Novel Mutations in c-Cbl Ubiquitin Ligase Gene in Taiwanese Lung Cancer

Abstract

BACKGROUND. Cbl (Casitas B-lineage lymphoma) is a mammalian gene located on human chromosome 11q23.3 and involves in cell signaling and protein ubiquitination. One of the Cbl family proteins, c-Cbl, has been recognized as a key player in the negative regulation of signaling pathways such as receptor tyrosine kinase (RTK) pathway. Recent studies found that RTKs, such as c-Met and EGFR, are overexpressed in many cancers. Thus, we hypothesized that the alteration of their negative regulators, such as c-Cbl mutations, may contribute to the oncogenic potential of c-Met and EGFR. METHODS. We investigated c-Cbl mutation spectrum in tumor and corresponding normal tissues from 30 Taiwanese lung cancer patients by polymerase chain reaction and direct sequencing and examined biological function of these c-Cbl mutations in cell models. RESULTS. We identified 9 c-Cbl mutations in 30 Taiwanese lung cancer samples. Only Q249E mutant did not appear in corresponding normal tissue, suggesting that Q249E is a novel somatic mutation. The total mutation rate for tumor was 30% (9/30) and for normal was 27% (8/30). The other 8 mutations included a known single nucleotide polymorphism L620F and 7 novel or known intronic polymorphisms in c-Cbl. In addition, transient expression of Q249E mutant increased cell viability in A549 lung cancer cell line. CONCLUSIONS. Our results provide new evidence that c-Cbl mutations play a role in lung tumorigenesis. In addition, c-Cbl may be a therapeutic target for patient who does not carry mutations in the RTK itself and is resistant to RTK inhibitors treatments.