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Identification of DOK genes as lung tumor suppressors

Alice H Berger1, Masaru Niki, Alessandro Morotti

  • 1Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Departments of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.

Nature Genetics
|February 9, 2010
PubMed

Insights

Downstream of tyrosine kinase (Dok) family members Dok1, Dok2, and Dok3 act as lung tumor suppressors. Their loss in mice causes lung cancer, and DOK2 is implicated in human lung adenocarcinoma.

Area of Science:

  • Oncology
  • Genetics
  • Molecular Biology

Background:

  • Genome-wide studies reveal copy-number alterations in lung adenocarcinoma, but key oncogenes and tumor suppressors are often unidentified.
  • Identifying these genes is crucial for understanding lung cancer development and for therapeutic targeting.

Purpose of the Study:

  • To identify novel tumor suppressor genes involved in human lung adenocarcinoma.
  • To investigate the role of the Downstream of tyrosine kinase (Dok) family in lung cancer.

Main Methods:

  • Utilized mouse models with single, double, and triple compound loss of Dok1, Dok2, and Dok3 genes.
  • Analyzed aberrant cell expansion and signaling in alveolar type II cells and bronchioalveolar stem cells.
  • Examined copy-number status and mRNA expression of DOK2 in human lung adenocarcinoma samples.

Main Results:

  • Loss of Dok1, Dok2, and Dok3 genes in mice led to lung cancer, with outcomes dependent on the number of lost alleles.
  • Aberrant expansion and signaling profiles were observed in specific lung cell populations preceding cancer development.
  • DOK2 was identified as a target of copy-number loss and mRNA downregulation in human lung adenocarcinoma.
  • DOK2 demonstrated suppression of lung cancer cell proliferation in vitro and in vivo.

Conclusions:

  • Dok1, Dok2, and Dok3 function as critical lung tumor suppressors.
  • DOK2 is a candidate 8p21.3 haploinsufficient tumor suppressor in human lung adenocarcinoma, suggesting its potential role in cancer pathogenesis.

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