title: Loss of maternal chromosome 11 is a signature event in SDHAF2, SDHD, and VHL-related paragangliomas, but less significant in SDHB-related paragangliomas.
abstract: Germline mutations in the succinate dehydrogenase (SDHA, SDHB, SDHC, SDHD, SDHAF2) or Von Hippel-Lindau (VHL) genes cause hereditary paraganglioma/pheochromocytoma. While SDHB (1p36) and VHL (3p25) are associated with autosomal dominant disease, SDHD (11q23) and SDHAF2 (11q13) show a remarkable parent-of-origin effect whereby tumor formation is almost completely dependent on paternal transmission of the mutant allele. Loss of the entire maternal copy of chromosome 11 occurs frequently in SDHD-linked tumors, and has been suggested to be the basis for this typical inheritance pattern.Using fluorescent in situ hybridization, microsatellite marker and SNP array analysis, we demonstrate that loss of the entire copy of chromosome 11 is also frequent in SDHAF2-related PGLs, occurring in 89% of tumors. Analysis of two imprinted differentially methylated regions (DMR) in 11p15, H19-DMR and KvDMR, showed that this loss always affected the maternal copy of chromosome 11. Likewise, loss of maternal chromosome 11p15 was demonstrated in 85% of SDHD and 75% of VHL-related PGLs/PCCs. By contrast, both copies of chromosome 11 were found to be retained in 62% of SDHB-mutated PGLs/PCCs, while only 31% showed loss of maternal chromosome 11p15. Genome-wide copy number analysis revealed frequent loss of 1p in SDHB mutant tumors and show greater genomic instability compared to SDHD and SDHAF2.These results show that loss of the entire copy of maternal chromosome 11 is a highly specific and statistically significant event in SDHAF2, SDHD and VHL-related PGLs/PCCs, but is less significant in SDHB-mutated tumors, suggesting that these tumors have a distinct genetic etiology.
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Attje S
authors.initials: AS
authors.lastname: Hoekstra
authors.affiliation: Department of Otolaryngology/Head and Neck Surgery, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Erik F
authors.initials: EF
authors.lastname: Hensen
authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Ekaterina S
authors.initials: ES
authors.lastname: Jordanova
authors.affiliation: Department of Pathology, Josephine Nefkens Institute, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: Esther
authors.initials: E
authors.lastname: Korpershoek
authors.affiliation: Department of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Anouk Na
authors.initials: AN
authors.lastname: van der Horst-Schrivers
authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Cees
authors.initials: C
authors.lastname: Cornelisse
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 Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Frederik J
authors.initials: FJ
authors.lastname: Hes
authors.affiliation: Department of Otorhinolaryngology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Jeroen C
authors.initials: JC
authors.lastname: Jansen
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Henricus P M
authors.initials: HP
authors.lastname: Kunst
authors.affiliation: Department of Medicine, Division of Endocrinology, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Henri J L M
authors.initials: HJ
authors.lastname: Timmers
authors.affiliation: Department of Cellular Pathology, University Hospital Southampton, Southampton, UK.
authors.forename: Adrian
authors.initials: A
authors.lastname: Bateman
authors.affiliation: University of Southampton School of Medicine, Cancer Sciences Division, Somers Cancer Research Building, Southampton, UK.
authors.forename: Diana
authors.initials: D
authors.lastname: Eccles
authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Judith V M G
authors.initials: JV
authors.lastname: Bovée
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.|Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: Devilee
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Bayley
mesh_terms: D000483:Alleles; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics*; D005260:Female; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D019656:Loss of Heterozygosity; D024101:Mitochondrial Proteins / Q000235:genetics*; D010235:Paraganglioma / Q000235:genetics*; D013385:Succinate Dehydrogenase / Q000235:genetics*; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics*
chemical_list: D024101:Mitochondrial Proteins; C543341:SDHAF2 protein, human; C108095:SDHB protein, human; D013385:Succinate Dehydrogenase; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human
keywords: Von Hippel-Lindau; loss of heterozygosity; paraganglioma; pheochromocytoma; succinate dehydrogenase