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A genome-wide association study identifies new susceptibility loci for esophageal adenocarcinoma and Barrett's esophagus

Nature Genetics volume 45, pages 1487–1493 (2013)Cite this article

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Abstract

Esophageal adenocarcinoma is a cancer with rising incidence and poor survival. Most such cancers arise in a specialized intestinal metaplastic epithelium, which is diagnostic of Barrett's esophagus. In a genome-wide association study, we compared esophageal adenocarcinoma cases (n = 2,390) and individuals with precancerous Barrett's esophagus (n = 3,175) with 10,120 controls in 2 phases. For the combined case group, we identified three new associations. The first is at 19p13 (rs10419226: P = 3.6 × 10−10) in CRTC1 (encoding CREB-regulated transcription coactivator), whose aberrant activation has been associated with oncogenic activity. A second is at 9q22 (rs11789015: P = 1.0 × 10−9) in BARX1, which encodes a transcription factor important in esophageal specification. A third is at 3p14 (rs2687201: P = 5.5 × 10−9) near the transcription factor FOXP1, which regulates esophageal development. We also refine a previously reported association with Barrett's esophagus near the putative tumor suppressor gene FOXF1 at 16q24 and extend our findings to now include esophageal adenocarcinoma.

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Figure 1: Plot of genome-wide association results from the discovery data for combined Barrett's esophagus and esophageal adenocarcinoma cases using an additive logistic regression model with age, sex and the first four eigenvectors from PCA used as covariates.
Figure 2: Regional association plots showing genotyped and imputed SNPs from the discovery data for the combined Barrett's esophagus and esophageal adenocarcinoma cases.

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Acknowledgements

We thank P. Christopherson, P. Hansen, L. Nolan and T. Watson for their efforts in project management and the organization of biospecimens and data, and we thank Cathy Laurie, Cecelia Laurie and B. Weir for helpful suggestions regarding analyses.

This work was primarily funded by a US National Institutes of Health (NIH) grant (R01CA136725) to T.L.V. and D.C.W. T.L.V. is also supported by grant K05CA124911. D.C.W. is supported by a Future Fellowship (FT0990987) from the Australian Research Council. S.M. is supported by an Australian National Health and Medical Research Council (NHMRC) Career Development Award. N.K.H. is supported by Research Fellowships from the NHMRC of Australia. Y.R. is supported in part by a grant from the US NIH (NIDDK 02956), the Robert Wood Johnson Foundation Harold Amos Medical Faculty Development Program and the Fraternal Order of the Eagles.

The Swedish Esophageal Cancer Study was funded by grants (R01 CA57947-03) from the National Cancer Institute and the Swedish Cancer Society (4559-B01-01XAA and 4758-B02-01XAB). The Kaiser-Permanente Study was supported by grants from the US NIH (R01DK63616 and R01CA59636) and from the California Tobacco-Related Research Program (3RT-0122 and 10RT-0251). The UK Barrett's oesophagus gene study was funded by a Medical Research Council Programme grant, and the UK SOCS study was funded by Cancer Research UK as well as by the Cambridge National Institute for Health Research Biomedical Research Centre and the Cambridge Experimental Cancer Medicine Centre. The SEARCH grant was funded by Cancer Research UK grants C490/A10119 and C490/A10124.

Genotyping of MD Anderson controls (C. Amos, PI) was performed through the University of Texas MD Anderson Cancer Center (UTMDACC) and the Johns Hopkins University Center for Inherited Disease Research (CIDR), supported in part by US NIH grants R01CA100264, P30CA016672 and R01CA133996 and the UTMDACC NIH SPORE in Melanoma 2P50CA093459, as well as by the Marit Peterson Fund for Melanoma Research. CIDR is supported by contract HHSN268200782096C from the US NIH.

This study made use of data generated by the Wellcome Trust Case Control Consortium. Funding for the project was provided by the Wellcome Trust under award 076113. A full list of the investigators who contributed to the generation of the data is available from the website (see URLs).

The Romero Registry is supported in part by the American Digestive Health Foundation Endoscopic Research Award, the American College of Gastroenterology Junior Faculty Development Award, the Glaxo Wellcome, Inc., Institute for Digestive Health Clinical Research Award and the Miles and Shirley Fiterman Center for Digestive Diseases at the Mayo Clinic (Rochester, Minnesota). The Romero Registry also receives charitable gifts from five industry partners (Affymetrix, AstraZeneca, Santarus, Takeda and Wyeth). The US Multicenter Study was funded by grants U01CA57949, U01CA57983 and U01CA57923 from the US NIH.

