Epigenetic Deregulation of Protocadherin PCDHGC3 in Pheochromocytomas/Paragangliomas Associated With SDHB Mutations.

Autor:	Bernardo-Castiñeira C; Head and Neck Oncology Laboratory, Hospital Universitario Central de Asturias, Oviedo, Spain.; Institute of Oncology of Asturias, Spain.; Institute of Sanitary Research of Principado Asturias, Oviedo, Spain.; Centro de Investigación Biomédica en Red de Oncología, Oviedo, Spain., Valdés N; Service of Endocrinology and Nutrition, Hospital Universitario Central de Asturias, Oviedo, Spain., Celada L; Head and Neck Oncology Laboratory, Hospital Universitario Central de Asturias, Oviedo, Spain.; Institute of Sanitary Research of Principado Asturias, Oviedo, Spain.; Centro de Investigación Biomédica en Red de Oncología, Oviedo, Spain., Martinez ASJ; Institute of Sanitary Research of Principado Asturias, Oviedo, Spain., Sáenz-de-Santa-María I; Head and Neck Oncology Laboratory, Hospital Universitario Central de Asturias, Oviedo, Spain.; Institute of Oncology of Asturias, Spain.; Institute of Sanitary Research of Principado Asturias, Oviedo, Spain., Bayón GF; Institute of Sanitary Research of Principado Asturias, Oviedo, Spain.; Cancer Epigenetics Laboratory, Hospital Universitario Central de Asturias, Oviedo, Spain., Fernández AF; Institute of Sanitary Research of Principado Asturias, Oviedo, Spain.; Cancer Epigenetics Laboratory, Hospital Universitario Central de Asturias, Oviedo, Spain., Sierra MI; Institute of Oncology of Asturias, Spain.; Cancer Epigenetics Laboratory, Hospital Universitario Central de Asturias, Oviedo, Spain., Fraga MF; Institute of Sanitary Research of Principado Asturias, Oviedo, Spain.; Nanomaterials and Nanotechnology Research Center, Spanish Council for Scientific Research, Universidad de Oviedo, Oviedo, Spain., Astudillo A; Institute of Sanitary Research of Principado Asturias, Oviedo, Spain.; Service of Pathology, Hospital Universitario Central de Asturias, Oviedo, Spain., Jiménez-Fonseca P; Institute of Sanitary Research of Principado Asturias, Oviedo, Spain.; Service of Medical Oncology, Hospital Universitario Central de Asturias, Oviedo, Spain., Rial JC; Service of Neurosurgery, Hospital Universitario Central de Asturias, Oviedo, Spain., Hevia MÁ; Service of Medical Oncology, Hospital Universitario Central de Asturias, Oviedo, Spain.; Service of Urology Surgery, Hospital Universitario Central de Asturias, Oviedo, Spain., Turienzo E; Service of Surgery, Hospital Universitario Central de Asturias, Oviedo, Spain., Bernardo C; Service of Surgery, Hospital Universitario Central de Asturias, Oviedo, Spain., Forga L; Service of Endocrinology and Nutrition, Complejo Universitario de Navarra, Pamplona, Spain., Tena I; Service of Medical Oncology, Hospital Provincial de Castellón, Castellón, Spain., Molina-Garrido MJ; Unit of Cancer in the Elderly, Hospital General Virgen de la Luz, Cuenca, Spain., Cacho L; Service of Endocrinology and Nutrition, Hospital Universitario Central de Asturias, Oviedo, Spain., Villabona C; Service of Endocrinology and Nutrition, Hospital Universitario de Bellvitge, Barcelona, Spain., Serrano T; Service of Pathology, Hospital Universitario de Bellvitge, Barcelona, Spain., Scola B; Service of Head and Neck Surgery, Hospital Gregorio Marañón, Madrid, Spain., Chirivella I; Unit of Genetic Counsel in Cancer, Hospital Clínico Universitario de Valencia, Valencia, Spain., Del Olmo M; Service of Endocrinology and Nutrition, Hospital Universitario La Fe, Valencia, Spain., Menéndez CL; Service of Pathology, Hospital de Cabueñes, Gijón, Spain., Navarro E; Service of Endocrinology, Hospital Universitario Virgen del Rocío, Seville, Spain., Tous M; Unidad de Gestión Clínica of Endocrinology and Nutrition, Hospital Virgen Macarena, Seville, Spain., Vallejo A; Unidad de Gestión Clínica of Pathology, Hospital Virgen Macarena, Seville, Spain., Athimulam S; Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, Minnesota., Bancos I; Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, Minnesota., Suarez C; Institute of Oncology of Asturias, Spain.; Institute of Sanitary Research of Principado Asturias, Oviedo, Spain., Chiara MD; Head and Neck Oncology Laboratory, Hospital Universitario Central de Asturias, Oviedo, Spain.; Institute of Oncology of Asturias, Spain.; Institute of Sanitary Research of Principado Asturias, Oviedo, Spain.; Centro de Investigación Biomédica en Red de Oncología, Oviedo, Spain.
Jazyk:	angličtina
Zdroj:	The Journal of clinical endocrinology and metabolism [J Clin Endocrinol Metab] 2019 Nov 01; Vol. 104 (11), pp. 5673-5692.
DOI:	10.1210/jc.2018-01471
Abstrakt:	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. (Copyright © 2019 Endocrine Society.)
Databáze:	MEDLINE
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