Identification of DOK genes as lung tumor suppressors.
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.
Berger
Alice H
AH
Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Departments of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
Niki
Masaru
M
Morotti
Alessandro
A
Taylor
Barry S
BS
Socci
Nicholas D
ND
Viale
Agnes
A
Brennan
Cameron
C
Szoke
Janos
J
Motoi
Noriko
N
Rothman
Paul B
PB
Teruya-Feldstein
Julie
J
Gerald
William L
WL
Ladanyi
Marc
M
Pandolfi
Pier Paolo
PP
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000502:physiology*; D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D000818:Animals; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor / Q000502:physiology; D020022:Genetic Predisposition to Disease; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D010750:Phosphoproteins / Q000235:genetics / Q000502:physiology*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D014183:Transplantation, Heterologous; D047368:Tumor Burden / Q000235:genetics; D014407:Tumor Cells, Cultured
D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C489561:Dok1 protein, mouse; C498444:Dok2 protein, mouse; C406768:Dok3 protein, mouse; D010750:Phosphoproteins; D016601:RNA-Binding Proteins