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J Med Genet 2001;38:165-170 doi:10.1136/jmg.38.3.165
  • Original article

Association of a novel constitutional translocation t(1q;3q) with familial renal cell carcinoma

  1. Hiro-omi Kanayamaa,
  2. Weng-Onn Luib,
  3. Masayuki Takahashia,c,
  4. Takushi Narodaa,
  5. Darek Kedrac,
  6. Fung Ki Wongb,
  7. Yoko Kurokid,
  8. Yutaka Nakahorid,
  9. Catharina Larssonb,
  10. Susumu Kagawaa,
  11. Bin Tean Tehb,c
  1. aDepartment of Urology, School of Medicine, The University of Tokushima, Japan, bDepartment of Molecular Medicine, Karolinska Hospital, Stockholm, Sweden, cVan Andel Research Institute, 333 Bostwick NE, Grand Rapids, MI 49503, USA, dDepartment of Public Health, School of Medicine, The University of Tokushima, Japan
  1. Dr Teh, USA, bin.teh{at}vai.org
  • Revised 21 December 2000
  • Accepted 22 December 2000

Abstract

Four cases of late onset clear cell renal cell carcinoma (RCC), a case of gastric cancer, and a case of exocrine pancreatic cancer were identified in a Japanese family. In order to elucidate the underlying mechanism for tumorigenesis in this family, extensive genetic studies were performed including routine and spectral karyotyping (SKY), fluorescence in situ hybridisation (FISH), comparative genomic hybridisation (CGH), loss of heterozygosity studies (LOH), andVHL mutation analysis. A germline translocation t(1;3)(q32-q41;q13-q21) was identified by karyotyping in five members of the family including all three RCC cases tested. The translocation was refined to t(1;3)(q32;q13.3) by FISH analysis using locus specific genomic clones, and the two breakpoints were mapped to a 5 cM region in 3q13.3 and a 3.6 cM region in 1q32. Both CGH and allelotyping using microsatellite markers showed loss of the derivative chromosome 3 carrying a 1q segment in the three familial RCCs analysed. Additional chromosomal imbalances were identified by CGH, including amplifications of chromosomes 5 and 7 and loss of 8p and 9. No germlineVHL mutation was found but two different somatic mutations, a splice (IVS1-2A>C) and a frameshift (726delG), were identified in two RCCs from the same patient confirming their distinct origin.Taken together, these results firmly support a three step model for tumorigenesis in this family. A constitutional translocation t(1q;3q) increased the susceptibility to loss of the derivative chromosome 3 which is then followed by somatic mutations of the RCC related tumour suppressor gene VHLlocated in the remaining copy of chromosome 3.

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