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

Journal name:
Nature Genetics
Volume:
45,
Pages:
1487–1493
Year published:
DOI:
doi:10.1038/ng.2796
Received
Accepted
Published online

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.

At a glance

Figures

  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 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.

    Results are shown for 3,928 cases (2,414 Barrett's esophagus, 1,514 esophageal adenocarcinoma) and 3,207 controls for 801,552 autosomal and X-chromosome SNPs that passed quality control and have a minor allele frequency of >1%. Chromosomes are delineated by alternating colors, as labeled on the x axis. The y axis shows −log10 P values.

  2. Regional association plots showing genotyped and imputed SNPs from the
                    discovery data for the combined Barrett's esophagus and esophageal
                    adenocarcinoma cases.
    Figure 2: Regional association plots showing genotyped and imputed SNPs from the discovery data for the combined Barrett's esophagus and esophageal adenocarcinoma cases.

    (ad) Plots are shown for three newly discovered loci (ac) and one previously identified locus (d). Genotyped SNPs are indicated by solid triangles, and imputed SNPs are indicated by unfilled circles. The top-ranked SNP at each locus is shown as a solid purple diamond, except in d, where it is rs9936833. SNPs are ordered by genomic location. The color scheme indicates LD between the top-ranked SNP and other SNPs in the region using r2 values calculated from the 1000 Genomes Project. The y axis shows −log10 P values computed from 3,928 cases (2,414 Barrett's esophagus, 1,514 esophageal adenocarcinoma) and 3,207 controls. Imputation P values for all SNPs are plotted. Note that imputed and genotyped P values for genotyped SNPs differ slightly because, for the imputed result, the analysis was based on dosage scores, whereas, with genotyped SNPs, the hard genotype calls were used. The recombination rate from CEU (Utah residents of Northern and Western European ancestry) HapMap data (right y axis) is shown in light blue. (a) Chromosome 19p13 region. (b) Chromosome 9q22 region. (c) Chromosome 3p13 region. (d) Chromosome 16q24 region.

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Author information

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, Brisbane, Queensland, 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, Brisbane, Queensland, Australia.

    • Nicholas K Hayward
  29. Cancer Control, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.

    • David C Whiteman

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.

Competing financial interests

The authors declare no competing financial interests.

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