Identification of DOK genes as lung tumor suppressors

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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Figure 1: Dok1, Dok2 and Dok3 single- and compound-knockout mice develop lung cancer.
Figure 2: Histopathology of lung tumors in Dok knockout mice.
Figure 3: Hyperplasia and tumors in Dok knockout mice consist of AT2 cells and BASCs.
Figure 4: Lung tumorigenesis in Dok TKO mice is preceded by an expansion of AT2 cells and BASCs.
Figure 5: Loss of DOK2 expression in human lung adenocarcinomas and functional data implicate DOK2 as a human lung tumor suppressor.
Figure 6: DOK2 suppresses lung cancer cell proliferation in vitro and in vivo.
Figure 7: Lung tumorigenesis in Dok2+/− mice.

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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.).

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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.

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Correspondence to Pier Paolo Pandolfi.

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The authors declare no competing financial interests.

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Berger, A., Niki, M., Morotti, A. et al. Identification of DOK genes as lung tumor suppressors. Nat Genet 42, 216–223 (2010). https://doi.org/10.1038/ng.527

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