Abstract
BackgroundNon-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 FindingsUsing 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.ConclusionsTaking 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.
Highlights
In the US alone, each year approximately 219,400 people are diagnosed with lung cancers, out of which more than 145,000 of them succumb to the disease [1]
Taking the overall mutation rate of c-CBL to be a combination as somatic missense mutation and loss of heterozygosity (LOH), it is clear that c-CBL is highly mutated in lung cancers and may play an essential role in lung tumorigenesis and metastasis
We show that c-CBL mutations occur with or without MET or EGFR mutations but are mutually exclusive of a LOH at the c-CBL locus
Summary
In the US alone, each year approximately 219,400 people are diagnosed with lung cancers, out of which more than 145,000 of them succumb to the disease [1]. This number is roughly equivalent to the combined mortality rates of cancers of the breast, prostate, colon, liver, kidney and melanoma [1]. In NSCLC, mutations in KRAS, p53, EGFR and MET have been identified Many of these pathways, especially Receptor Tyrosine Kinases (RTKs) are controlled by c-CBL. We determined the genetic variations of c-CBL, relationship to receptor tyrosine kinases (EGFR and MET), and functionality in NSCLC
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