Duplication and overexpression of the mutant allele of the MET proto-oncogene in multiple hereditary papillary renal cell tumours

Abstract

Previous karyotyping showed a combined trisomy of chromosome 7 and 17 in sporadic and hereditary papillary renal cell tumours (RCT). A recent molecular analysis revealed a mutation in the MET tyrosine kinase (chromosome 7q31) in the germline of four out of seven families with hereditary papillary RCT (HPRCT). We have analysed germline cells as well as multiple tumours obtained from HPRCT families and sporadic cases for alteration of the MET tyrosine kinase and for allelic duplication at chromosome 7 and 17. We have detected a germ line mutation in the MET tyrosine kinase in one of the two families with HPRCTs and also found the same mutation in the germ line of one patient with clinically recognized multiple, bilateral papillary RCTs but without family history. The mutant MET allele is consequently duplicated and overexpressed in tumour cells indicating that duplication of the mutant MET allele is necessary before cells enter the tumorigenic pathway. The lack of germline mutation in two members of another HPRT family and duplication of the same parental allele of chromosome 7 in multiple tumours suggests that a germ line event other than mutation of MET tyrosine kinase is involved in the development of these tumours. Duplication of di erent alleles of chromosome 7 in sporadic and of chromosome 17 in both types of tumours excludes a germline mutation at these chromosomal sites.

Mutations in the met Oncogene Unveil a “Dual Switch” Mechanism Controlling Tyrosine Kinase Activity

“…For example, long latency and incomplete penetrance usually reflect the requirement for loss of heterozygosity. In the case of met, it could be more appropriate to speak about "gain of homozygosity," because duplication of the chromosome bearing the mutant met allele is invariably selected during tumor progression (17,18). This leads to both higher expression of the mutant protein and increased autocrine stimulation because HGF and met lie both on chromosome 7 (this is a peculiarity not shared by other oncogenic RTKs).…”

“…Interestingly, although the mutant forms of Met possess an intrinsic higher kinase activity in vitro, their transforming ability in vivo is latent and can be unmasked only in the presence of HGF (16). Patients harboring a germ line mutation in the met gene develop cancer only late in life and with incomplete penetrance (10), most probably because duplication of the mutant allele is required for tumor progression (17,18). All together, these observations indicate that a met mutation provides tumor predisposition, but increased dosage and/or sustained ligand stimulation is required to actually determine tumor formation.…”

A proteomic analysis reveals the loss of expression of the cell death regulatory gene GRIM-19 in human renal cell carcinomas

“…Anomalies within the p53 tumor suppressor gene are not common in RCC. Mutations in the Von Hippel-Lindau (VHL) tumor-suppressor gene (Latif et al, 1993;Herman et al, 1994;Iliopoulos et al, 1995) or amplification and activation of the tyrosine kinase c-Met (Schmidt et al, 1997;Fischer et al, 1998;Zhuang et al, 1998;Lubensky et al, 1999) have been shown to play critical roles in the development of some RCCs. Despite these advances, the full spectrum of molecular changes that occur in the tumor is far from clear.…”

Concomitant activation of pathways downstream of Grb2 and PI 3-kinase is required for MET-mediated metastasis

“…c-MET is overexpressed and ampli®ed in a number of human tumors (reviewed in Bardelli et al, 1997a). Recently, a direct genetic link between c-MET and human cancer was established by the identi®cation of activating mutations in the c-MET gene in hereditary papillary renal carcinomas (Schmidt et al, 1997;Fischer et al, 1998;Zhuang et al, 1998). c-MET was originally identi®ed as the cellular counterpart of a transforming gene, TPR ± MET, resulting from a chromosomal rearrangement (Cooper et al, 1984;Park et al, 1986).…”