Trisomy 7-Harbouring Non-Random Duplication of the Mutant MET Allele in Hereditary Papillary Renal Carcinomas

The gene defect for hereditary papillary renal carcinoma 1 (HPRC) has recently been mapped to chromosome 7q, and germline mutations of MET (also known as c-met) at 7q31 have been detected in patients with HPRC (ref. 2). Tumours from these patients commonly show trisomy of chromosome 7 when analysed by cytogenetic studies and comparative genomic hybridization 3 (CGH). However, the relationship between trisomy 7 and MET germline mutations is not clear. We studied 16 renal tumours from two patients with documented germline mutations in exon 16 of MET. Flourescent in situ hybridization (FISH) analysis showed trisomy 7 in all tumours. To determine whether the chromosome bearing the mutant or wild-type MET gene was duplicated, we performed duplex PCR and phosphoimage densitometry using polymorphic microsatellite markers D7S1801 and D7S1822, which were linked to the disease gene locus, and D1S1646 as an internal control. We determined the parental origin of chromosome alleles by genotyping parental DNA. In all 16 tumours there was an increased signal intensity (2:1 ratio) of the microsatellite allele from the chromosome bearing the mutant MET compared with the allele from the chromosome bearing the wild-type MET. Our study demonstrates a non-random duplication of the chromosome bearing the mutated MET in HPRC and implicates this event in tumorigenesis. All tumours analysed using FISH were trisomic for chromosome 7 using chromosome 7-specific painting and centromeric α-satellite probes (Fig. 1d). In addition, three copies of the MET gene were consistently detected in the tumour cells using cosmid c182b3 (which contains MET) as a probe (Fig. 1b). In contrast,