H-RAS mutations are restricted to sporadic pheochromocytomas lacking specific clinical or pathological features: data from a multi-institutional series.

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.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.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.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.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.