Members of the Romero Registry: Sami R. Achem (Mayo Clinic, Jacksonville, Florida, USA), Yvonne Romero (Mayo Clinic, Rochester, Minnesota, USA), David A. Ahlquist (Mayo Clinic, Rochester, Minnesota, USA), Steven R. Alberts (Mayo Clinic, Rochester, Minnesota, USA), Jeffrey A. Alexander (Mayo Clinic, Rochester, Minnesota, USA), Mark S. Allen (Mayo Clinic, Rochester, Minnesota, USA), Amindra S. Arora (Mayo Clinic, Rochester, Minnesota, USA), Jonathan B. Ashman (Mayo Clinic, Phoenix, Arizona, USA), Pamela J. Atherton (Mayo Clinic, Rochester, Minnesota, USA), Lisa A. Boardman (Mayo Clinic, Rochester, Minnesota, USA), Ernest P. Bouras (Mayo Clinic, Jacksonville, Florida, USA), Vicki A. Bryhn (Mayo Clinic, Rochester, Minnesota, USA), Patrick A. Burch (Mayo Clinic, Rochester, Minnesota, USA), George E. Burdick (Mayo Clinic, Rochester, Minnesota, USA), Navtej S. Buttar (Mayo Clinic, Rochester, Minnesota, USA), John K. Camoriano (Mayo Clinic, Phoenix, Arizona, USA), John R. Cangemi (Mayo Clinic, Jacksonville, Florida, USA), Stephen D. Cassivi (Mayo Clinic, Rochester, Minnesota, USA), Frances K. Cayer (Mayo Clinic, Jacksonville, Florida, USA), Amy C. Clayton (Mayo Clinic, Rochester, Minnesota, USA), Michael D. Crowell (Mayo Clinic, Phoenix, Arizona, USA), Julie M. Cunningham (Mayo Clinic, Rochester, Minnesota, USA), Mariza de Andrade (Mayo Clinic, Rochester, Minnesota, USA), Piet de Groen (Mayo Clinic, Rochester, Minnesota, USA), Giovani De Petris (Mayo Clinic, Phoenix, Arizona, USA), Claude Deschamps (Mayo Clinic, Rochester, Minnesota, USA), Kenneth R. DeVault (Mayo Clinic, Jacksonville, Florida, USA), Robert B. Diasio (Mayo Clinic, Rochester, Minnesota, USA), John K. DiBaise (Mayo Clinic, Phoenix, Arizona, USA), Eric S. Edell (Mayo Clinic, Rochester, Minnesota, USA), Sharon Elcombe (Mayo Clinic, Rochester, Minnesota, USA), Charles Erlichman (Mayo Clinic, Rochester, Minnesota, USA), Douglas O. Faigel (Mayo Clinic, Phoenix, Arizona, USA), Tom R. Fitch (Mayo Clinic, Phoenix, Arizona, USA), David E. Fleischer (Mayo Clinic, Phoenix, Arizona, USA), Jean C. Fox (Mayo Clinic, Rochester, Minnesota, USA), Amy E. Foxx-Orenstein (Mayo Clinic, Rochester, Minnesota, USA), Dawn Francis (Mayo Clinic, Rochester, Minnesota, USA), Mary B. Fredericksen (Mayo Clinic, Rochester, Minnesota, USA), Evanthia Galanis (Mayo Clinic, Rochester, Minnesota, USA), Debra M. Geno (Mayo Clinic, Rochester, Minnesota, USA), Axel Grothey (Mayo Clinic, Rochester, Minnesota, USA), Michael G. Haddock (Mayo Clinic, Rochester, Minnesota, USA), Kevin C. Halling (Mayo Clinic, Rochester, Minnesota, USA), Denise M. Harnois (Mayo Clinic, Jacksonville, Florida, USA), Tracy W. Hilton (Mayo Clinic, Jacksonville, Florida, USA), Timothy Hobday (Mayo Clinic, Rochester, Minnesota, USA), Lesley A. Houghton (Mayo Clinic, Jacksonville, Florida, USA), Prasad A. Iyer (Mayo Clinic, Rochester, Minnesota, USA), Dawn E. Jaroszewski (Mayo Clinic, Phoenix, Arizona, USA), Aminah Jatoi (Mayo Clinic, Rochester, Minnesota, USA), Robert B. Jenkins (Mayo Clinic, Rochester, Minnesota, USA), Elizabeth A. Johnson (Mayo Clinic, Jacksonville, Florida, USA), Rajni Katipamula (Mayo Clinic, Rochester, Minnesota, USA), David A. Katzka (Mayo Clinic, Rochester, Minnesota, USA), Sharon F. Kaufman (Mayo Clinic, Rochester, Minnesota, USA), Andrew P. Keaveny (Mayo Clinic, Jacksonville, Florida, USA), Daniel A. Keller (Mayo Clinic, Rochester, Minnesota, USA), George