Epigenetic Deregulation of Protocadherin PCDHGC3 in Pheochromocytomas/Paragangliomas Associated With SDHB Mutations
Journal: Journal of Clinical Endocrinology & Metabolism, Volume 104, Issue 11, November 2019, Pages 5673–5692
Authors: Cristóbal Bernardo-Castiñeira, Nuria Valdés, Lucía Celada, Andrés San José Martinez, I Sáenz-de-Santa-María, Gustavo F Bayón, Agustín F Fernández, Marta I Sierra, Mario F Fraga, Aurora Astudillo, Paula Jiménez-Fonseca, Juan Carlos Rial, Miguel Ángel Hevia, Estrella Turienzo, Carmen Bernardo, Lluis Forga, Isabel Tena, María-José Molina-Garrido, Laura Cacho, Carles Villabona, Teresa Serrano, Bartolomé Scola, Isabel Chirivella, Maribel del Olmo, Carmen Luz Menéndez, Elena Navarro, María Tous, Ana Vallejo, Shobana Athimulam, Irina Bancos, Carlos Suarez, María-Dolores Chiara
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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.
This study aimed to identify gene methylation changes relevant for metastatic SDHB-PPGLs.
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.
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.
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.