hai-Lin Liu
    • , Zhi-Qing Yuan
    • , Zhi-Guo Chen
    • , Tian-Yun Wang
    • , Wan-Cai Yang
    •  & Liang Wang
  2. Henan Key Laboratory for Esophageal Cancer Research, Department of Basic Oncology and Pathology at College of Medicine, The First and The Second Affiliated Hospital, Zhengzhou University, Zhengzhou, Henan, China.

    • Li-Dong Wang
    • , Fu-You Zhou
    • , Xue-Min Li
    • , Xin Song
    • , Jiang-Man Li
    • , Guo-Qiang Kong
    • , Hong Qi
    • , Juan Cui
    • , Jie-Zhi Yang
    • , Xing-Chuan Li
    • , Jing-Li Ren
    • , Ling Yuan
    • , Wei-Peng Wang
    • , Dan Li
    • , Zong-Min Fan
    • , Shuang Song
    • , Tao Guo
    • , Jing Huang
    • , Chao Yuan
    • , Jia Huang
    • , Yue Wu
    • , Chang-Wei Feng
    • , Hong-Lei Li
    • , Yan Wang
    • , Jin-Ya Tian
    • , Yue Lu
    • , Wen-Liang Zhu
    • , Min Liu
    • , Wen-Jing Fu
    • , Xia Yang
    • , Han-Jing Wang
    • , Suo-Li Han
    • , Jie Chen
    • , Jin-Cheng Dong
    • , Guo-Lan Xing
    • , Ran Wang
    • , Ming Guo
    • , Zhi-Wei Chang
    • , Li Guo
    • , Qin Lu
    • , Jian-Po Wang
    • , Guang-Cheng Ding
    • , Xiang Zhuang
    • , Ying-Fa Zhou
    • , Zi-Ming Dong
    • , Dong-Mei Fan
    • , Xin He
    • , Jin Wang
    • , Qi Zhou
    • , Qin-Xian Zhang
    •  & Song-Liang Qiu
  3. Department of Thoracic Surgery and Tumor Prevention Treatment, Anyang Tumor Hospital, Anyang, Henan, China.

    • Fu-You Zhou
    • , Jian-Po Wang
    •  & Chang-Dong Lu
  4. Department of Pathology and Thoracic Surgery, Centre for Health Screening and Endoscopy, Cixian Hospital, Cixian, Hebei, China.

    • Xue-Min Li
    • , Wei-Peng Wang
    • , Zhi-Qin Bao
    • , Ji-Li Chen
    • , Jian-Jun Miao
    •  & Zeng-Lin Fan
  5. Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, China, Hefei, Anhui, China.

    • Liang-Dan Sun
    • , Hou-Feng Zheng
    • , Zheng Zhang
    • , Xian-Bo Zuo
    •  & Xue-Jun Zhang
  6. Department of Pathology and Thoracic Surgery, Linzhou Esophageal Cancer Hospital, Linzhou, Henan, China.

    • Ji-Lin Li
    • , Xin-Ying Jiao
    •  & Jin-Chang Wei
  7. Department of Thoracic Surgery, Tumor Hospital of Linzhou, Linzhou, Henan, China.

    • Zhi-Cai Liu
    •  & Shi-Yong Lian
  8. Department of Thoracic Surgery, People's Hospital and Chinese Medicine Hospital of Linzhou, Linzhou, Henan, China.

    • Wen-Jun Gao
    •  & Fu-Bao Chang
  9. Department of Thoracic Surgery and Radiotherapy, Cancer Hospital of Henan Province, Zhengzhou, Henan, China.

    • Ling Yuan
    •  & Yin Li
  10. Institute of Hematologic Disease and Department of Pathology, Changzhi Medical University, Changzhi, Shanxi, China.

    • Wu Wei
    • , Ai-Fang Ji
    •  & Jin-Sheng Wang
  11. Department of Gastroenterology, Henan Provincial People's Hospital, Zhengzhou, Henan, China.

    • Yan-Rui Zhang
  12. Department of Thoracic Surgery and Medical Research Center, The First Affiliated Hospital, Xinjiang Medical University, Urumqi, Xinjiang, China.

    • Ilyar Sheyhidin
    •  & Xiao-Mei Lu
  13. Department of Pathology, Shihezi University School of Medicine, Shihezi, Xinjiang, China.

    • Feng Li
  14. Department of Nephrology, Huaihe Hospital, Henan University, Kaifeng, Henan, China.

    • Bao-Ping Chen
  15. Department of Oncology, Xinyang Central Hospital, Xinyang, Henan, China.

    • Shu-Wei Ren
  16. Department of Gastroenterology, Beijing Tongren Hospital Affiliated to Capital Medical University, Beijing, China.

    • Bin Liu
    •  & Fu-Sheng Gao
  17. Department of Oncology, The First Affiliated Hospital of Nanyang Medical College, Nanyang, Henan, China.

    • Jian-Wei Ku
  18. Department of Oncology, People's Hospital of Puyang, Puyang, Henan, China.

    • Wen-Bin Yue
  19. Department of Gastroenterology and Thoracic Surgery, The First People's Hospital of Shangqiu, Shangqiu, Henan, China.

    • Min Han
    •  & Fu-Guo Zhu
  20. Department of Gastroenterology, The Third People's Hospital of Yunnan Province, Kunming, Yunnan, China.

    • Hai Liu
  21. Department of Radiotherapy, Central Hospital of Xinxiang, Xinxiang, Henan, China.

