Haller Florian, Moskalev Evgeny A, Faucz Fabio R, Barthelmeß Sarah, Wiemann Stefan, Bieg Matthias, Assie Guillaume, Bertherat Jerome, Schaefer Inga-Marie, Otto Claudia, Rattenberry Eleanor, Maher Eamonn R, Ströbel Philipp, Werner Martin, Carney J Aidan, Hartmann Arndt, Stratakis Constantine A, Agaimy Abbas
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
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.
Endocr Relat Cancer. 2014 Aug;21(4):567-77. doi: 10.1530/ERC-14-0254. Epub 2014 May 23.
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.
卡尼三联征（CT）是一种罕见病症，患者会同时或先后出现胃肠道间质瘤（GIST）、副神经节瘤（PGL）和肺软骨瘤。与卡尼-斯特拉塔基斯综合征（CSS）和家族性PGL综合征不同，在大多数患有CT的肿瘤和/或患者中，未发现琥珀酸脱氢酶（SDH）复合体亚基A、B、C或D存在种系或体细胞突变。尽管如此，CT、CSS或家族性PGL患者所患肿瘤在蛋白水平上具有相似的形态，均存在SDHB亚基缺失。在本研究中，我们采用大规模平行亚硫酸氢盐测序来评估所有四个SDH亚基基因座附近CpG岛中的DNA甲基化模式。我们首次报告，CT患者肿瘤中SDHC基因座存在复发性异常密集DNA甲基化，而CSS或PGL患者的肿瘤以及携带KIT突变的散发性GIST中均未出现这种情况。这种DNA甲基化模式与SDHC的mRNA表达降低以及蛋白水平上SDHC亚基的同时缺失相关。总体而言，这些数据表明SDHC基因座的表观遗传失活以及SDH复合体的功能受损可能是CT肿瘤发生的另一种合理机制。
