Abstract

Barrett's esophagus is thought to progress to esophageal adenocarcinoma (EAC) through a stepwise progression with loss of CDKN2A followed by TP53 inactivation and aneuploidy. Here we present whole-exome sequencing from 25 pairs of EAC and Barrett's esophagus and from 5 patients whose Barrett's esophagus and tumor were extensively sampled. Our analysis showed that oncogene amplification typically occurred as a late event and that TP53 mutations often occurred early in Barrett's esophagus progression, including in non-dysplastic epithelium. Reanalysis of additional EAC exome data showed that the majority (62.5%) of EACs emerged following genome doubling and that tumors with genomic doubling had different patterns of genomic alterations, with more frequent oncogenic amplification and less frequent inactivation of tumor suppressors, including CDKN2A. These data suggest that many EACs emerge not through the gradual accumulation of tumor-suppressor alterations but rather through a more direct path whereby a TP53-mutant cell undergoes genome doubling, followed by the acquisition of oncogenic amplifications.

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Acknowledgements

We thank the members of the Broad Institute Genome Sequencing Platform and the molecular laboratories at Brigham and Women's Hospital and Massachusetts General Hospital for their assistance. We are grateful to the patients and families who agreed to contribute their samples to enable this research and to the physicians and hospital staff whose efforts in collecting these samples are essential to this work. This work was supported by US National Institutes of Health grant T32 HL007627 and the Dana-Farber/Harvard Gastrointestinal Cancer Specialized Programs of Research Excellence P50CA127003 (M.D.S.), the National Human Genome Research Institute (NHGRI) Large-Scale Sequencing Program (U54 HG0003067; E.S.L.), National Cancer Institute grant U54 CA163059 (D.G.B.), Broad Institute SPARC funding (A.J.B., S.L.C. and G.G.), a Research Scholar Grant from the American Cancer Society (A.J.B.) and the National Cancer Institute (P01 CA098101 and U54 CA163004; A.J.B.).

Author information

Author notes

    • Matthew D Stachler
    •  & Amaro Taylor-Weiner

    These authors contributed equally to this work.

    • Gad Getz
    • , Scott L Carter
    •  & Adam J Bass

    These authors jointly supervised this work.

Affiliations

  1. Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

    • Matthew D Stachler
    • , Agoston T Agoston
    • , Robert D Odze
    •  & Massimo Loda
  2. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

    • Matthew D Stachler
    • , Shouyong Peng
    • , Massimo Loda
    •  & Adam J Bass
  3. Eli and Edythe L. Broad Institute, Cambridge, Massachusetts, USA.

    • Amaro Taylor-Weiner
    • , Ignaty Leshchiner
    • , Chip Stewart
    • , Petar Stojanov
    • , Sara Seepo
    • , Michael S Lawrence
    • , Stacey B Gabriel
    • , Eric S Lander
    • , Gad Getz
    • , Scott L Carter
    •  & Adam J Bass
  4. University of Washington, Seattle, Washington, USA.

    • Aaron McKenna
  5. University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

    • Jon M Davison
    •  & Katie S Nason
  6. Section of Thoracic Surgery, University of Michigan, Ann Arbor, Michigan, USA.

    • Daysha Ferrer-Torres
    • , Jules Lin
    • , Andrew C Chang
    •  & David G Beer
  7. Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

    • Eric S Lander
  8. Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Gad Getz
  9. Joint Center for Cancer Precision Medicine, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Broad Institute of Harvard and MIT, Harvard Medical School, Boston, Massachusetts, USA.

    • Scott L Carter
  10. Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

    • Scott L Carter
  11. Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA.

    • Scott L Carter

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Contributions

M.D.S. performed experiments and interpreted results. A.T.-W., S.P., A.M., P.S., I.L., M.S.L. and S.L.C. performed computational analysis. A.T.A. and R.D.O. performed pathological slide review. J.M.D., K.S.N., D.F.-T., J.L., A.C.C. and D.G.B. contributed samples and clinical annotation. M.L. contributed laser-capture microdissection guidance and manuscript review. C.S., S.S., S.B.G. and E.S.L. organized and supervised sequencing. G.G., S.L.C. and A.J.B. supervised all studies. M.D.S., A.T.-W., S.L.C., G.G. and A.J.B. prepared the manuscript, and all authors read and approved the final manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Gad Getz or Scott L Carter or Adam J Bass.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–21 and Supplementary Tables 3–5.

Excel files

  1. 1.

    Supplementary Table 1

    Patient, Barrett's and tumor characteristics in the 25 paired samples.

  2. 2.

    Supplementary Table 2

    List of tumor suppressors and their given coverage.

  3. 3.

    Supplementary Table 6

    EAC gene alterations.

Zip files

  1. 1.

    Supplementary Data Set 1

    Frozen sample MAF files.

  2. 2.

    Supplementary Data Set 2

    Frozen sample ABSOLUTE plots.

  3. 3.

    Supplementary Data Set 3

    FFPE sample MAF files.

  4. 4.

    Supplementary Data Set 4

    FFPE sample ABSOLUTE plots.

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DOI

https://doi.org/10.1038/ng.3343

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