CBL is frequently altered in lung cancers: Its relationship to mutations in met and EGFR tyrosine kinases

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

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81 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article numbere8972
JournalPloS one
Volume5
Issue number1
DOIs
Publication statusPublished - 2010 Jan 29

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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