title: Somatic mutations in H-RAS in sporadic pheochromocytoma and paraganglioma identified by exome sequencing.
abstract: BACKGROUND
  Up to 60% of pheochromocytoma (PCC) and paraganglioma (PGL) are associated with either somatic or germline mutations in established PCC and PGL susceptibility loci. Most unexplained cases are characterized by an increased activity of the RAS/RAF/ERK signaling pathway. Mutations in RAS subtypes H, K, and N are common in human cancers; however, previous studies have been inconsistent regarding the mutational status of RAS in PCC and PGL.
  
  
  OBJECTIVE
  The aim of this study was to identify novel disease causing genes in PCC and PGL tumors.
  
  
  METHODS
  Four benign and sporadic PCC and PGL tumors were subjected to whole exome sequencing using the Illumina HiSeq Platform. Sequences were processed by CLC genomics 4.9 bioinformatics software and the acquired list of genetic variants was filtered against the Catalogue of Somatic Mutations in Cancer database. Findings were validated in an additional 78 PCC and PGL tumor lesions.
  
  
  RESULTS
  Exome sequencing identified 2 cases with somatic mutations in the H-RAS. In total, 6.9% (n = 4/58) of tumors negative for mutations in major PCC and PGL loci had mutations in H-RAS: G13R, Q61K, and Q61R. There were 3 PCC and 1 PGL; all had sporadic presentation with benign tumor characteristics and substantial increases in norepinephrine and/or epinephrine. H-RAS tumors were exclusively found in male patients (P = .007).
  
  
  CONCLUSIONS
  We identified recurrent somatic H-RAS mutations in pheochromocytoma and paraganglioma. Tumors with H-RAS mutations had activation of the RAS/RAF/ERK signaling pathway and were associated with male PCC patients having benign and sporadic disease characteristics. H-RAS could serve as a prognostic and predictive marker as well as a novel therapeutic target.
authors: Department of Surgical, Uppsala University, 75185 Uppsala, Sweden.
authors: Joakim
authors: J
authors: Crona
authors: Alberto
authors: A
authors: Delgado Verdugo
authors: Rajani
authors: R
authors: Maharjan
authors: Peter
authors: P
authors: Stålberg
authors: Dan
authors: D
authors: Granberg
authors: Per
authors: P
authors: Hellman
authors: Peyman
authors: P
authors: Björklund
mesh_terms: D000008:Abdominal Neoplasms / Q000097:blood / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000293:Adolescent; D000310:Adrenal Gland Neoplasms / Q000097:blood / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D059472:Exome; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010235:Paraganglioma / Q000097:blood / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010673:Pheochromocytoma / Q000097:blood / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016283:Proto-Oncogene Proteins p21(ras) / Q000097:blood / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D012189:Retrospective Studies; D017678:Sex Distribution; D013548:Sweden; D055815:Young Adult
chemical_list: C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)