    • Liu-Qin Yang
  22. Department of Surgery, Hebi Dahejian Hospital, Hebi, Henan, China.

    • Xiu-Feng Yang
  23. Department of Oncology, The First Affiliated Hospital, Henan University of Science and Technology, Luoyang, Henan, China.

    • Xiao-Shan Feng
    •  & She-Gan Gao
  24. Department of Thoracic Surgery, Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, China.

    • Zhou Wang
  25. Department of Internal Mongolia Medicine, The Affiliated Hospital, Inner Mongolia Medical College, Huhhot, Inner Mongolia, China.

    • Qirenwang Qige
    •  & Long-Tang Bai
  26. Department of Biotechnology, Ningxia Medical University, Yinchuan, Ningxia, China.

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

    • Guang-Yan Lei
  28. Department of Oncologic Pathology, and Department of Biochemistry and Molecular Biology, Medical College of Shantou University, Shantou, Guangdong, China.

    • Zhong-Ying Shen
    • , En-Min Li
    • , Li-Yan Xu
    •  & Zhi-Yong Wu
  29. Department of Thoracic and Cardiovascular Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China.

    • Long-Qi Chen
  30. Central Laboratory, Huaian No.1 Hospital, Nanjing Medical University, Huaian, Jiangsu, China.

    • Wei-Ke Cao
  31. Department of Thoracic Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, China.

    • Ruo-Bai Lin
  32. Department of Surgery, The Red Cross Hospital of Huojia, Xinxiang, Henan, China.

    • Tai-Jiang Liu
  33. State Key Laboratory of Genetic Resource and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China.

    • Qing-Peng Kong
  34. Department of Gastroenterology, Beijing Jishuitan Hospital, The Fourth Medical College of Peking University, Beijing, China.

    • Yu Lan
    •  & Yu-Jing Fan
  35. Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.

    • Dong Xie
  36. College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China.

    • Shu-Qing Chen
    •  & Jun-Yan Hong
  37. Guangdong Key Laboratory of Male Reprodutive Medicine and Genetics, Peking University Shenzhen Hospital, Shenzhen, Guangdong, China.

    • Zhi-Ming Cai

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Contributions

L.-D.W. and X.-J.Z. conceived of this study and obtained financial support. L.-D.W. and X.-J.Z. designed the study. Subject recruitment, biological material collection and handling along with DNA extraction in Henan, Hebei and Shanxi Provinces were supervised by L.-D.W., F.-Y.Z., Xue-Min Li and carried out by J.-L.L., X.S., Y.J., H.-L. Liu, J.-M.L., G.-Q.K., H.Q., J. Cui, L.-Q.Z., J.-Z.Y., X.-C.L., J.-L.R., Z.-C.L., W.-J.G., W.W., Y.-R.Z., W.-P.W., B.-P.C., S.-W.R., D.L., J.-W.K., Z.-M.F., S.-L.Z., Z.-G.G., X.-K.Z., N.L., Y.-H.A., F.-F.S., W.-Y.C., S.S., T.G., Jing Huang, C.Y., Jia Huang, Y. Wu, W.-B.Y., C.-W.F., H.-L. Li, L.Y., Y. Wang, J.-Y.T., Y. Lu, Y.Y., W.-L.Z., M.L., W.-J.F., X.Y., H.-J.W., S.-L.H., J. Chen, M.H., H.-Y.W., P.Z., Xiu-Min Li, J.-C.D., G.-L.X., R.W., M.G., Z.-W.C., Z.-Q.Y., Q.L., L.-Q.Y., F.-G.Z., X.-F.Y., X.-S.F., Yin Li, S.-G.G., J.-P.W., J.W., Z.-Q.B., L.G., J.-L.C., G.-C.D., X.Z., Y.-F.Z., Z.-M.D., X.-Y.J., D.-M.F., A.-F.J., J.-S.W., Q.Z., Q.-X.Z., F.-B.C., C.-D.L., J.-J.M., Z.-L.F., T.-J.L., S.-L.Q., Z.-G.C., J.-C.W., T.-Y.W. and X.H. The following authors from the various collaborating groups undertook assembly of case-control series in their respective regions and collected samples and data: I.S., F.L. and X.-M.L. in Xinjiang Uygur Autonomous Region; Q.Q. and L.-T.B. in Inner Mongolia Autonomous Region; Z.-Y.S., E.-M.L., L.-Y.X. and Z.-Y.W. in Guangdong Province; W.-K.C. in Jiangsu Province; G.-Y.L. in Shaanxi Province; Z.W. in Shandong Province; W.-J.Y. in Ningxia Hui Tribe Autonomous Region; L.-Q.C. in Sichuan Province; R.-B.L. in Fujian Province; B.L., F.-S.G., Yu Lan and Y.-J.F. in Beijing; Z.-M.C. in Guangdong Province; H.L. in Yunnan Province; S.-Q.C., W.C.Y., J.-Y.H., D.X., L.W. and Q.-P.K. participated in study design, results discussion and manuscript preparation; L.-D.S., H.-F.Z., Z.Z., X.-B.Z., X.S., G.-Q.K. and L.-Q.Z. performed the two-staged genotyping and sequencing, data manipulation, statistical and bioinformatic analyses. The manuscript was drafted by L.-D.W., and all authors contributed to the final draft.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Li-Dong Wang.

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DOI

https://doi.org/10.1038/ng.648

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