2024-03-29T10:45:36Zhttp://digital.csic.es/dspace-oai/requestoai:digital.csic.es:10261/2108182021-07-22T09:54:04Zcom_10261_28457com_10261_3col_10261_28462
http://hdl.handle.net/10261/210818
10.1210/jc.2018-01471
391487
Epigenetic deregulation of protocadherin PCDHGC3 in pheochromocytomas/paragangliomas associated with SDHB mutations
Oxford University Press
2019
artículo
Bernardo-Castiñeira, Cristóbal
Valdés, Nuria
Celada, Lucía
San José Martinez, Andrés
Sáenz-de-Santa-María, Inés
Bayón, Gustavo F.
Sierra, Marta I.
Fraga, Mario F.
Astudillo, Aurora
Jiménez-Fonseca, Paula
Rial, Juan Carlos
Hevia, Miguel Ángel
Turienzo, Estrella
Bernardo, Carmen
Forga, Lluis
Tena, Isabel
Molina-Garrido, María-José
Cacho, Laura
Villabona, Carles
Serrano, Teresa
Scola, Bartolomé
Chirivella, Isabel
Olmo, Maribel del
Menéndez, Carmen Luz
Navarro, Elena
Tous, María
Vallejo, Ana
Athimulam, Shobana
Bancos, Irina
Suárez, Carlos
Chiara, María-Dolores
2019
[Context]: SDHB mutations are found in an increasing number of neoplasms, most notably in paragangliomas and pheochromocytomas (PPGLs). SDHB-PPGLs are slow-growing tumors, but ∼50% of them may develop metastasis. The molecular basis of metastasis in these tumors is a long-standing and unresolved problem. Thus, a better understanding of the biology of metastasis is needed.
[Objective]: This study aimed to identify gene methylation changes relevant for metastatic SDHB-PPGLs. DESIGN: We performed genome-wide profiling of DNA methylation in diverse clinical and genetic PPGL subtypes, and validated protocadherin γ-C3 (PCDHGC3) gene promoter methylation in metastatic SDHB-PPGLs.
[Results]: We define an epigenetic landscape specific for metastatic SDHB-PPGLs. DNA methylation levels were found significantly higher in metastatic SDHB-PPGLs than in SDHB-PPGLs without metastases. One such change included long-range de novo methylation of the PCDHA, PCDHB, and PCDHG gene clusters. High levels of PCDHGC3 promoter methylation were validated in primary metastatic SDHB-PPGLs, it was found amplified in the corresponding metastases, and it was significantly correlated with PCDHGC3 reduced expression. Interestingly, this epigenetic alteration could be detected in primary tumors that developed metastasis several years later. We also show that PCDHGC3 down regulation engages metastasis-initiating capabilities by promoting cell proliferation, migration, and invasion.
[Conclusions]: Our data provide a map of the DNA methylome episignature specific to an SDHB-mutated cancer and establish PCDHGC3 as a putative suppressor gene and a potential biomarker to identify patients with SDHB-mutated cancer at high risk of metastasis who might benefit from future targeted therapies.
Instituto de Salud Carlos III
European Commission
Fundación para el Fomento en Asturias de la Investigación Científica Aplicada y la Tecnología
Journal of Clinical Endocrinology and Metabolism
2019
104
5673
692