Letter | Published:

Genome-wide association study identifies three new susceptibility loci for esophageal squamous-cell carcinoma in Chinese populations

Nature Genetics volume 43, pages 679684 (2011) | Download Citation


Esophageal squamous-cell carcinoma (ESCC) is one of the most prevalent cancers worldwide and occurs at a relatively high frequency in China. To identify genetic susceptibility loci for ESCC, we conducted a genome-wide association study on 2,031 individuals with ESCC (cases) and 2,044 controls of Chinese descent using 666,141 autosomal SNPs. We evaluated promising associations in an additional 6,276 cases and 6,165 controls of Chinese descent from different areas of China. We identified seven susceptibility loci on chromosomes 5q11, 6p21, 10q23, 12q24 and 21q22 (ranging from P = 7.48 × 10−12 to P = 2.44 × 10−31); among these loci, 5q11, 6p21 and 21q22 were newly identified. Three variants in high linkage disequilibrium on 12q24 confer their risks to ESCC in a gene-lifestyle interaction manner, with more pronounced risk enhancement seen in tobacco and alcohol users. Furthermore, the identified variants had a cumulative association with ESCC risk (Ptrend = 7.92 × 10−56). These findings highlight the involvement of multiple genetic loci and gene-environment interaction in the development of esophageal cancer.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1.

    , , , & Methylenetetrahydrofolate reductase polymorphisms increases risk of esophageal squamous cell carcinoma in a Chinese population. Cancer Res. 61, 3272–3275 (2001).

  2. 2.

    et al. Polymorphisms of death pathway genes FAS and FASL in esophageal squamous-cell carcinoma. J. Natl. Cancer Inst. 96, 1030–1036 (2004).

  3. 3.

    et al. Identification of functional genetic variants in cyclooxygenase-2 and their association with risk of esophageal cancer. Gastroenterology 129, 565–576 (2005).

  4. 4.

    et al. A six-nucleotide insertion-deletion polymorphism in the CASP8 promoter is associated with susceptibility to multiple cancers. Nat. Genet. 39, 605–613 (2007).

  5. 5.

    et al. Functional variants in ADH1B and ALDH2 coupled with alcohol and smoking synergistically enhance esophageal cancer risk. Gastroenterology 137, 1768–1775 (2009).

  6. 6.

    et al. Genome-wide association study of esophageal squamous cell carcinoma in Chinese subjects identifies susceptibility loci at PLCE1 and C20orf54. Nat. Genet. 42, 759–763 (2010).

  7. 7.

    et al. A shared susceptibility locus in PLCE1 at 10q23 for gastric adenocarcinoma and esophageal squamous cell carcinoma. Nat. Genet. 42, 764–767 (2010).

  8. 8.

    et al. Cumulative association of five genetic variants with prostate cancer. N. Engl. J. Med. 358, 910–919 (2008).

  9. 9.

    et al. Genome-wide identification of recessive cancer genes by combinatorial mutation analysis. PLoS ONE 3, e3380 (2008).

  10. 10.

    et al. Regulation of multidrug resistance by ribosomal protein l6 in gastric cancer cells. Cancer Biol. Ther. 4, 242–247 (2005).

  11. 11.

    et al. Molecular characterization of breast cancer cell lines by expression profiling. J. Cancer Res. Clin. Oncol. 128, 125–134 (2002).

  12. 12.

    et al. Identification of discriminators of hepatoma by gene expression profiling using a minimal dataset approach. Hepatology 39, 944–953 (2004).

  13. 13.

    et al. Ribosomal protein L6 promotes growth and cell cycle progression through upregulating cyclin E in gastric cancer cells. Biochem. Biophys. Res. Commun. 393, 788–793 (2010).

  14. 14.

    , & Protein-tyrosine phosphatases and cancer. Nat. Rev. Cancer 6, 307–320 (2006).

  15. 15.

    & The role of Shp2 (PTPN11) in cancer. Curr. Opin. Genet. Dev. 17, 23–30 (2007).

  16. 16.

    et al. A large-scale genome-wide association study of Asian populations uncovers genetic factors influencing eight quantitative traits. Nat. Genet. 41, 527–534 (2009).

  17. 17.

    et al. Genome-wide association study of blood pressure and hypertension. Nat. Genet. 41, 677–687 (2009).

  18. 18.

    et al. A genome-wide meta analysis identifies 22 loci associated with eight hematological parameters in the HaemGen consortium. Nat. Genet. 41, 1182–1190 (2009).

  19. 19.

    et al. Genome-wide copy number analysis in esophageal adenocarcinoma using high-density single-nucleotide polymorphism arrays. Cancer Res. 68, 4263–4272 (2008).

  20. 20.

    et al. Homozygous deletion scanning of the lung cancer genome at a 100-kb resolution. Genes Chromosom. Cancer 46, 1000–1010 (2007).

  21. 21.

    , & The RUNX genes: gain or loss of function in cancer. Nat. Rev. Cancer 5, 376–387 (2005).

  22. 22.

    et al. A differential gene expression profile reveals overexpression of RUNX1/AML1 in invasive endometrioid carcinoma. Cancer Res. 64, 8846–8853 (2004).

