Journal Article

Identification of DOK family genes as lung tumor suppressors

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

2010

Overview

Genome-wide analyses in 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 the mouse results in lung cancer with penetrance and latency dependent on the number of lost Dok alleles, and which is associated with 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.