Nullifying the CDKN2AB locus promotes mutant K-ras lung tumorigenesis

Katja Schuster, Niranjan Venkateswaran, Andrea Rabellino, Luc Girard, Samuel Penã-Llopis, Pier Paolo Scaglioni

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

Lung cancer commonly displays a number of recurrent genetic abnormalities, and about 30% of lung adenocarcinomas carry activating mutations in the Kras gene, often concomitantly with inactivation of tumor suppressor genes p16 INK4A and p14ARF of the CDKN2AB locus. However, little is known regarding the function of p15INK4B translated from the same locus. To determine the frequency of CDKN2AB loss in human mutant KRAS lung cancer, The Cancer Genome Atlas (TCGA) database was interrogated. Two-hit inactivation of CDKN2A and CDKN2B occurs frequently in patients with mutant KRAS lung adenocarcinoma. Moreover, p15INK4B loss occurs in the presence of biallelic inactivation of p16INK4A and p14ARF, suggesting that p15INK4B loss confers a selective advantage to mutant KRAS lung cancers that are p16INK4A and p14ARF deficient. To determine the significance of CDKN2AB loss in vivo, genetically engineered lung cancer mouse models that express mutant Kras in the respiratory epithelium were utilized. Importantly, complete loss of CDKN2AB strikingly accelerated mutant Kras -driven lung tumorigenesis, leading to loss of differentiation, increased metastatic disease, and decreased overall survival. Primary mutant Kras lung epithelial cells lacking Cdkn2ab had increased clonogenic potential. Furthermore, comparative analysis of mutant Kras;Cdkn2a null with Kras;Cdkn2ab null mice and experiments with mutant KRAS; CDKN2AB-deficient human lung cancer cells indicated that p15INK4B is a critical tumor suppressor. Thus, the loss of CDKN2AB is of biologic significance in mutant KRAS lung tumorigenesis by fostering cellular proliferation, cancer cell differentiation, and metastatic behavior.

Original languageEnglish (US)
Pages (from-to)912-923
Number of pages12
JournalMolecular Cancer Research
Volume12
Issue number6
DOIs
StatePublished - Jun 2014

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

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    Schuster, K., Venkateswaran, N., Rabellino, A., Girard, L., Penã-Llopis, S., & Scaglioni, P. P. (2014). Nullifying the CDKN2AB locus promotes mutant K-ras lung tumorigenesis. Molecular Cancer Research, 12(6), 912-923. https://doi.org/10.1158/1541-7786.MCR-13-0620-T