title: Nullifying the CDKN2AB locus promotes mutant K-ras lung tumorigenesis.
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 p14(ARF) 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 p16(INK4A) and p14(ARF), suggesting that p15INK4B loss confers a selective advantage to mutant KRAS lung cancers that are p16(INK4A) and p14(ARF) 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.
  
  
  CONCLUSIONS
  These findings indicate that mutant Kras;Cdkn2ab null mice provide a platform for accurately modeling aggressive lung adenocarcinoma and testing therapeutic modalities.
authors.affiliation: Authors' Affiliations: Department of Internal Medicine; Simmons Cancer Center;
authors.forename: Katja
authors.initials: K
authors.lastname: Schuster
authors.affiliation: Authors' Affiliations: Department of Internal Medicine; Simmons Cancer Center;
authors.forename: Niranjan
authors.initials: N
authors.lastname: Venkateswaran
authors.affiliation: Authors' Affiliations: Department of Internal Medicine; Simmons Cancer Center;
authors.forename: Andrea
authors.initials: A
authors.lastname: Rabellino
authors.affiliation: Hamon Center for Therapeutic Oncology Research; Departments of Pharmacology and.
authors.forename: Luc
authors.initials: L
authors.lastname: Girard
authors.affiliation: Authors' Affiliations: Department of Internal Medicine; Simmons Cancer Center; Developmental Biology, The University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Samuel
authors.initials: S
authors.lastname: Peña-Llopis
authors.affiliation: Authors' Affiliations: Department of Internal Medicine; Simmons Cancer Center; Pier.Scaglioni@UTSouthwestern.edu.
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Scaglioni
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000818:Animals; D063646:Carcinogenesis / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D004195:Disease Models, Animal; D011905:Genes, ras; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D046228:Microarray Analysis; D010957:Plasmids
chemical_list: D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16