Lindsey Oudijk1, Ronald R de Krijger, Ida Rapa, Felix Beuschlein, Aguirre A de Cubas, Angelo P Dei Tos, Winand N M Dinjens, Esther Korpershoek, Veronika Mancikova, Massimo Mannelli, Mauro Papotti, Simona Vatrano, Mercedes Robledo, Marco Volante. 1. Department of Pathology (L.O., R.R.d.K., W.N.M.D., E.K.), Erasmus MC University Medical Center, 3015 CN Rotterdam, The Netherlands; Department of Pathology (R.R.d.K.), Reinier de Graaf Hospital, 2625 AD Delft, The Netherlands; Department of Oncology (I.R., M.P., S.V., M.V.), University of Turin at San Luigi Hospital, 10043 Orbassano, Turin, Italy; Endocrine Research Unit (F.B), Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, D-81675 Munich, Germany; Hereditary Endocrine Cancer Group (A.A.d.C., V.M., M.R.), Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain; Department of Pathology and Molecular Genetics (A.P.D.T.), General Hospital, 31100 Treviso, Italy; Department of Clinical Pathophysiology (M.M.), University of Florence, 50121 Florence Italy; and Centre for Biomedical Network Research on Rare Diseases (CIBERER) (M.R.), 28029 Madrid, Spain.
Abstract
CONTEXT: Somatic or germline mutations in up to 15 disease-causative genes are detectable in up to 50% of patients with pheochromocytoma (PCC) and paraganglioma (PGL). Very recently, somatic H-RAS mutations were identified by exome sequencing in approximately 7% in sporadic PCCs and PGLs, in association with male sex and benign behavior. OBJECTIVE: To explore the prevalence of RAS mutations in a cohort of 271 PCC and PGL from a European registry and to compare the genotype with clinical and pathological characteristics of potential clinical interest. SETTING AND DESIGN: Genetic screening for hotspot mutations in H-, N-, and K-RAS genes was performed by means of Sanger sequencing or pyrosequencing methods on tumor DNA in a series of patients with (n = 107) or without (n = 164) germline or somatic PCC/PGL-related gene mutations. RESULTS: Overall, H-RAS mutations were detected in 5.2% of cases (14/271), which were confined to sporadic PCCs resulting in a prevalence of 10% (14/140) in this cohort. In contrast, no mutations were found in PCC with PCC/PGL-related gene mutations (0/76) or in PGL (0/55) harboring or not mutations in PCC/PGL susceptibility genes. In this large series, H-RAS mutations in PCCs lacked any significant correlation with pathological or basic clinical endpoints. CONCLUSIONS: Somatic H-RAS mutations are restricted to a relevant proportion of sporadic PCC. These findings provide the basis to study potential H-RAS-dependent correlations with long-term outcome data.
CONTEXT: Somatic or germline mutations in up to 15 disease-causative genes are detectable in up to 50% of patients with pheochromocytoma (PCC) and paraganglioma (PGL). Very recently, somatic H-RAS mutations were identified by exome sequencing in approximately 7% in sporadic PCCs and PGLs, in association with male sex and benign behavior. OBJECTIVE: To explore the prevalence of RAS mutations in a cohort of 271 PCC and PGL from a European registry and to compare the genotype with clinical and pathological characteristics of potential clinical interest. SETTING AND DESIGN: Genetic screening for hotspot mutations in H-, N-, and K-RAS genes was performed by means of Sanger sequencing or pyrosequencing methods on tumor DNA in a series of patients with (n = 107) or without (n = 164) germline or somatic PCC/PGL-related gene mutations. RESULTS: Overall, H-RAS mutations were detected in 5.2% of cases (14/271), which were confined to sporadic PCCs resulting in a prevalence of 10% (14/140) in this cohort. In contrast, no mutations were found in PCC with PCC/PGL-related gene mutations (0/76) or in PGL (0/55) harboring or not mutations in PCC/PGL susceptibility genes. In this large series, H-RAS mutations in PCCs lacked any significant correlation with pathological or basic clinical endpoints. CONCLUSIONS: Somatic H-RAS mutations are restricted to a relevant proportion of sporadic PCC. These findings provide the basis to study potential H-RAS-dependent correlations with long-term outcome data.
Authors: Thomas G Papathomas; Diederik P D Suurd; Alfred K Lam; Ronald R de Krijger; Karel Pacak; Arthur S Tischler; Menno R Vriens Journal: Endocr Pathol Date: 2021-01-12 Impact factor: 3.943
Authors: Maria Currás-Freixes; Elena Piñeiro-Yañez; Cristina Montero-Conde; María Apellániz-Ruiz; Bruna Calsina; Veronika Mancikova; Laura Remacha; Susan Richter; Tonino Ercolino; Natalie Rogowski-Lehmann; Timo Deutschbein; María Calatayud; Sonsoles Guadalix; Cristina Álvarez-Escolá; Cristina Lamas; Javier Aller; Julia Sastre-Marcos; Conxi Lázaro; Juan C Galofré; Ana Patiño-García; Amparo Meoro-Avilés; Judith Balmaña-Gelpi; Paz De Miguel-Novoa; Milagros Balbín; Xavier Matías-Guiu; Rocío Letón; Lucía Inglada-Pérez; Rafael Torres-Pérez; Juan M Roldán-Romero; Cristina Rodríguez-Antona; Stephanie M J Fliedner; Giuseppe Opocher; Karel Pacak; Esther Korpershoek; Ronald R de Krijger; Laurent Vroonen; Massimo Mannelli; Martin Fassnacht; Felix Beuschlein; Graeme Eisenhofer; Alberto Cascón; Fátima Al-Shahrour; Mercedes Robledo Journal: J Mol Diagn Date: 2017-05-25 Impact factor: 5.568