Abstract

Genome-wide analyses of human lung adenocarcinoma have identified regions of consistent copy-number gain or loss, but in many cases the oncogenes and tumor suppressors presumed to reside in these loci remain to be determined. Here we identify the downstream of tyrosine kinase (Dok) family members Dok1, Dok2 and Dok3 as lung tumor suppressors. Single, double or triple compound loss of these genes in mice results in lung cancer, with penetrance and latency dependent on the number of lost Dok alleles. Cancer development is preceded by an aberrant expansion and signaling profile of alveolar type II cells and bronchioalveolar stem cells. In human lung adenocarcinoma, we identify DOK2 as a target of copy-number loss and mRNA downregulation and find that DOK2 suppresses lung cancer cell proliferation in vitro and in vivo. Given the genomic localization of DOK2, we propose it as an 8p21.3 haploinsufficient human lung tumor suppressor.

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Acknowledgements

We thank K. Politi, H.E. Varmus, L.F. Cai, C.F. Kim, T. Motoi, R. Hobbs, J. Clohessy, T. Yung, A. Carracedo, K. Ito, Pandolfi lab members, members of the Memorial Sloan-Kettering Cancer Center (MSKCC) Lung Cancer Oncogenome Group and members of the Dana-Farber/Harvard Cancer Center Lung Cancer Research Program for advice and discussion; B. Clarkson (MSKCC) for reagents and discussion; M. Asher, T. Matos and A. Egia for histology services and immunohistochemistry; and the MSKCC, University of Iowa, and Dana-Farber Cancer Institute flow cytometry core facilities for technical assistance. This work was funded by National Cancer Institute grants and CA-129243 (to M.L.) CA-64593 (to P.P.P.) and by the Steps for Breath Fund from the Society of MSKCC and the Thomas G. Labrecque Foundation (to M.N.).

Author information

Author notes

    • William L Gerald

    Deceased.

    • Alice H Berger
    •  & Masaru Niki

    These authors contributed equally to this work.

Affiliations

  1. Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Departments of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.

    • Alice H Berger
    • , Alessandro Morotti
    •  & Pier Paolo Pandolfi
  2. Cancer Biology and Genetics Program, Sloan-Kettering Institute, New York, New York, USA.

    • Alice H Berger
    • , Masaru Niki
    • , Alessandro Morotti
    •  & Pier Paolo Pandolfi
  3. Department of Pathology, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.

    • Alice H Berger
    • , Masaru Niki
    • , Alessandro Morotti
    • , Janos Szoke
    • , Noriko Motoi
    • , Julie Teruya-Feldstein
    • , William L Gerald
    • , Marc Ladanyi
    •  & Pier Paolo Pandolfi
  4. Weill Graduate School of Medical Sciences, Cornell University, New York, New York, USA.

    • Alice H Berger
    •  & Pier Paolo Pandolfi
  5. Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA.

    • Masaru Niki
    •  & Paul B Rothman
  6. Computational Biology Center, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.

    • Barry S Taylor
  7. Bioinformatics Core, Sloan-Kettering Institute, New York, New York, USA.

    • Nicholas D Socci
  8. Genomics Core Laboratory, Sloan-Kettering Institute, New York, New York, USA.

    • Agnes Viale
  9. Department of Neurosurgery, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.

    • Cameron Brennan
  10. Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.

    • Cameron Brennan
    • , William L Gerald
    •  & Marc Ladanyi

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Contributions

A.H.B., M.N., A.M. and P.P.P. designed and analyzed the experiments. B.S.T., C.B., W.L.G. and M.L. conducted the human genetic studies. A.V. and N.D.S. analyzed the SNP array data. J.S., N.M., J.T.F., W.L.G. and M.L. coordinated the human pathological sample acquisition and distribution. J.T.-F. reviewed all mouse pathology. Some of the experiments were conducted in the laboratory of P.B.R. A.H.B., M.N. and P.P.P. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Pier Paolo Pandolfi.

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DOI

https://doi.org/10.1038/ng.527

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