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Trisomy 7-harbouring non-random duplication of the mutant MET allele in hereditary papillary renal carcinomas

Nature Genetics volume 20, pages 66–69 (1998)Cite this article

Abstract

The gene defect for hereditary papillary renal carcinoma1 (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 hybridization3 (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.

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Figure 1: FISH analysis of lymphoblastoid cell line and tumour tissues from HPRC patients.
Figure 2: Genotyping, quantitative duplex PCR amplification and sequencing analysis of normal and tumour samples in patient 1.
Figure 3: Clonality analysis of 10 different tumours from a female patient (patient 1).
Figure 4: Quantitive PCR amplification of normal kidney and tumour tissues to analyse allelic imbalance of chromsome 17 from patient 2.

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Author notes

  1. Berton Zbar and Gregor Weirich: Laboratory of Immunobiology, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, Maryland , USA. Z.Z., W.-S.P. & S.P. contributed equally to this work.

Authors and Affiliations

  1. Laboratory of Pathology, National Cancer Institute , Bethesda, Maryland, USA

    Zhengping Zhuang, Won-Sang Park, Svetlana Pack, Alexander O. Vortmeyer, Evgenia Pak, Thu Pham, Robert J. Weil & Irina A. Lubensky

  2. Intramural Research Support Program, Scientific Applications International Corporation, Frederick, Maryland, USA

    Laura Schmidt

  3. Institute of Pathology, Technical University of Munich , Germany

    Sonja Candidus

  4. Urologic Oncology Branch, National Cancer Institute , Bethesda, Maryland, USA

    W. Marston Linehan

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  1. Zhengping Zhuang
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  2. Won-Sang Park
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Correspondence to Zhengping Zhuang.

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Zhuang, Z., Park, WS., Pack, S. et al. Trisomy 7-harbouring non-random duplication of the mutant MET allele in hereditary papillary renal carcinomas. Nat Genet 20, 66–69 (1998). https://doi.org/10.1038/1727

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