RT Journal Article
SR Electronic
T1 Association of a novel constitutional translocation t(1q;3q) with familial renal cell carcinoma
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP 165
OP 170
DO 10.1136/jmg.38.3.165
VO 38
IS 3
A1 Hiro-omi Kanayama
A1 Weng-Onn Lui
A1 Masayuki Takahashi
A1 Takushi Naroda
A1 Darek Kedra
A1 Fung Ki Wong
A1 Yoko Kuroki
A1 Yutaka Nakahori
A1 Catharina Larsson
A1 Susumu Kagawa
A1 Bin Tean Teh
YR 2001
UL http://jmg.bmj.com/content/38/3/165.abstract
AB 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.