Cristóbal Bernardo-Castiñeira1,2,3,4, Nuria Valdés5, Lucía Celada1,3,4, Andrés San José Martinez3, I Sáenz-de-Santa-María1,2,3, Gustavo F Bayón3,6, Agustín F Fernández3,6, Marta I Sierra2,6, Mario F Fraga3,7, Aurora Astudillo3,8, Paula Jiménez-Fonseca3,9, Juan Carlos Rial10, Miguel Ángel Hevia9,11, Estrella Turienzo12, Carmen Bernardo12, Lluis Forga13, Isabel Tena14, María-José Molina-Garrido15, Laura Cacho5, Carles Villabona16, Teresa Serrano17, Bartolomé Scola18, Isabel Chirivella19, Maribel Del Olmo20, Carmen Luz Menéndez21, Elena Navarro22, María Tous23, Ana Vallejo24, Shobana Athimulam25, Irina Bancos25, Carlos Suarez2,3, María-Dolores Chiara1,2,3,4. 1. Head and Neck Oncology Laboratory, Hospital Universitario Central de Asturias, Oviedo, Spain. 2. Institute of Oncology of Asturias, Spain. 3. Institute of Sanitary Research of Principado Asturias, Oviedo, Spain. 4. Centro de Investigación Biomédica en Red de Oncología, Oviedo, Spain. 5. Service of Endocrinology and Nutrition, Hospital Universitario Central de Asturias, Oviedo, Spain. 6. Cancer Epigenetics Laboratory, Hospital Universitario Central de Asturias, Oviedo, Spain. 7. Nanomaterials and Nanotechnology Research Center, Spanish Council for Scientific Research, Universidad de Oviedo, Oviedo, Spain. 8. Service of Pathology, Hospital Universitario Central de Asturias, Oviedo, Spain. 9. Service of Medical Oncology, Hospital Universitario Central de Asturias, Oviedo, Spain. 10. Service of Neurosurgery, Hospital Universitario Central de Asturias, Oviedo, Spain. 11. Service of Urology Surgery, Hospital Universitario Central de Asturias, Oviedo, Spain. 12. Service of Surgery, Hospital Universitario Central de Asturias, Oviedo, Spain. 13. Service of Endocrinology and Nutrition, Complejo Universitario de Navarra, Pamplona, Spain. 14. Service of Medical Oncology, Hospital Provincial de Castellón, Castellón, Spain. 15. Unit of Cancer in the Elderly, Hospital General Virgen de la Luz, Cuenca, Spain. 16. Service of Endocrinology and Nutrition, Hospital Universitario de Bellvitge, Barcelona, Spain. 17. Service of Pathology, Hospital Universitario de Bellvitge, Barcelona, Spain. 18. Service of Head and Neck Surgery, Hospital Gregorio Marañón, Madrid, Spain. 19. Unit of Genetic Counsel in Cancer, Hospital Clínico Universitario de Valencia, Valencia, Spain. 20. Service of Endocrinology and Nutrition, Hospital Universitario La Fe, Valencia, Spain. 21. Service of Pathology, Hospital de Cabueñes, Gijón, Spain. 22. Service of Endocrinology, Hospital Universitario Virgen del Rocío, Seville, Spain. 23. Unidad de Gestión Clínica of Endocrinology and Nutrition, Hospital Virgen Macarena, Seville, Spain. 24. Unidad de Gestión Clínica of Pathology, Hospital Virgen Macarena, Seville, Spain. 25. Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, Minnesota.
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.
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.
Authors: R Garcia-Carbonero; F Matute Teresa; E Mercader-Cidoncha; M Mitjavila-Casanovas; M Robledo; I Tena; C Alvarez-Escola; M Arístegui; M R Bella-Cueto; C Ferrer-Albiach; F A Hanzu Journal: Clin Transl Oncol Date: 2021-05-06 Impact factor: 3.405