title: Promoter swapping between the genes for a novel zinc finger protein and beta-catenin in pleiomorphic adenomas with t(3;8)(p21;q12) translocations.
abstract: Pleiomorphic adenoma of the salivary glands is a benign epithelial tumour occurring primarily in the major and minor salivary glands. It is by far the most common type of salivary gland tumour. Microscopically, pleiomorphic adenomas show a marked histological diversity with epithelial, myoepithelial and mesenchymal components in a variety of patterns. In addition to a cytogenetic subgroup with normal karyotypes, pleiomorphic adenomas are characterized by recurrent chromosome rearrangements, particularly reciprocal translocations, with breakpoints at 8q12, 3p21, and 12q13-15, in that order of frequency. The most common abnormality is a reciprocal t(3;8)(p21;q12). We here demonstrate that the t(3;8)(p21;q12) results in promoter swapping between PLAG1, a novel, developmentally regulated zinc finger gene at 8q12, and the constitutively expressed gene for beta-catenin (CTNNB1), a protein interface functioning in the WG/WNT signalling pathway and specification of cell fate during embryogenesis. Fusions occur in the 5'-non-coding regions of both genes, exchanging regulatory control elements while preserving the coding sequences. Due to the t(3;8)(p21;q12), PLAG1 is activated and expression levels of CTNNB1 are reduced. Activation of PLAG1 was also observed in an adenoma with a variant translocation t(8;15)(q12;q14). Our results indicate that PLAG1 activation due to promoter swapping is a crucial event in salivary gland tumourigenesis.
authors.affiliation: Laboratory for Molecular Oncology, University of Leuven, Belgium.
authors.forename: K
authors.initials: K
authors.lastname: Kas
authors.forename: M L
authors.initials: ML
authors.lastname: Voz
authors.forename: E
authors.initials: E
authors.lastname: Röijer
authors.forename: A K
authors.initials: AK
authors.lastname: Aström
authors.forename: E
authors.initials: E
authors.lastname: Meyen
authors.forename: G
authors.initials: G
authors.lastname: Stenman
authors.forename: W J
authors.initials: WJ
authors.lastname: Van de Ven
mesh_terms: D008949:Adenoma, Pleomorphic / Q000235:genetics* / Q000473:pathology; D000595:Amino Acid Sequence; D001483:Base Sequence; D016386:Chromosome Walking; D018244:Chromosomes, Artificial, Yeast / Q000235:genetics; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics* / Q000648:ultrastructure; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics* / Q000648:ultrastructure; D003598:Cytoskeletal Proteins / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005796:Genes; D006801:Humans; D008969:Molecular Sequence Data; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D011401:Promoter Regions, Genetic; D012468:Salivary Gland Neoplasms / Q000235:genetics* / Q000473:pathology; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D015534:Trans-Activators; D014178:Translocation, Genetic / Q000235:genetics*; D016335:Zinc Fingers / Q000235:genetics*; D051176:beta Catenin
chemical_list: C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D015514:Oncogene Proteins, Fusion; C104382:PLAG1 protein, human; C104383:PLAG1-CTNNB1 fusion protein, human; D015534:Trans-Activators; D051176:beta Catenin