CBL is frequently altered in lung cancers: its relationship to mutations in MET and EGFR tyrosine kinases.
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.


RESULTS
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.
Tan
Yi-Hung Carol
YH
Department of Life Science, National Taiwan Normal University, Taipei, Taiwan.
Krishnaswamy
Soundararajan
S
Nandi
Suvobroto
S
Kanteti
Rajani
R
Vora
Sapana
S
Onel
Kenan
K
Hasina
Rifat
R
Lo
Fang-Yi
FY
El-Hashani
Essam
E
Cervantes
Gustavo
G
Robinson
Matthew
M
Hsu
Han-Shui
HS
Kales
Stephen C
SC
Lipkowitz
Stanley
S
Karrison
Theodore
T
Sattler
Martin
M
Vokes
Everett E
EE
Wang
Yi-Ching
YC
Salgia
Ravi
R
D001483:Base Sequence; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002880:Chromosomes, Human, Pair 11; D017931:DNA Primers; D066246:ErbB Receptors / Q000235:genetics*; D005434:Flow Cytometry; D006801:Humans; D019656:Loss of Heterozygosity; D008175:Lung Neoplasms / Q000235:genetics*; D016297:Mutagenesis, Site-Directed; D020125:Mutation, Missense; D016612:Paraffin Embedding; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics*; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics*; D017978:Receptors, Growth Factor / Q000235:genetics*
D017931:DNA Primers; D017978:Receptors, Growth Factor; D050721:Proto-Oncogene Proteins c-cbl; D066246:ErbB Receptors; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; C067419:CBL protein, human