Identification of DOK genes as lung tumor suppressors

Alice H. Berger, Masaru Niki, Alessandro Morotti, Barry S. Taylor, Nicholas D. Socci, Agnes Viale, Cameron Brennan, Janos Szoke, Noriko Motoi, Paul B. Rothman, Julie Teruya-Feldstein, William L. Gerald, Marc Ladanyi, Pier Paolo Pandolfi

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)216-223
Number of pages8
JournalNature genetics
Volume42
Issue number3
DOIs
StatePublished - Mar 1 2010

ASJC Scopus subject areas

  • Genetics

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    Berger, A. H., Niki, M., Morotti, A., Taylor, B. S., Socci, N. D., Viale, A., Brennan, C., Szoke, J., Motoi, N., Rothman, P. B., Teruya-Feldstein, J., Gerald, W. L., Ladanyi, M., & Pandolfi, P. P. (2010). Identification of DOK genes as lung tumor suppressors. Nature genetics, 42(3), 216-223. https://doi.org/10.1038/ng.527