Research Papers:
Loss of maternal chromosome 11 is a signature event in SDHAF2, SDHD, and VHL-related paragangliomas, but less significant in SDHB-related paragangliomas
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Abstract
Attje S. Hoekstra1, Erik F. Hensen2, Ekaterina S. Jordanova3, Esther Korpershoek4, Anouk N.A. van der Horst-Schrivers5, Cees Cornelisse3, Eleonora P.M. Corssmit6, Frederik J. Hes7, Jeroen C. Jansen8, Henricus P.M. Kunst9, Henri J.L.M. Timmers10, Adrian Bateman11, Diana Eccles12, Judith V.M.G. Bovée3, Peter Devilee1,3, Jean-Pierre Bayley1
1Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands
2Department of Otolaryngology/Head and Neck Surgery, VU University Medical Center, Amsterdam, The Netherlands
3Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
4Department of Pathology, Josephine Nefkens Institute, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands
5Department of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
6Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden, The Netherlands
7Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
8Department of Otorhinolaryngology, Leiden University Medical Center, Leiden, The Netherlands
9Department of Otorhinolaryngology, Head and Neck Surgery, Radboud University Medical Centre, Nijmegen, The Netherlands
10Department of Medicine, Division of Endocrinology, Radboud University Medical Centre, Nijmegen, The Netherlands
11Department of Cellular Pathology, University Hospital Southampton, Southampton, UK
12University of Southampton School of Medicine, Cancer Sciences Division, Somers Cancer Research Building, Southampton, UK
Correspondence to:
Jean-Pierre Bayley, email: [email protected]
Peter Devilee, email: [email protected]
Keywords: paraganglioma, pheochromocytoma, succinate dehydrogenase, Von Hippel-Lindau, loss of heterozygosity
Received: September 06, 2016 Accepted: January 04, 2017 Published: January 14, 2017
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.
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