P. Kim (Mayo Clinic, Jacksonville, Florida, USA), Benjamin R. Kipp (Mayo Clinic, Rochester, Minnesota, USA), Dora M. Lam-Himlin (Mayo Clinic, Rochester, Minnesota, USA), Stephen M. Lange (Mayo Clinic, Jacksonville, Florida, USA), Louis Lanza (Mayo Clinic, Phoenix, Arizona, USA), Shauna N. Legrand (Mayo Clinic, Jacksonville, Florida, USA), Paul J. Limburg (Mayo Clinic, Rochester, Minnesota, USA), Wilma L. Lingle (Mayo Clinic, Rochester, Minnesota, USA), Wanguo Liu (Mayo Clinic, Rochester, Minnesota, USA), G. Richard Locke III (Mayo Clinic, Rochester, Minnesota, USA), David S. Loeb (Mayo Clinic, Jacksonville, Florida, USA), Lori S. Lutzke (Mayo Clinic, Rochester, Minnesota, USA), James A. Martenson Jr. (Mayo Clinic, Rochester, Minnesota, USA), Robert R. McWilliams (Mayo Clinic, Rochester, Minnesota, USA), Robert C. Miller (Mayo Clinic, Rochester, Minnesota, USA), Joseph A. Murray (Mayo Clinic, Rochester, Minnesota, USA), Cuong C. Nguyen (Mayo Clinic, Phoenix, Arizona, USA), Francis C. Nichols III (Mayo Clinic, Rochester, Minnesota, USA), John A. Odell (Mayo Clinic, Jacksonville, Florida, USA), Rahul Pannala (Mayo Clinic, Phoenix, Arizona, USA), Harshita R. Paripati (Mayo Clinic, Rochester, Minnesota, USA), Alexander S. Parker (Mayo Clinic, Jacksonville, Florida, USA), Shabana F. Pasha (Mayo Clinic, Rochester, Minnesota, USA), Bret T. Petersen (Mayo Clinic, Rochester, Minnesota, USA), Gloria M. Petersen (Mayo Clinic, Rochester, Minnesota, USA), Michael F. Picco (Mayo Clinic, Jacksonville, Florida, USA), Henry C. Pitot (Mayo Clinic, Rochester, Minnesota, USA), J. Fernando Quevedo (Mayo Clinic, Rochester, Minnesota, USA), Massimo Raimondo (Mayo Clinic, Jacksonville, Florida, USA), Elizabeth Rajan (Mayo Clinic, Rochester, Minnesota, USA), Francisco (Pancho) C. Ramirez (Mayo Clinic, Rochester, Minnesota, USA), Renee M. Root (Mayo Clinic, Rochester, Minnesota, USA), Helen J. Ross, M.D. (Mayo Clinic, Phoenix, Arizona, USA), Joseph Rubin (Mayo Clinic, Rochester, Minnesota, USA), Schuyler O. Sanderson (Mayo Clinic, Rochester, Minnesota, USA), Daniel J. Sargent (Mayo Clinic, Rochester, Minnesota, USA), Daniel J. Schaid (Mayo Clinic, Rochester, Minnesota, USA), K. Robert Shen (Mayo Clinic, Rochester, Minnesota, USA), Qian Shi (Mayo Clinic, Rochester, Minnesota, USA), Frank A. Sinicrope (Mayo Clinic, Rochester, Minnesota, USA), Jeff A. Sloan (Mayo Clinic, Rochester, Minnesota, USA), Dan C. Smith (Mayo Clinic, Jacksonville, Florida, USA), David I. Smith (Mayo Clinic, Rochester, Minnesota, USA), Thomas C. Smyrk (Mayo Clinic, Rochester, Minnesota, USA), Mark E. Stark (Mayo Clinic, Jacksonville, Florida, USA), Nicholas Talley (Mayo Clinic, Rochester, Minnesota, USA), Stephen N. Thibodeau (Mayo Clinic, Rochester, Minnesota, USA), Michael D. Van Norstrand (Mayo Clinic, Rochester, Minnesota, USA), Michael B. Wallace (Mayo Clinic, Jacksonville, Florida, USA), Kenneth K. Wang (Mayo Clinic, Rochester, Minnesota, USA), Richard M. Weinshilboum (Mayo Clinic, Rochester, Minnesota, USA), Dennis Wigle (Mayo Clinic, Rochester, Minnesota, USA), Herbert C. Wolfsen (Mayo Clinic, Jacksonville, Florida, USA), Louis M. Wong Kee Song (Mayo Clinic, Rochester, Minnesota, USA), Timothy A. Woodward (Mayo Clinic, Jacksonville, Florida, USA), Tsung-The Wu (Mayo Clinic, Rochester, Minnesota, USA), Harry H. Yoon (Mayo Clinic, Rochester, Minnesota, USA) & Alan R. Zinsmeister (Mayo Clinic, Rochester, Minnesota, USA).

