Compound haploinsufficiency of Dok2 and Dusp4 promotes lung tumorigenesis.

Published

Journal Article

Recurrent broad-scale heterozygous deletions are frequently observed in human cancer. Here we tested the hypothesis that compound haploinsufficiency of neighboring genes at chromosome 8p promotes tumorigenesis. By targeting the mouse orthologs of human DOK2 and DUSP4 genes, which were co-deleted in approximately half of human lung adenocarcinomas, we found that compound-heterozygous deletion of Dok2 and Dusp4 in mice resulted in lung tumorigenesis with short latency and high incidence, and that their co-deletion synergistically activated MAPK signaling and promoted cell proliferation. Conversely, restoration of DOK2 and DUSP4 in lung cancer cells suppressed MAPK activation and cell proliferation. Importantly, in contrast to downregulation of DOK2 or DUSP4 alone, concomitant downregulation of DOK2 and DUSP4 was associated with poor survival in human lung adenocarcinoma. Therefore, our findings lend in vivo experimental support to the notion that compound haploinsufficiency, due to broad-scale chromosome deletions, constitutes a driving force in tumorigenesis.

Full Text

Duke Authors

Cited Authors

  • Chen, M; Zhang, J; Berger, AH; Diolombi, MS; Ng, C; Fung, J; Bronson, RT; Castillo-Martin, M; Thin, TH; Cordon-Cardo, C; Plevin, R; Pandolfi, PP

Published Date

  • January 2, 2019

Published In

Volume / Issue

  • 129 / 1

Start / End Page

  • 215 - 222

PubMed ID

  • 30475228

Pubmed Central ID

  • 30475228

Electronic International Standard Serial Number (EISSN)

  • 1558-8238

Digital Object Identifier (DOI)

  • 10.1172/JCI99699

Language

  • eng

Conference Location

  • United States