title: Parent-of-origin tumourigenesis is mediated by an essential imprinted modifier in SDHD-linked paragangliomas: SLC22A18 and CDKN1C are candidate tumour modifiers.
abstract: Mutations in SDHD and SDHAF2 (both located on chromosome 11) give rise to hereditary paraganglioma almost exclusively after paternal transmission of the mutation, and tumours often show loss of the entire maternal copy of chromosome 11. The 'Hensen' model postulates that a tumour modifier gene located on chromosome 11p15, a region known to harbour a cluster of imprinted genes, is essential to tumour formation. We observed decreased protein expression of the 11p15 candidate genes CDKN1C, SLC22A18 and ZNF215 evaluated in 60 SDHD-mutated tumours compared to normal carotid body tissue and non-SDH mutant tumours.We then created stable knockdown in vitro models, reasoning that the simultaneous knockdown of SDHD and a maternally expressed 11p15 modifier gene would enhance paraganglioma-related cellular characteristics compared to SDHD knockdown alone. Knockdown of SDHD in SNB19 and SHSY5Y cells resulted in the accumulation of succinate, the stabilization of HIF1 protein and a reduction in cell proliferation.Compared to single knockdown of SDHD, knockdown of SDHD together with SLC22A18 or with CDKN1C led to small but significant increases in cell proliferation and resistance to apoptosis, and to a gene expression profile closely related to the known transcriptional profile of SDH-deficient tumours. Of the 60 SDHD tumours investigated, four tumours showing retention of chromosome 11 showed SLC22A18 and CDKN1C expression levels comparable to levels in tumours showing loss of chromosome 11, suggesting loss of protein expression despite chromosomal retention.Our data strongly suggest that SLC22A18 and/or CDKN1C are tumour modifier genes involved in the tumourigenesis of SDHD-linked paraganglioma.
authors.affiliation: Department of Human Genetics.
authors.forename: Attje S
authors.initials: AS
authors.lastname: Hoekstra
authors.affiliation: Center for Proteomics and Metabolomics.|Department of Pathology.
authors.forename: Ruben D
authors.initials: RD
authors.lastname: Addie
authors.affiliation: Department of Biotechnology, Delft University of Technology, Delft, The Netherlands.
authors.forename: Cor
authors.initials: C
authors.lastname: Ras
authors.affiliation: Department of Biotechnology, Delft University of Technology, Delft, The Netherlands.
authors.forename: Reza M
authors.initials: RM
authors.lastname: Seifar
authors.affiliation: Department of Clinical Genetics.
authors.forename: Claudia A
authors.initials: CA
authors.lastname: Ruivenkamp
authors.affiliation: Department of Pathology.
authors.forename: Inge H
authors.initials: IH
authors.lastname: Briaire-de Bruijn
authors.affiliation: Department of Clinical Genetics.
authors.forename: Frederik J
authors.initials: FJ
authors.lastname: Hes
authors.affiliation: Department of Otorhinolaryngology.
authors.forename: Jeroen C
authors.initials: JC
authors.lastname: Jansen
authors.affiliation: Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Eleonora P M
authors.initials: EP
authors.lastname: Corssmit
authors.affiliation: Department of Pathology.
authors.forename: Willem E
authors.initials: WE
authors.lastname: Corver
authors.affiliation: Department of Pathology.
authors.forename: Hans
authors.initials: H
authors.lastname: Morreau
authors.affiliation: Department of Pathology.
authors.forename: Judith V M G
authors.initials: JV
authors.lastname: Bovée
authors.affiliation: Department of Human Genetics.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Bayley
authors.affiliation: Department of Human Genetics p.devilee@lumc.nl.|Department of Pathology.
authors.forename: Peter
authors.initials: P
authors.lastname: Devilee
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D050761:Cyclin-Dependent Kinase Inhibitor p57 / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D008957:Models, Genetic; D054802:Molecular Imprinting; D027701:Organic Cation Transport Proteins / Q000378:metabolism*; D010235:Paraganglioma / Q000235:genetics* / Q000378:metabolism; D013385:Succinate Dehydrogenase / Q000235:genetics*; D019802:Succinic Acid / Q000378:metabolism
chemical_list: C493964:CDKN1C protein, human; D050761:Cyclin-Dependent Kinase Inhibitor p57; D027701:Organic Cation Transport Proteins; C491545:SDHD protein, human; C111653:SLC22A18 protein, human; D019802:Succinic Acid; D013385:Succinate Dehydrogenase