Format

Send to

Choose Destination
See comment in PubMed Commons below
Endocr Relat Cancer. 2014 Aug;21(4):567-77. doi: 10.1530/ERC-14-0254. Epub 2014 May 23.

Aberrant DNA hypermethylation of SDHC: a novel mechanism of tumor development in Carney triad.

Author information

1
Institute of PathologyUniversity Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Krankenhausstraße 8-10, D-91054 Erlangen, GermanyProgram on Developmental Endocrinology and GeneticsEunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USADivision Molecular Genome AnalysisDivision of Theoretical BioinformaticsGerman Cancer Research Center (DKFZ), Heidelberg, GermanyInstitut CochinINSERM U1016, CNRS UMR 8104, Université Paris Descartes, Sorbonne Paris Cité, Paris, FranceDepartment of EndocrinologyReferal Center for Rare Adrenal Diseases, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, FranceInstitute of PathologyUniversity Medical Center, Georg-August University, Göttingen, GermanyInstitute of PathologyUniversity Hospital, Albert-Ludwigs University Freiburg, Freiburg, GermanySchool of Clinical and Experimental MedicineCollege of Medical and Dental Sciences, Centre for Rare Diseases and Personalised Medicine, Birmingham Women's Hospital, University of Birmingham and West Midlands Regional Genetics Service, Birmingham, UKDepartment of Medical GeneticsUniversity of Cambridge, Cambridge CB2 0QQ, UKLaboratory Medicine and PathologyEmeritus Staff, Mayo Clinic, Rochester, Minnesota, USA florian.haller@uk-erlangen.de stratakc@cc1.nichd.nih.gov.
2
Institute of PathologyUniversity Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Krankenhausstraße 8-10, D-91054 Erlangen, GermanyProgram on Developmental Endocrinology and GeneticsEunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USADivision Molecular Genome AnalysisDivision of Theoretical BioinformaticsGerman Cancer Research Center (DKFZ), Heidelberg, GermanyInstitut CochinINSERM U1016, CNRS UMR 8104, Université Paris Descartes, Sorbonne Paris Cité, Paris, FranceDepartment of EndocrinologyReferal Center for Rare Adrenal Diseases, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, FranceInstitute of PathologyUniversity Medical Center, Georg-August University, Göttingen, GermanyInstitute of PathologyUniversity Hospital, Albert-Ludwigs University Freiburg, Freiburg, GermanySchool of Clinical and Experimental MedicineCollege of Medical and Dental Sciences, Centre for Rare Diseases and Personalised Medicine, Birmingham Women's Hospital, University of Birmingham and West Midlands Regional Genetics Service, Birmingham, UKDepartment of Medical GeneticsUniversity of Cambridge, Cambridge CB2 0QQ, UKLaboratory Medicine and PathologyEmeritus Staff, Mayo Clinic, Rochester, Minnesota, USA.
3
Institute of PathologyUniversity Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Krankenhausstraße 8-10, D-91054 Erlangen, GermanyProgram on Developmental Endocrinology and GeneticsEunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USADivision Molecular Genome AnalysisDivision of Theoretical BioinformaticsGerman Cancer Research Center (DKFZ), Heidelberg, GermanyInstitut CochinINSERM U1016, CNRS UMR 8104, Université Paris Descartes, Sorbonne Paris Cité, Paris, FranceDepartment of EndocrinologyReferal Center for Rare Adrenal Diseases, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, FranceInstitute of PathologyUniversity Medical Center, Georg-August University, Göttingen, GermanyInstitute of PathologyUniversity Hospital, Albert-Ludwigs University Freiburg, Freiburg, GermanySchool of Clinical and Experimental MedicineCollege of Medical and Dental Sciences, Centre for Rare Diseases and Personalised Medicine, Birmingham Women's Hospital, University of Birmingham and West Midlands Regional Genetics Service, Birmingham, UKDepartment of Medical GeneticsUniversity of Cambridge, Cambridge CB2 0QQ, UKLaboratory Medicine and PathologyEmeritus Staff, Mayo Clinic, Rochester, Minnesota, USAInstitute of PathologyUniversity Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Krankenhausstraße 8-10, D-91054 Erlangen, GermanyProgram on Developmental Endocrinology and GeneticsEunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USADivision Molecular Genome AnalysisDivision of Theoretical BioinformaticsGerman Cancer Research Center (DKFZ), Heidelberg, GermanyInstitut CochinINSERM U1016, CNRS UMR 8104, Université Paris Descartes, Sorbonne Paris Cité, Paris, FranceDepartment of EndocrinologyReferal Center for Rare Adrenal Diseases, Assistance Publique Hôpitaux de Paris,

Abstract

Carney triad (CT) is a rare condition with synchronous or metachronous occurrence of gastrointestinal stromal tumors (GISTs), paragangliomas (PGLs), and pulmonary chondromas in a patient. In contrast to Carney-Stratakis syndrome (CSS) and familial PGL syndromes, no germline or somatic mutations in the succinate dehydrogenase (SDH) complex subunits A, B, C, or D have been found in most tumors and/or patients with CT. Nonetheless, the tumors arising among patients with CT, CSS, or familial PGL share a similar morphology with loss of the SDHB subunit on the protein level. For the current study, we employed massive parallel bisulfite sequencing to evaluate DNA methylation patterns in CpG islands in proximity to the gene loci of all four SDH subunits. For the first time, we report on a recurrent aberrant dense DNA methylation at the gene locus of SDHC in tumors of patients with CT, which was not present in tumors of patients with CSS or PGL, or in sporadic GISTs with KIT mutations. This DNA methylation pattern was correlated to a reduced mRNA expression of SDHC, and concurrent loss of the SDHC subunit on the protein level. Collectively, these data suggest epigenetic inactivation of the SDHC gene locus with functional impairment of the SDH complex as a plausible alternate mechanism of tumorigenesis in CT.

KEYWORDS:

Carney triad; GIST; SDH complex; SDHC; paraganglioma

PMID:
24859990
PMCID:
PMC4722532
DOI:
10.1530/ERC-14-0254
[Indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for HighWire Icon for PubMed Central
    Loading ...
    Support Center