  23. 23.

    et al. Runx1 directly promotes proliferation of hair follicle stem cells and epithelial tumor formation in mouse skin. Mol. Cell. Biol. 30, 2518–2536 (2010).

  24. 24.

    et al. Delineating genetic alterations for tumor progression in the MCF10A series of breast cancer cell lines. PLoS ONE 5, e9201 (2010).

  25. 25.

    et al. Frequent downregulation of the runt domain transcription factors RUNX1, RUNX3 and their cofactor CBFB in gastric cancer. Int. J. Cancer 113, 221–228 (2005).

  26. 26.

    et al. Novel regions of chromosomal amplification at 6p21, 5p13, and 12q14 in gastric cancer identified by array comparative genomic hybridization. Genes Chromosom. Cancer 42, 247–259 (2010).

  27. 27.

    et al. Mapping of novel regions of DNA gain and loss by comparative genomic hybridization in esophageal carcinoma in the black and colored populations of South Africa. Cancer Res. 59, 1877–1883 (1999).

  28. 28.

    , , & Identification of a ZU5 and death domain-containing inhibitor of NF-kappaB. J. Biol. Chem. 279, 17819–17825 (2004).

  29. 29.

    & Quantifying and correcting for the winner's curse in genetic association studies. Genet. Epidemiol. 33, 453–462 (2009).

  30. 30.

    et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007).

  31. 31.

    et al. Principal components analysis corrects for stratification in genome-wide association studies. Nat. Genet. 38, 904–909 (2006).

  32. 32.

    , , & Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21, 263–265 (2005).

Download references


We would like to thank Y. Li of University of North Carolina for her help in imputation analysis and helpful review of the manuscript. This work is funded by the National High-Tech Research and Development Program of China (2009AA022706 to D.L.), National Basic Research Program of China (2011CB504303 to D.L. and W.T.) and the National Natural Science Foundation of China (30721001 to Q.Z., D.L. and Z.L.).

Author information

Author notes

    • Zhibin Hu
    • , Zhonghu He
    • , Weihua Jia
    • , Feng Wang
    • , Hongbing Shen
    • , Yang Ke
    • , Yixin Zeng
    •  & Tangchun Wu

    These authors contributed equally to this work.


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

    • Chen Wu
    • , Zhihua Liu
    • , Qimin Zhan
    • , Yu Liu
    • , Dianke Yu
    • , Kan Zhai
    • , Jiang Chang
    • , Yan Qiao
    • , Wen Tan
    •  & Dongxin Lin
  2. Department of Epidemiology and Biostatistics, Cancer Center, Nanjing Medical University, Nanjing, China.

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

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

    • Weihua Jia
    • , Jianhua Fu
    •  & Yixin Zeng
  5. Key Laboratory for Environment and Health (Ministry of Education), School of Public Health, Huazhong University of Sciences and Technology, Wuhan, China.

    • Feng Wang
    • , Xiaoping Miao
    •  & Tangchun Wu
  6. Laboratory of Cancer Molecular Genetics, Medical College of Soochow University, Suzhou, China.

    • Yifeng Zhou
  7. Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.

    • Zhe Liu
    •  & Yuanyuan Shen


  1. Search for Chen Wu in:

  2. Search for Zhibin Hu in:

  3. Search for Zhonghu He in:

  4. Search for Weihua Jia in:

  5. Search for Feng Wang in:

  6. Search for Yifeng Zhou in:

  7. Search for Zhihua Liu in:

  8. Search for Qimin Zhan in:

  9. Search for Yu Liu in:

  10. Search for Dianke Yu in:

  11. Search for Kan Zhai in:

  12. Search for Jiang Chang in:

  13. Search for Yan Qiao in:

  14. Search for Guangfu Jin in:

  15. Search for Zhe Liu in:

  16. Search for Yuanyuan Shen in:

  17. Search for Chuanhai Guo in:

  18. Search for Jianhua Fu in:

  19. Search for Xiaoping Miao in:

  20. Search for Wen Tan in:

  21. Search for Hongbing Shen in:

  22. Search for Yang Ke in:

  23. Search for Yixin Zeng in:

  24. Search for Tangchun Wu in:

  25. Search for Dongxin Lin in:


D.L. was the overall study principal investigator who conceived the study and obtained financial support and was responsible for study design, oversaw the entire study, interpreted the results and wrote parts of and synthesized the paper. C.W. performed overall project management, oversaw laboratory analyses and statistical analyses and drafted the initial manuscript. Z. Hu, G.J. and H.S. were responsible for subject recruitment and sample preparation of Nanjing samples. Z. He, C.G. and Y.K. were responsible for subject recruitment and sample preparation of the Anyang samples. W.J., J.F. and Y. Zeng were responsible for subject recruitment and sample preparation of Guangzhou samples. F.W. and T.W. provided some of the control samples. Y. Zhou was responsible for subject recruitment and sample preparation of the additional independent validation cohort. D.Y., K.Z., J.C., Y.Q. and W.T. performed subject recruitment and sample preparation of the Beijing samples. Y.L., X.M., Zhe Liu and Y.S. performed statistical analyses. Q.Z. and Zhihua Liu provided financial support and reviewed the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Dongxin Lin.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Tables 1–7 and Supplementary Figures 1–4.

About this article

Publication history






Further reading