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

J Clin Endocrinol Metab. 2014 Jul;99(7):E1376-80. doi: 10.1210/jc.2013-3879. Epub 2014 Mar 31.


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.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adrenal Gland Neoplasms / epidemiology
  • Adrenal Gland Neoplasms / genetics*
  • Adult
  • Aged
  • Aged, 80 and over
  • Female
  • Genes, ras*
  • Genetic Predisposition to Disease
  • Genetic Testing
  • Humans
  • Male
  • Middle Aged
  • Mutation*
  • Paraganglioma / epidemiology
  • Paraganglioma / genetics
  • Pheochromocytoma / epidemiology
  • Pheochromocytoma / genetics*
  • Young Adult