Mutation and expression analyses of the MET and CDKN2A genes in rhabdomyosarcoma with emphasis on MET overexpression
Article first published online: 22 JAN 2007
Copyright © 2007 Wiley-Liss, Inc.
Genes, Chromosomes and Cancer
Volume 46, Issue 4, pages 348–358, April 2007
How to Cite
Chen, Y., Takita, J., Mizuguchi, M., Tanaka, K., Ida, K., Koh, K., Igarashi, T., Hanada, R., Tanaka, Y., Park, M.-J. and Hayashi, Y. (2007), Mutation and expression analyses of the MET and CDKN2A genes in rhabdomyosarcoma with emphasis on MET overexpression. Genes Chromosom. Cancer, 46: 348–358. doi: 10.1002/gcc.20416
- Issue published online: 6 FEB 2007
- Article first published online: 22 JAN 2007
- Manuscript Accepted: 21 NOV 2006
- Manuscript Received: 22 JUN 2006
- A Grant-in-Aid for Cancer Research
- Research on Children and Families from Ministry of Health, Labor and Welfare of Japan
- Ministry of Education, Culture, Sports, Science and Technology of Japan
Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma of childhood. The simultaneous loss of Ink4a/Arf function and disruption of Met signaling in Ink4a/Arf−/− mice transgenic for hepatocyte growth factor/scatter factor (HGF/SF) induces RMS with extremely high penetrance and short latency. To address the roles of MET and CDKN2A (p16INK4A/p14ARF) in human RMS, we performed mutational analyses in 39 samples of RMS by PCR-SSCP. No mutations were detected in exons 14–21 of MET whereas a nonsense mutation at codon 80 of p16INK4A was identified in an alveolar RMS cell line. We also quantified the relative expression levels and DNA copy numbers of these genes in seven cell lines and 17 fresh tumors by real-time quantitative PCR. Expression of MET was detected in all samples; however, more than 10-fold difference was found in the samples with higher or lower expression level, despite a normal DNA copy number. The protein expression level was consistent with that of mRNA, and in cell lines with a higher expression level, MET was constitutively activated. Notably, the expression level of MET was significantly higher in patients who died (P = 0.02), in patients with stage IV (P = 0.04), as well as in patients with PAX3-FKHR chimeric transcript (P = 0.04). On the other hand, reduced or absent expression of p16INK4A and/or p14ARF showed no significant correlation with the clinicopathological parameters, except for the age at diagnosis. Our data suggest that MET plays a role in the progression of RMS. © 2007 Wiley-Liss, Inc.