title: H-RAS mutations are restricted to sporadic pheochromocytomas lacking specific clinical or pathological features: data from a multi-institutional series.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.affiliation: 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.
authors.forename: Lindsey
authors.initials: L
authors.lastname: Oudijk
authors.forename: Ronald R
authors.initials: RR
authors.lastname: de Krijger
authors.forename: Ida
authors.initials: I
authors.lastname: Rapa
authors.forename: Felix
authors.initials: F
authors.lastname: Beuschlein
authors.forename: Aguirre A
authors.initials: AA
authors.lastname: de Cubas
authors.forename: Angelo P
authors.initials: AP
authors.lastname: Dei Tos
authors.forename: Winand N M
authors.initials: WN
authors.lastname: Dinjens
authors.forename: Esther
authors.initials: E
authors.lastname: Korpershoek
authors.forename: Veronika
authors.initials: V
authors.lastname: Mancikova
authors.forename: Massimo
authors.initials: M
authors.lastname: Mannelli
authors.forename: Mauro
authors.initials: M
authors.lastname: Papotti
authors.forename: Simona
authors.initials: S
authors.lastname: Vatrano
authors.forename: Mercedes
authors.initials: M
authors.lastname: Robledo
authors.forename: Marco
authors.initials: M
authors.lastname: Volante
mesh_terms: D000293:Adolescent; D000310:Adrenal Gland Neoplasms / Q000453:epidemiology / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D011905:Genes, ras; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010235:Paraganglioma / Q000453:epidemiology / Q000235:genetics; D010673:Pheochromocytoma / Q000453:epidemiology / Q000235:genetics*; D055815:Young Adult