Identification of DOK family genes as lung tumor suppressors

By A. Berger, M. Niki, A. Morotti, Barry S. Taylor, Nicholas D. Socci, A. Viale, C. Brennan, J. Szőke, N. Motoi, P. Rothman and 4 more. 2010

122 citations recorded by the source corpus.

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.

Subfields: Cancer Research, Molecular Biology, Pulmonary and Respiratory Medicine

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In Molecular Biology

1. Zhaohui S. Qin
2. Yun Bai
3. Zdenko Herceg
4. Rendong Yang
5. Tianwei Yu

Citations in the corpus

• EgoNet: identification of human disease ego-network modules (2014, background): “DOK1 is known to be a tumor suppressor gene in epithelial ovarian cancer [45] and lung cancer [46].”
• Characterization of DOK1, a candidate tumor suppressor gene, in epithelial ovarian cancer (2011, background): “It was recently shown that triple (DOK1 / , DOK2 / and DOK3 / ) KO mice spontaneously develop aggressive histiocytic sarcoma (Mashima et al., 2010) and lung adenocarcinoma (Berger et al., 2010), as these studies were indicative for a strong combinatorial effectwhenmore thanoneDOKgenewas knockedout.”
• Transcriptional Regulation of the Human Tumor Suppressor DOK1 by E2F1 (2012, background): “Given that DOK1 is frequently altered in a variety of human cancers, it could potentially serve as a new marker and/or a therapeutic target for cancer control (1, 2, 14, 24).”