1. Epigenetic Deregulation of Protocadherin PCDHGC3 in Pheochromocytomas/Paragangliomas Associated With SDHB Mutations.
- Author
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Bernardo-Castiñeira C, Valdés N, Celada L, Martinez ASJ, Sáenz-de-Santa-María I, Bayón GF, Fernández AF, Sierra MI, Fraga MF, Astudillo A, Jiménez-Fonseca P, Rial JC, Hevia MÁ, Turienzo E, Bernardo C, Forga L, Tena I, Molina-Garrido MJ, Cacho L, Villabona C, Serrano T, Scola B, Chirivella I, Del Olmo M, Menéndez CL, Navarro E, Tous M, Vallejo A, Athimulam S, Bancos I, Suarez C, and Chiara MD
- Subjects
- Adrenal Gland Neoplasms metabolism, Adrenal Gland Neoplasms pathology, Cadherin Related Proteins, Cadherins metabolism, Cell Movement genetics, Cell Proliferation genetics, Female, Humans, Male, Neoplasm Invasiveness genetics, Neoplasm Invasiveness pathology, Paraganglioma metabolism, Paraganglioma pathology, Pheochromocytoma metabolism, Pheochromocytoma pathology, Succinate Dehydrogenase metabolism, Adrenal Gland Neoplasms genetics, Cadherins genetics, Epigenesis, Genetic, Mutation, Paraganglioma genetics, Pheochromocytoma genetics, Succinate Dehydrogenase genetics
- Abstract
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.)
- Published
- 2019
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