Association of a novel constitutional translocation t(1q;3q) with familial renal cell carcinoma
Hiro-omi Kanayamaa, Weng-Onn Luib, Masayuki Takahashia c, Takushi Narodaa, Darek Kedrac, Fung Ki Wongb, Yoko Kurokid, Yutaka Nakahorid, Catharina Larssonb, Susumu Kagawaa, Bin Tean Tehb c
a Department of
Urology, School of Medicine, The University of Tokushima, Japan, b Department of Molecular Medicine,
Karolinska Hospital, Stockholm, Sweden, c Van Andel
Research Institute, 333 Bostwick NE, Grand Rapids, MI 49503, USA, d Department
of Public Health, School of Medicine, The University of Tokushima,
Japan
Correspondence to: Dr Teh, USA, bin.teh{at}vai.org
Revised version received 21 December 2000;
Accepted for publication 22
December 2000
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), and
VHL 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 germline
VHL 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 VHL
located in the remaining copy of chromosome 3.
Keywords: familial renal cell carcinoma; translocation; von Hippel-Lindau disease; loss of heterozygosity
© 2001 by J Med Genet
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