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

Four cases of late onset clear cell renal cell carcinoma (RCC), a case of g astric cancer, and a case of exocrine pancreatic cancer were identified in a Japanese family. In order to elucidate the underlying mechanism for tumor igenesis 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 st udies (LOH), and VHL mutation analysis. A germline translocation t(1;3) (q3 2-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 los s of the derivative chromosome 3 carrying a Iq segment in the three familia l RCCs analysed. Additional chromosomal imbalances were identified by CGH, including amplifications of chromosomes 5 and 7 and loss of 8p and 9. No ge rmline VHL mutation was found but two different somatic mutations, a splice (IVS1-2A>C) and a frameshift (726delG), were identified in two RCCs from t he same patient confirming their distinct origin. Taken together, these res ults firmly support a three step model for tumorigenesis in this family. A constitutional translocation t(lq;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.