Portal de investigación
SDHC Promoter Methylation, a Novel Pathogenic Mechanism in Parasympathetic Paragangliomas
Fecha de publicación:
Autores de IIS La Fe
Participantes ajenos a IIS La Fe
- Bernardo-Castineira C
- Valdes N
- Sierra MI
- Saenz-de-Santa-Maria I
- Bayon GF
- Perez RF
- Fernandez AF
- Fraga MF
- Astudillo A
- Menendez R
- Fernandez B
- Suarez C
- Chiara MD
Grupos
Abstract
Context: Germline mutations in the succinate dehydrogenase A, B, C, and D genes (collectively, SDHx) predispose to the development of paragangliomas (PGLs) arising at the parasympathetic or sympathetic neuroendocrine systems. SDHx mutations cause absence of tumoral immunostaining for SDHB. However, negative SDHB immunostaining has also been found in a subset of PGLs that lack SDHx mutations. Settings: Here, we report the comprehensive molecular characterization of one such a tumor of parasympathetic origin compared with healthy paraganglia and other PGLs with or without SDHx mutations. Results: Integration of multiplatform data revealed somatic SDHC methylation and loss of the 1q23.3 region containing the SDHC gene. This correlated with decreased SDHC messenger RNA (mRNA) and protein levels. Furthermore, another genetic event found affected the VHL gene, which showed a decreased DNA copy number, associated with low VHL mRNA levels, and an absence of VHL protein detected by immunohistochemistry. In addition, the tumor displayed a pseudohypoxic phenotype consisting in overexpression of the hypoxia-inducible factor (HIF)-1 alpha and miR-210, as well as downregulation of the iron-sulfur cluster assembly enzyme (ISCU) involved in SDHB maturation. This profile resembles that of SDHx- or VHL-mutated PGLs but not of PGLs with decreased VHL copy number, pointing to SDHC rather than VHL as the pathogenic driver. Conclusions: Collectively, these findings demonstrate the potential importance of both the SDHC epigenomic event and the activation of the HIF-1 alpha/miR-210/ISCU axis in the pathogenesis of SDHx wild-type/SDHB-negative PGLs. To our knowledge, this is the first case of a sporadic parasympathetic PGL that carries silencing of SDHC, fulfilling the two-hit Knudson's model for tumorigenesis.
Datos de la publicación
- ISSN/ISSNe:
- 0021-972X, 1945-7197
- Tipo:
- Article
- Páginas:
- 295-305
- PubMed:
- 29126304
- Factor de Impacto:
- 2,793 SCImago ℠
- Cuartil:
- Q1 SCImago ℠
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM ENDOCRINE SOC
Citas Recibidas en Web of Science: 7
Documentos
- No hay documentos
Filiaciones
Keywords
- GENE-MUTATIONS; NECK PARAGANGLIOMAS; PHEOCHROMOCYTOMA; IMMUNOHISTOCHEMISTRY; IDENTIFICATION; SUCCINATE; HEAD
Proyectos y Estudios Clínicos
ESTUDIO EPIDEMIOLÓGICO, RETROSPECTIVO, LONGITUDINAL PARA CARACTERIZAR LA HISTORIA NATURAL DE LOS PACIENTES CON CARCINOMA DIFERENCIADO DE TIROIDES AVANZADO EN ESPAÑA Y PORTUGAL.
Investigador Principal: ÁNGEL AGUSTÍN SEGURA HUERTA
EIS-CDT-2017-01 . 2018
PROTOCOLO H9X-MC-GBDX. ESTUDIO ALEATORIZADO, ABIERTO Y DE GRUPOS PARALELOS EN EL QUE SE COMPARA EL EFECTO SOBRE EL CONTROL GLUCÉMICO DEL TRATAMIENTO CON DULAGLUTIDA UNA VEZ A LA SEMANA JUNTO CON INSULINA GLARGINA EN PACIENTES CON DIABETES TIPO 2 Y ENFE RMEDAD RENAL CRÓNICA GRAVE O MODERADA.
Investigador Principal: JUAN FRANCISCO MERINO TORRES
H9X-MC-GBDX
Cita
Bernardo C,Valdes N,Sierra MI,Saenz I,Bayon GF,Perez RF,Fernandez AF,Fraga MF,Astudillo A,Menendez R,Fernandez B,DEL OLMO M,Suarez C,Chiara MD. SDHC Promoter Methylation, a Novel Pathogenic Mechanism in Parasympathetic Paragangliomas. J Clin Endocrinol Metab. 2018. 103. (1):p. 295-305. IF:5,605. (1).