title: Disruption of a novel MFS transporter gene, DIRC2, by a familial renal cell carcinoma-associated t(2;3)(q35;q21).
abstract: Previously, we described a family with a significantly increased predisposition for renal cell cancer co-segregating with a t(2;3)(q35;q21) chromosomal translocation. Several primary tumors of the clear cell type from different family members were analyzed at a molecular level. Loss of the derivative chromosome 3 was consistently found. In addition, different somatic Von Hippel Lindau (VHL) gene mutations were observed in most of the tumors analyzed, even within the same patient. Based on these results a multistep tumorigenesis model was proposed in which (non-disjunctional) loss of the derivative chromosome 3 represents an early event and somatic mutation of the VHL gene represents a late event related to tumor progression. More recently, however, we noted that these two anomalies were absent in at least one early-stage tumor sample that we tested. Similar results were obtained in another family with renal cell cancer and t(3;6)(q12;q15), thus suggesting that another genetic event may precede these two oncogenetic steps. We speculate that deregulation of a gene(s) located at or near the translocation breakpoint may act as such. In order to identify such genes, a detailed physical map encompassing the 3q21 breakpoint region was constructed. Through a subsequent positional cloning effort we found that this breakpoint targets a hitherto unidentified gene, designated DIRC2 (disrupted in renal cancer 2). Computer predictions of the putative DIRC2 protein showed significant homology to different members of the major facilitator superfamily (MFS) of transporters. Based on additional DIRC2 expression and mutation analyses, we propose that the observed gene disruption may result in haplo-insufficiency and, through this mechanism, in the onset of tumor growth.
authors.affiliation: Department of Human Genetics, University Medical Center Nijmegen, Nijmegen, The Netherlands. d.bodmer@antrg.azn.nl
authors.forename: Daniëlle
authors.initials: D
authors.lastname: Bodmer
authors.forename: Marc
authors.initials: M
authors.lastname: Eleveld
authors.forename: Ellen
authors.initials: E
authors.lastname: Kater-Baats
authors.forename: Irene
authors.initials: I
authors.lastname: Janssen
authors.forename: Bert
authors.initials: B
authors.lastname: Janssen
authors.forename: Marian
authors.initials: M
authors.lastname: Weterman
authors.forename: Eric
authors.initials: E
authors.lastname: Schoenmakers
authors.forename: Michael
authors.initials: M
authors.lastname: Nickerson
authors.forename: Marston
authors.initials: M
authors.lastname: Linehan
authors.forename: Berton
authors.initials: B
authors.lastname: Zbar
authors.forename: Ad Geurts
authors.initials: AG
authors.lastname: van Kessel
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D002292:Carcinoma, Renal Cell / Q000235:genetics*; D022201:Chromosomes, Artificial / Q000235:genetics / Q000378:metabolism; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics*; D003001:Cloning, Molecular; D023061:Gene Order; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007680:Kidney Neoplasms / Q000235:genetics*; D007687:Kidney Tubules, Proximal / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D016133:Polymerase Chain Reaction; D014178:Translocation, Genetic / Q000235:genetics*; D006623:von Hippel-Lindau Disease / Q000235:genetics
chemical_list: D005819:Genetic Markers; D009363:Neoplasm Proteins