title: HRAS mutation prevalence and associated expression patterns in pheochromocytoma.
abstract: Pheochromocytomas (PCC) and abdominal paragangliomas (PGL) display a highly diverse genetic background and recent gene expression profiling studies have shown that PCC and PGL (together PPGL) alter either kinase signaling pathways or the pseudo-hypoxia response pathway dependent of the genetic composition. Recurrent mutations in the Harvey rat sarcoma viral oncogene homolog (HRAS) have recently been verified in sporadic PPGLs. In order to further establish the HRAS mutation frequency and to characterize the associated expression profiles of HRAS mutated tumors, 156 PPGLs for exon 2 and 3 hotspot mutations in the HRAS gene was screened, and compared with microarray-based gene expression profiles for 93 of the cases. The activating HRAS mutations G13R, Q61R, and Q61K were found in 10/142 PCC (7.0%) and a Q61L mutation was revealed in 1/14 PGL (7.1%). All HRAS mutated cases included in the mRNA expression profiling grouped in Cluster 2, and 21 transcripts were identified as altered when comparing the mutated tumors with 91 HRAS wild-type PPGL. Somatic HRAS mutations were not revealed in cases with known PPGL susceptibility gene mutations and all HRAS mutated cases were benign. The HRAS mutation prevalence of all PPGL published up to date is 5.2% (49/950), and 8.8% (48/548) among cases without a known PPGL susceptibility gene mutation. The findings support a role of HRAS mutations as a somatic driver event in benign PPGL without other known susceptibility gene mutations. HRAS mutated PPGL cluster together with NF1- and RET-mutated tumors associated with activation of kinase-signaling pathways.
authors.affiliation: Department of Oncology and Pathology, Karolinska Institutet, Stockholm, SE-17176, Sweden.|Cancer Center Karolinska, CCK, Karolinska University Hospital Solna, Stockholm, SE-171 76, Sweden.
authors.forename: Adam
authors.initials: A
authors.lastname: Stenman
authors.affiliation: Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, SE-581 85, Sweden.
authors.forename: Jenny
authors.initials: J
authors.lastname: Welander
authors.affiliation: Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, SE-581 85, Sweden.
authors.forename: Ida
authors.initials: I
authors.lastname: Gustavsson
authors.affiliation: Department of Digestive, Hepato-Biliary and Endocrine Surgery, CHU Nancy - Hospital Brabois Adultes, University De Lorraine, Vandoeuvre-les-Nancy, F-54511, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Brunaud
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, SE-171 76, Sweden.
authors.forename: Martin
authors.initials: M
authors.lastname: Bäckdahl
authors.affiliation: Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, SE-581 85, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Söderkvist
authors.affiliation: Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, SE-581 85, Sweden.|Department of Surgery, Region Östergötland, Linköping, SE-58185, Sweden.
authors.forename: Oliver
authors.initials: O
authors.lastname: Gimm
authors.affiliation: Department of Oncology and Pathology, Karolinska Institutet, Stockholm, SE-17176, Sweden.|Cancer Center Karolinska, CCK, Karolinska University Hospital Solna, Stockholm, SE-171 76, Sweden.
authors.forename: C Christofer
authors.initials: CC
authors.lastname: Juhlin
authors.affiliation: Department of Oncology and Pathology, Karolinska Institutet, Stockholm, SE-17176, Sweden.|Cancer Center Karolinska, CCK, Karolinska University Hospital Solna, Stockholm, SE-171 76, Sweden.
authors.forename: Catharina
authors.initials: C
authors.lastname: Larsson
mesh_terms: D000293:Adolescent; D000310:Adrenal Gland Neoplasms / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010673:Pheochromocytoma / Q000235:genetics*; D055815:Young Adult