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

2010; Public Library of Science; Volume: 5; Issue: 1 Linguagem: Inglês

10.1371/journal.pone.0008972

1932-6203

Yi‐Hung Carol Tan, Soundararajan Krishnaswamy, Suvobroto Nandi, Rajani Kanteti, Sapana Vora, Kenan Onel, Rifat Hasina, Fang-Yi Lo, Essam El‐Hashani, Gustavo M. Cervantes, Matthew R. Robinson, Stephen C. Kales, Stanley Lipkowitz, Theodore Karrison, Martin Sattler, Everett E. Vokes, Yi‐Ching Wang, Ravi Salgia,

PI3K/AKT/mTOR signaling in cancer

Background 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.