Abstract

Adenoid cystic carcinomas (ACCs) are among the most enigmatic of human malignancies. These aggressive salivary gland cancers frequently recur and metastasize despite definitive treatment, with no known effective chemotherapy regimen. Here we determined the ACC mutational landscape and report the exome or whole-genome sequences of 60 ACC tumor-normal pairs. These analyses identified a low exonic somatic mutation rate (0.31 non-silent events per megabase) and wide mutational diversity. Notably, we found mutations in genes encoding chromatin-state regulators, such as SMARCA2, CREBBP and KDM6A, suggesting that there is aberrant epigenetic regulation in ACC oncogenesis. Mutations in genes central to the DNA damage response and protein kinase A signaling also implicate these processes. We observed MYB-NFIB translocations and somatic mutations in MYB-associated genes, solidifying the role of these aberrations as critical events in ACC. Lastly, we identified recurrent mutations in the FGF-IGF-PI3K pathway (30% of tumors) that might represent new avenues for therapy. Collectively, our observations establish a molecular foundation for understanding and exploring new treatments for ACC.

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Acknowledgements

We thank A. Kayserian and S. Thomas for technical assistance. We are indebted to R.J. Wong (Memorial Sloan-Kettering Cancer Center), P.K. Brindle (St. Jude Children's Research Hospital) and O.J. Baker (State University of New York at Buffalo) for generously providing cell lines and constructs. We are additionally grateful to J.O. Boyle, S.G. Patel, A.R. Shaha, R.J. Wong, A.L. Ho, M.C. Mariano and L. Lopez for facilitating tissue procurement and contributing valuable input. This work was supported by the US National Institutes of Health (NIH) (RO1CA154767 (T.A.C.), R21DE023229 (T.A.C.), 5T32CA009685 (A.S.H.)), the Geoffrey Beene Foundation (T.A.C.), the Starr Cancer Consortium (T.A.C.) and the Louis Gerstner Foundation (T.A.C.). A.S.H. was supported by an American Head and Neck Society/American Academy of Otolaryngology–Head and Neck Surgery Foundation Young Investigator Combined Award. D.M.R. was supported by the Howard Hughes Medical Institute Medical Research Fellows Program. The cBio Portal was supported in part by the NIH National Resource for Network Biology (GM103504). T.A.C. would like to thank Jeff and Marnie Kaufman and the Adenoid Cystic Carcinoma Research Foundation for support of the work and inspiration to see it through for the benefit of patients.

Author information

Author notes

    • Allen S Ho
    • , Kasthuri Kannan
    •  & David M Roy

    These authors contributed equally to this work.

Affiliations

  1. Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.

    • Allen S Ho
    • , Kasthuri Kannan
    • , David M Roy
    • , Luc G T Morris
    • , Ian Ganly
    • , Deepa Ramaswami
    • , Logan A Walsh
    • , Stephanie Eng
    • , Jason T Huse
    • , Jianan Zhang
    • , Igor Dolgalev
    • , Kety Huberman
    • , Adriana Heguy
    • , Luke Peng
    • , Sevin Turcan
    • , Yongxing Gong
    •  & Timothy A Chan
  2. Head and Neck Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.

    • Allen S Ho
    • , Luc G T Morris
    • , Ian Ganly
    • , Bhuvanesh Singh
    •  & Jatin P Shah
  3. Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.

    • Nora Katabi
    •  & Jason T Huse
  4. Genomics Core, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.

    • Agnes Viale
  5. Pathology Core, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.

    • Marija Drobnjak
  6. Molecular Cytogenetics Core, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.

    • Margaret A Leversha
    •  & Christine E Rice
  7. Department of Surgical Oncology, National Cancer Center Singapore, Singapore.

    • N Gopalakrishna Iyer
  8. Department of Otolaryngology–Head and Neck Surgery, VU University Medical Center, Amsterdam, The Netherlands.

    • C Rene Leemans
  9. Department of Oral and Maxillofacial Surgery and Oral Pathology, VU University Medical Center, Academic Centre for Dentistry, Amsterdam, The Netherlands.

    • Elisabeth Bloemena
  10. Department of Otolaryngology–Head and Neck Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.

    • Robert L Ferris
    •  & Seungwon Kim
  11. Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.

    • Raja R Seethala
    •  & Simion Chiosea
  12. Computational Biology Center, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.

    • Benjamin E Gross
    • , Yupu Liang
    • , Rileen Sinha
    • , Chris Sander
    •  & William Lee
  13. Department of Computer Science, Brown University, Providence, Rhode Island, USA.

    • Benjamin J Raphael
  14. Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.

    • Nikolaus Schultz
    •  & Timothy A Chan

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Contributions

T.A.C., A.S.H., K.K. and W.L. designed the experiments. D.M.R., A.S.H., S.E., A.V., A.H., K.H., D.R., L.A.W., J.T.H., J.Z., N.G.I., Y.G., M.A.L. and C.E.R. performed the experiments. A.S.H., W.L., T.A.C., K.K., D.M.R., L.G.T.M. and S.T. analyzed the data. N.K. and R.R.S. provided histopathological confirmation of sample purity. A.S.H., T.A.C. and W.L. wrote the manuscript. A.S.H., I.G., L.G.T.M., M.D., J.P.S., B.S., N.G.I., C.R.L., E.B., R.L.F., R.R.S., S.C. and S.K. contributed new reagents and provided tissues for analysis. W.L., K.K., A.S.H., T.A.C., L.P., B.J.R., I.D., Y.L., R.S., N.S., B.E.G. and C.S. conducted the bioinformatics analysis.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Timothy A Chan.

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