CBL Is Frequently Altered in Lung Cancers: Its Relationship to Mutations in MET and EGFR Tyrosine Kinases

Tan, Yi-Hung CarolKrishnaswamy, SoundararajanNandi, SuvobrotoKanteti, RajaniVora, SapanaOnel, KenanHasina, RifatLo, Fang-YiEl-Hashani, EssamCervantes, GustavoLipkowitz, StanleyKarrison, TheodoreVokes, Everett E.Wang, Yi-ChingSalgia, RaviNajbauer, JosephRobinson, MatthewKales, Stephen C.Sattler, Martin2012-01-232010Tan, Yi-Hung Carol, Soundararajan Krishnaswamy, Suvobroto Nandi, Rajani Kanteti, Sapana Vora, Kenan Onel, Rifat Hasina, et al. 2010. CBL Is Frequently Altered in Lung Cancers: Its Relationship to Mutations in MET and EGFR Tyrosine Kinases. PLoS ONE 5(1): e8972.1932-6203http://nrs.harvard.edu/urn-3:HUL.InstRepos:8000934Background: Non-small cell lung cancer (NSCLC) is a heterogeneous group of disorders with a number of genetic and proteomic alterations. c-CBL is an E3 ubiquitin ligase and adaptor molecule important in normal homeostasis and cancer. We determined the genetic variations of c-CBL, relationship to receptor tyrosine kinases (EGFR and MET), and functionality in NSCLC. Methods and Findings: Using archival formalin-fixed paraffin embedded (FFPE) extracted genomic DNA, we show that c-CBL mutations occur in somatic fashion for lung cancers. c-CBL mutations were not mutually exclusive of MET or EGFR mutations; however they were independent of p53 and KRAS mutations. In normal/tumor pairwise analysis, there was significant loss of heterozygosity (LOH) for the c-CBL locus (22%, n = 8/37) and none of these samples revealed any mutation in the remaining copy of c-CBL. The c-CBL LOH also positively correlated with EGFR and MET mutations observed in the same samples. Using select c-CBL somatic mutations such as S80N/H94Y, Q249E and W802* (obtained from Caucasian, Taiwanese and African-American samples, respectively) transfected in NSCLC cell lines, there was increased cell viability and cell motility. Conclusions: Taking the overall mutation rate of c-CBL to be a combination as somatic missense mutation and LOH, it is clear that c-CBL is highly mutated in lung cancers and may play an essential role in lung tumorigenesis and metastasis.en-USoncologylung cancercell biologymolecular biologypost-translational regulation of gene expressionCBL Is Frequently Altered in Lung Cancers: Its Relationship to Mutations in MET and EGFR Tyrosine KinasesJournal Article2012-01-2310.1371/journal.pone.0008972