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 Kanayama, Hiro-omi
A1 Lui, Weng-Onn
A1 Takahashi, Masayuki
A1 Naroda, Takushi
A1 Kedra, Darek
A1 Wong, Fung Ki
A1 Kuroki, Yoko
A1 Nakahori, Yutaka
A1 Larsson, Catharina
A1 Kagawa, Susumu
A1 Teh, Bin Tean
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.