title: The tumor suppressor gene FBXW7 is disrupted by a constitutional t(3;4)(q21;q31) in a patient with renal cell cancer.
abstract: FBXW7 (alias CDC4) is a p53-dependent tumor suppressor gene that exhibits mutations or deletions in a variety of human tumors. Mutation or deletion of the FBXW7 gene has been associated with an increase in chromosomal instability and cell cycle progression. In addition, the FBXW7 protein has been found to act as a component of the ubiquitin proteasome system and to degrade several oncogenic proteins that function in cellular growth regulatory pathways. By using a rapid breakpoint cloning procedure in a case of renal cell cancer (RCC), we found that the FBXW7 gene was disrupted by a constitutional t(3;4)(q21;q31). Subsequent analysis of the tumor tissue revealed the presence of several anomalies, including loss of the derivative chromosome 3. Upon screening of a cohort of 29 independent primary RCCs, we identified one novel pathogenic mutation, suggesting that the FBXW7 gene may also play a role in the development of sporadic RCCs. In addition, we screened a cohort of 48 unrelated familial RCC cases with unknown etiology. Except for several known or benign sequence variants such as single nucleotide polymorphisms (SNPs), no additional pathogenic variants were found. Previous mouse models have suggested that the FBXW7 gene may play a role in the predisposition to tumor development. Here we report that disruption of this gene may predispose to the development of human RCC.
authors: Department of Human Genetics, Radboud University Nijmegen Medical Center, and Nijmegen Center for Molecular Life Sciences, PO Box 9101, 6500 HB Nijmegen, The Netherlands. r.kuiper@antrg.umcn.nl
authors: Roland P
authors: RP
authors: Kuiper
authors: Lilian
authors: L
authors: Vreede
authors: Ramprasath
authors: R
authors: Venkatachalam
authors: Chris
authors: C
authors: Ricketts
authors: Eveline
authors: E
authors: Kamping
authors: Eugene
authors: E
authors: Verwiel
authors: Lutgarde
authors: L
authors: Govaerts
authors: Maria
authors: M
authors: Debiec-Rychter
authors: Evelyne
authors: E
authors: Lerut
authors: Femke
authors: F
authors: van Erp
authors: Nicoline
authors: N
authors: Hoogerbrugge
authors: Lianne
authors: L
authors: van Kempen
authors: Eric F P M
authors: EF
authors: Schoenmakers
authors: Anita
authors: A
authors: Bonne
authors: Eamonn R
authors: ER
authors: Maher
authors: Ad
authors: A
authors: Geurts van Kessel
mesh_terms: D001483:Base Sequence; D002292:Carcinoma, Renal Cell / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics*; D002893:Chromosomes, Human, Pair 3; D002894:Chromosomes, Human, Pair 4; D017931:DNA Primers; D044783:F-Box Proteins / Q000235:genetics*; D000073979:F-Box-WD Repeat-Containing Protein 7; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007621:Karyotyping; D007680:Kidney Neoplasms / Q000235:genetics*; D009154:Mutation; D016133:Polymerase Chain Reaction; D014178:Translocation, Genetic; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
chemical_list: D018797:Cell Cycle Proteins; D017931:DNA Primers; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; D044767:Ubiquitin-Protein Ligases