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. © 2016 The Authors Genes, Chromosomes & Cancer Published by Wiley Periodicals, Inc.

Composite pheochromocytoma/paraganglioma-ganglioneuroma: analysis of SDH and ATRX status, and identification of frequent HRAS and BRAF mutations

“…A review of the English literature indicated a much lower BRAF and HRAS mutation rate in ordinary PCC/PGL and no concomitant mutations were reported ( 4 , 9 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 ). For ordinary GN, it is not usually associated with genetic abnormalities, and only RET gene has been considered to be causative in its pathogenesis ( 22 ).…”

Treatment for Patients With Malignant Pheochromocytomas and Paragangliomas: A Perspective From the Hallmarks of Cancer

“…Somatic mutations in other genes may also activate downstream pathways. For example, RAS mutations have been described in pheochromocytomas and paragangliomas ( 47 , 48 ). These mutations predict a constitutive activation of the mitogen-activated protein kinase and phosphoinositide 3-kinase (PI3K) pathways, leading to abnormal proliferation of pheochromocytoma and paraganglioma cells.…”

“…These mutations predict a constitutive activation of the mitogen-activated protein kinase and phosphoinositide 3-kinase (PI3K) pathways, leading to abnormal proliferation of pheochromocytoma and paraganglioma cells. RAS mutations have not, however, yet been associated with a clear MPPG phenotype ( 47 , 48 ).…”

Catecholamine-Secreting Tumors in Pediatric Patients With Cyanotic Congenital Heart Disease

“…PPGL are commonly associated with germline and/or somatic mutations in the susceptible genes resulting in these tumors. More than a third of these tumors are associated with at least one of the common germline mutations, including VHL , RET , NF1 , MAX , SDHA , SDHB , SDHC , SDHD , SDHAF2 , and TMEM127 genes, and about 25% to 30% are associated with somatic mutations, such as RET , VHL , NF1 , MAX , EPAS1/HIF2A , and Harvey rat sarcoma viral oncogene homolog ( HRAS ) genes [1, 12–16]. Some of these somatic mutations are linked with the processes involved in hypoxia adaptation.…”