Abstract

Polymorphous low-grade adenocarcinoma (PLGA) is the second most frequent type of malignant tumor of the minor salivary glands. We identified PRKD1 hotspot mutations encoding p.Glu710Asp in 72.9% of PLGAs but not in other salivary gland tumors. Functional studies demonstrated that this kinase-activating alteration likely constitutes a driver of PLGA.

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Acknowledgements

This work was supported in part by an IDEAS grant from Princess Margaret Hospital, the Head and Neck Translational Research Program (I.W., B.A.C., P.C.B. and J.D.M.), the Ontario Institute for Cancer Research and the government of Ontario (P.C.B. and J.D.M.) and by a Terry Fox Research Institute New Investigator Award (P.C.B.). C.H. and F.-F.L. acknowledge support from the Wharton family, Joe's Team, Gordon Tozer, the Campbell Family Institute for Cancer Research and the Ministry of Health and Long-Term Planning, Canada.

Author information

Author notes

    • Ilan Weinreb
    • , Salvatore Piscuoglio
    • , Luciano G Martelotto
    •  & Daryl Waggott

    These authors contributed equally to this work.

    • Blaise A Clarke
    • , Britta Weigelt
    • , Paul C Boutros
    •  & Jorge S Reis-Filho

    These authors jointly directed this work.

Affiliations

  1. Department of Pathology, University Health Network, Toronto, Ontario, Canada.

    • Ilan Weinreb
    • , Bayardo Perez-Ordonez
    •  & Blaise A Clarke
  2. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

    • Salvatore Piscuoglio
    • , Luciano G Martelotto
    • , Charlotte K Y Ng
    • , Nicola Fusco
    • , Arnaud da Cruz Paula
    • , Caterina Marchio
    • , Raymond Lim
    • , Y Hannah Wen
    • , Nora Katabi
    • , Britta Weigelt
    •  & Jorge S Reis-Filho
  3. Informatics and Bio-Computing Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.

    • Daryl Waggott
    • , Nicholas J Harding
    • , Javier Alfaro
    • , Kenneth C Chu
    • , Jianxin Wang
    • , Richard de Borja
    • , Michelle Chan-Seng-Yue
    •  & Paul C Boutros
  4. Ontario Cancer Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Onatrio, Canada.

    • Daryl Waggott
    • , Javier Alfaro
    • , Christine How
    • , Thomas Kislinger
    • , Bradly G Wouters
    •  & Fei-Fei Liu
  5. Campbell Family Institute for Cancer Research, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.

    • Daryl Waggott
    • , Javier Alfaro
    • , Christine How
    • , Thomas Kislinger
    • , Bradly G Wouters
    •  & Fei-Fei Liu
  6. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.

    • Javier Alfaro
    • , Thomas Kislinger
    • , Bradly G Wouters
    • , Fei-Fei Liu
    • , John D McPherson
    •  & Paul C Boutros
  7. Integrated Genomics Operation, Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

    • Agnes Viale
  8. School of Pathology, University of Milan, Milan, Italy.

    • Nicola Fusco
  9. Instituto Português de Oncologia, Oporto, Portugal.

    • Arnaud da Cruz Paula
  10. Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

    • Rita A Sakr
  11. Department of Pathology, Kaiser Permanente, Woodland Hills Medical Center, Woodland Hills, California, USA.

    • Lester D R Thompson
  12. Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.

    • Simion I Chiosea
    •  & Raja R Seethala
  13. Department of Pathology and Laboratory Medicine, Charles University in Prague, Plzen, Czech Republic.

    • Alena Skalova
  14. Department of Pathology, University of Virginia Medical Center, Charlottesville, Virginia, USA.

    • Edward B Stelow
  15. Instituto Português de Oncologia Francisco Gentil, Lisbon, Portugal.

    • Isabel Fonseca
  16. Faculdade de Medicina de Lisboa, Lisbon, Portugal.

    • Isabel Fonseca
  17. Department of Pathology, Virginia Mason Hospital and Seattle Medical Center, Seattle, Washington, USA.

    • Adel Assaad
    •  & John D McPherson
  18. Western University, London, Ontario, Canada.

    • Christopher J Howlett
    •  & Anthony C Nichols
  19. Cancer Genomics Platform, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.

    • Nicholas Buchner
    •  & Laura Mullen
  20. Department of Radiation Oncology, Princess Margaret Hospital and University of Toronto, Toronto, Ontario, Canada.

    • Fei-Fei Liu
  21. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

    • Larry Norton
  22. Department of Molecular Genetics, Lerner Research Institute, Cleveland, Ohio, USA.

    • Brian P Rubin
  23. Robert J. Tomsich Pathology and Laboratory Medicine Institute, Taussig Cancer Center, Cleveland Clinic, Cleveland, Ohio, USA.

    • Brian P Rubin
  24. Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.

    • Paul C Boutros
  25. Affiliated member of the Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

    • Jorge S Reis-Filho

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Contributions

I.W., L.N., J.D.M., B.A.C., B.W., P.C.B. and J.S.R.-F. conceived the study and supervised the work. I.W., L.D.R.T., S.I.C., R.R.S., A.S., E.B.S., I.F., A.A., C.H., J.W., R.d.B., M.C.-S.-Y., C.J.H., A.C.N., Y.H.W., N.K. and B.P.R. provided samples. I.W., B.P.-O., Y.H.W. and N.K. reviewed the cases. Sample processing, Sanger sequencing and amplicon sequencing were performed by S.P., N.F., A.d.C.P., C.H. and F.-F.L. Massively parallel RNA sequencing and whole-exome sequencing were carried out by A.V., J.D.M. and P.C.B. RNA sequencing analysis was performed by C.K.Y.N. and R.L. Whole-exome sequencing analysis was performed by D.W., C.K.Y.N., N.J.H., R.L., N.B. and L.M. J.D.M., P.C.B. and J.S.R.-F. coordinated the bioinformatics analyses. In silico protein structure analysis was performed by S.P., L.G.M., J.A., T.K., B.G.W. and P.C.B. Functional in vitro experiments were carried out by L.G.M. and B.W. R.A.S. carried out immunohistochemical analysis. J.S.R.-F. and C.M. interpreted the immunohistochemical results. C.K.Y.N., K.C.C. and P.C.B. performed statistical analyses. B.W. and J.S.R.-F. wrote the first draft of the manuscript, which was initially reviewed by I.W., S.P., L.G.M., D.W., L.N., B.P.R. and P.C.B. All authors edited and approved the final draft.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Jorge S Reis-Filho.

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DOI

https://doi.org/10.1038/ng.3096

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