Abstract

The incidence of esophageal adenocarcinoma (EAC) has risen 600% over the last 30 years. With a 5-year survival rate of 15%, the identification of new therapeutic targets for EAC is greatly important. We analyze the mutation spectra from whole-exome sequencing of 149 EAC tumor-normal pairs, 15 of which have also been subjected to whole-genome sequencing. We identify a mutational signature defined by a high prevalence of A>C transversions at AA dinucleotides. Statistical analysis of exome data identified 26 significantly mutated genes. Of these genes, five (TP53, CDKN2A, SMAD4, ARID1A and PIK3CA) have previously been implicated in EAC. The new significantly mutated genes include chromatin-modifying factors and candidate contributors SPG20, TLR4, ELMO1 and DOCK2. Functional analyses of EAC-derived mutations in ELMO1 identifies increased cellular invasion. Therefore, we suggest the potential activation of the RAC1 pathway as a contributor to EAC tumorigenesis.

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Acknowledgements

We thank M. Meyerson for helpful discussions and review of the manuscript and members of the Broad Institute Biological Samples Platform, Genetic Analysis Platform and Genome Sequencing Platform for their assistance. We are also grateful for the physicians and hospital staff whose efforts in collecting these samples are essential to this research. This work was supported by the US National Human Genome Research Institute (NHGRI) Large-Scale Sequencing Program (U54 HG003067 to the Broad Institute, E.S.L.), the National Cancer Institute (K08 CA134931 to A.J.B.), the DeGregorio Family Foundation (A.J.B.), the Karin Grunebaum Cancer Research Foundation (A.J.B.), the Target Cancer (A.J.B.) and Connecticut Conquers Cancer (A.J.B.). S.O. and Y.I. are supported by the National Cancer Institute (R01 CA151993 to S.O.) and the Dana-Farber/Harvard Cancer Center GI Cancer Specialized Programs of Research Excellence (US National Institutes of Health (NIH) grant P50 CA127003). D.G.B. is supported by NIH grants CA163059 and CA46592. J.D.L. is supported by NIH grant CA090665. T.E.G. is supported by NIH grant CA130853.

Author information

Author notes

    • Austin M Dulak
    •  & Petar Stojanov

    These authors contributed equally to this work.

    • Gad Getz
    •  & Adam J Bass

    These authors jointly directed this work.

Affiliations

  1. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

    • Austin M Dulak
    • , Petar Stojanov
    • , Shouyong Peng
    • , Cameron Fox
    • , Yu Imamura
    • , Steven E Schumacher
    • , Rameen Beroukhim
    • , Shuji Ogino
    • , Todd R Golub
    •  & Adam J Bass
  2. Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

    • Austin M Dulak
    • , Petar Stojanov
    • , Shouyong Peng
    • , Michael S Lawrence
    • , Chip Stewart
    • , Steven E Schumacher
    • , Erica Shefler
    • , Aaron McKenna
    • , Scott L Carter
    • , Kristian Cibulskis
    • , Andrey Sivachenko
    • , Gordon Saksena
    • , Douglas Voet
    • , Alex H Ramos
    • , Daniel Auclair
    • , Kristin Thompson
    • , Carrie Sougnez
    • , Robert C Onofrio
    • , Candace Guiducci
    • , Rameen Beroukhim
    • , Todd R Golub
    • , Stacey B Gabriel
    • , Eric S Lander
    • , Gad Getz
    •  & Adam J Bass
  3. Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

    • Petar Stojanov
    •  & Eric S Lander
  4. Department of Surgery, University of Rochester, Rochester, New York, USA.

    • Santhoshi Bandla
    • , Zhongren Zhou
    •  & Tony E Godfrey
  5. Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • Rameen Beroukhim
    •  & Adam J Bass
  6. Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.

    • Rameen Beroukhim
    • , Shuji Ogino
    • , Todd R Golub
    • , Eric S Lander
    •  & Adam J Bass
  7. Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA.

    • Lin Lin
    • , Jules Lin
    • , Rishindra Reddy
    • , Andrew Chang
    •  & David G Beer
  8. Department of Cardiothoracic Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.

    • Rodney Landrenau
    • , Arjun Pennathur
    •  & James D Luketich
  9. Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA.

    • Shuji Ogino
  10. Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • Shuji Ogino
  11. Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.

    • Todd R Golub
  12. Massachusetts General Hospital Cancer Center and Department of Pathology, Boston, Massachusetts, USA.

    • Gad Getz

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Contributions

P.S., S.P., M.S.L., C.F., C. Stewart, S.E.S., A.M., K.C., A.S., S.L.C., G.S., D.V., A.H.R. and R.B. performed computational analyses. E.S., D.A., K.T., C. Sougnez, R.C.O., C.G. and S.B.G. processed samples and supervised exome sequencing. A.M.D., S.B., D.Z., L.L., J.L., R.R., A.C., R.L., J.D.L., A.P., D.G.B., T.E.G. and A.J.B. coordinated sample acquisition, processing, pathological review and analysis. Y.I. and S.O. performed MSI testing. A.M.D., P.S., T.R.G., S.B.G., E.S.L., G.G. and A.J.B. designed the study. A.M.D., P.S., S.P., M.S.L., G.G. and A.J.B. analyzed the data and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Gad Getz or Adam J Bass.

Supplementary information

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  1. 1.

    Supplementary Text and Figures

    Supplementary Note, Supplementary Figures 1–6 and Supplementary Tables 1–3, 5, 6, 8, 10–13 and 16–18

Excel files

  1. 1.

    Supplementary Table 4

    Predicted rearrangements by dRanger algorithm

  2. 2.

    Supplementary Table 7

    Frequencies of all middle-base mutations with 5' and 3' base context identified by WGS (n=16)

  3. 3.

    Supplementary Table 9

    Rates of all middle-base mutations with 5' and 3' base context identified by WGS in exons

  4. 4.

    Supplementary Table 14

    Somatic mutations in MSI positive samples detected by WES (n=4)

  5. 5.

    Supplementary Table 15

    Somatic mutations in non-MSI positive samples detected by WES (n=145)

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https://doi.org/10.1038/ng.2591

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