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Authors and Affiliations

  1. Department of Biostatistics, University of Washington, School of Public Health, Seattle, Washington, USA

    David M Levine & Rui Zhang

  2. Statistical Genetics, QIMR Berghofer Medical Research Institute, Queensland, Brisbane, Australia

    Weronica E Ek & Stuart MacGregor

  3. Medical Research Council (MRC) Cancer Cell Unit, Hutchison-MRC Research Centre and University of Cambridge, Cambridge, UK

    Xinxue Liu, Pierre Lao-Sirieix, Irene Debiram-Beecham & Rebecca C Fitzgerald

  4. Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA

    Lynn Onstad, Brian J Reid & Thomas L Vaughan

  5. Genomics Shared Resource, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA

    Cassandra Sather

  6. Department of Epidemiology, University of North Carolina School of Public Health, Chapel Hill, North Carolina, USA

    Marilie D Gammon

  7. Division of Research, Kaiser Permanente Northern California, Oakland, California, USA

    Douglas A Corley

  8. San Francisco Medical Center, Kaiser Permanente Northern California, San Francisco, California, USA

    Douglas A Corley

  9. Division of Gastroenterology and Hepatology, University of North Carolina School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA

    Nicholas J Shaheen

  10. Department of Oncology, Medical School, University of Sheffield, Sheffield, UK

    Nigel C Bird

  11. Division of Epidemiology, University of Leeds, Leeds, UK

    Laura J Hardie

  12. Centre for Public Health, Queen's University, Belfast, UK

    Liam J Murray

  13. Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA

    Brian J Reid

  14. Department of Epidemiology, MD Anderson Cancer Center, Houston, Texas, USA

    Wong-Ho Chow

  15. Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, Connecticut, USA

    Harvey A Risch

  16. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden

    Olof Nyrén & Weimin Ye

  17. Pharmacogenomic Epidemiology, Ontario Cancer Institute, Toronto, Ontario, Canada

    Geoffrey Liu

  18. Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA

    Yvonne Romero

  19. The Romero Registry, Mayo Clinic, Rochester, Minnesota, USA

    Yvonne Romero

  20. Department of Populations Sciences, Beckman Research Institute and City of Hope Comprehensive Cancer Center, Duarte, California, USA

    Leslie Bernstein

  21. Department of Preventive Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, California, USA

    Anna H Wu

  22. Department of Surgery, University of Saskatchewan, Saskatoon, Saskatchewan, Canada

    Alan G Casson

  23. Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA

    Stephen J Chanock

  24. Department of Public Health, University of Cambridge, Cambridge, UK

    Patricia Harrington & Paul D Pharoah

  25. Department of Primary Care, University of Cambridge, Cambridge, UK

    Patricia Harrington & Paul D Pharoah

  26. Department of Oncology, University of Cambridge, Cambridge, UK

    Patricia Harrington, Isabel Caldas, Carlos Caldas & Paul D Pharoah

  27. Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK

    Carlos Caldas

  28. Oncogenomics Laboratory, QIMR Berghofer Medical Research Institute, Queensland, Brisbane, Australia

    Nicholas K Hayward

  29. Cancer Control, QIMR Berghofer Medical Research Institute, Queensland, Brisbane, Australia

    David C Whiteman

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Contributions

L.B., N.C.B., C.C., A.G.C., S.J.C., W.-H.C., D.A.C., R.C.F., M.D.G., L.J.H., N.K.H., G.L., L.J.M., O.N., P.D.P., B.J.R., H.A.R., Y.R., N.J.S., T.L.V., D.C.W., A.H.W. and W.Y. planned the study. P.D.P., T.L.V. and D.C.W. obtained funding. C.C., R.C.F., D.M.L., T.L.V. and D.C.W. oversaw the study. L.B., N.C.B., I.C., A.G.C., D.A.C., I.D.-B., R.C.F., M.D.G., L.J.H., N.K.H., G.L., L.J.M., O.N., B.J.R., Y.R., N.J.S., T.L.V., D.C.W., A.H.W. and W.Y. recruited participants. P.H., P.L.-S. and C.S. processed samples. P.H., P.L.-S. and C.S. undertook genotyping. W.E.E., D.M.L., X.L., S.M., L.O., P.D.P. and R.Z. analyzed data. W.E.E., R.C.F., D.M.L., S.M., L.O., T.L.V. and D.C.W. drafted the manuscript. All authors critically revised the manuscript for intellectual content. T.L.V. and D.C.W. jointly led the project.

Corresponding author

Correspondence to Thomas L Vaughan.

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The authors declare no competing financial interests.

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Levine, D., Ek, W., Zhang, R. et al. A genome-wide association study identifies new susceptibility loci for esophageal adenocarcinoma and Barrett's esophagus. Nat Genet 45, 1487–1493 (2013). https://doi.org/10.1038/ng.2796

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