title: Molecular study of a new family with hereditary renal cell carcinoma and a translocation t(3;8)(p13;q24.1).
abstract: An alternative model has been proposed for the development of clear-cell renal cell carcinoma (RCC) in families where chromosome 3 translocations segregate with the disease. In this model, the existence of a translocation involving chromosome 3 would favour the non-disjunctional loss of the derivative chromosome carrying the 3p segment. Additionally, subsequent somatic mutations in the VLH gene, located in 3p25-26, would inactivate this tumour suppressor gene. In the present work, we describe a new family with two clear-cell RCC affected members and a t(3;8)(p13;q24.1) translocation in two consecutive generations. We observed loss of the derivative chromosome carrying the 3p segment (der(8)) and somatic mutation of the VHL gene in the left-kidney tumoral tissue of the proband. His right-kidney tumour carried a different VHL mutation and loss of heterozygosity (LOH) was not detected. The mother of the proband was also clear-cell RCC-affected but the tumoral tissue analysed did not carry any VHL gene mutations. Another member of the family, a maternal aunt, had a papillary RCC and did not carry this translocation, the LOH on 3p or the VHL somatic mutations. Haplotype analysis of the three affected members revealed that they did not inherit a common region on 3p, confirming the different genetic origin of both tumour types. Finally, the presence of RCC in other non-available members of the family highlights the overall risk for RCC in families with chromosome 3 translocations. In the present work, we have confirmed the proposed mechanism for the development of clear-cell RCC in this family, although we cannot discard the existence of other genes, in addition to VHL, being involved in hereditary RCC.
authors.affiliation: Department of Human Genetics, Spanish National Cancer Center (CNIO), C/ Melchor Fernández Almagro 3, 28029 Madrid, Spain. bmelendez@cnio.es
authors.forename: Bárbara
authors.initials: B
authors.lastname: Meléndez
authors.forename: Sandra
authors.initials: S
authors.lastname: Rodríguez-Perales
authors.forename: Beatriz
authors.initials: B
authors.lastname: Martínez-Delgado
authors.forename: Ignacio
authors.initials: I
authors.lastname: Otero
authors.forename: Mercedes
authors.initials: M
authors.lastname: Robledo
authors.forename: Angel
authors.initials: A
authors.lastname: Martínez-Ramírez
authors.forename: Sergio
authors.initials: S
authors.lastname: Ruiz-Llorente
authors.forename: Miguel
authors.initials: M
authors.lastname: Urioste
authors.forename: Juan Cruz
authors.initials: JC
authors.lastname: Cigudosa
authors.forename: Javier
authors.initials: J
authors.lastname: Benítez
mesh_terms: D018262:Adenocarcinoma, Clear Cell / Q000235:genetics* / Q000473:pathology; D000328:Adult; D000368:Aged; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000473:pathology; D002869:Chromosome Aberrations; D002874:Chromosome Mapping; D020090:Chromosome Segregation; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics*; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics*; D004273:DNA, Neoplasm; D005260:Female; D016147:Genes, Tumor Suppressor; D030342:Genetic Diseases, Inborn; D006579:Heterozygote; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007680:Kidney Neoplasms / Q000235:genetics* / Q000473:pathology; D008025:Ligases / Q000235:genetics; D019656:Loss of Heterozygosity; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D009154:Mutation; D009693:Nucleic Acid Hybridization; D010375:Pedigree; D016133:Polymerase Chain Reaction; D014178:Translocation, Genetic; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D006623:von Hippel-Lindau Disease / Q000235:genetics
chemical_list: D004273:DNA, Neoplasm; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D008025:Ligases; C497446:VHL protein, human