Centers and Institutes
Published January 29, 2010 | Version v1
Journal article Open

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

Creators

  • 1. National Taiwan Normal University
  • 2. University of Chicago
  • 3. National Cancer Institute
  • 4. Dana-Farber Cancer Institute
  • 5. National Cheng Kung University

Description

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.

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Additional details

Identifiers

DOI
10.1371/journal.pone.0008972
Other
oai:uchicago.tind.io:10367

Funding

National Cancer Institute
5RO1CA125541-03
National Cancer Institute
3RO1CA125541-03S109
National Cancer Institute
5RO1CA129501-02
National Cancer Institute
3RO1CA129501-02S109
National Cancer Institute
1R21CA140003-01
MARF
V-Foundation
Cancer Research Foundation
Respiratory Health Association of America
National Science Council, Taiwan
NSC96-2628-B-006-048-MY3
National Institutes of Health
Intramural Research Program

UChicago Information

Division(s)
Physical Sciences Division, Pritzker School of Medicine
Department(s)
Medicine, Pediatrics, Statistics
Center(s) or Institute(s)
Comprehensive Cancer Center