HRAS mutation prevalence and associated expression patterns in pheochromocytoma

Area of Science:

• Endocrinology
• Oncology
• Genetics

Background:

• Pheochromocytomas and paragangliomas (PPGLs) exhibit genetic diversity, influencing kinase signaling or pseudo-hypoxia pathways.
• Recent studies identified Harvey rat sarcoma viral oncogene homolog (HRAS) mutations in sporadic PPGLs.

Purpose of the Study:

• To determine the frequency of HRAS mutations in PPGLs.
• To characterize gene expression profiles associated with HRAS-mutated tumors.

Main Methods:

• Screened 156 PPGLs for HRAS hotspot mutations in exons 2 and 3.
• Compared gene expression profiles of HRAS-mutated tumors with wild-type PPGLs using microarrays.

Main Results:

• Activating HRAS mutations (G13R, Q61R, Q61K, Q61L) were found in 7.0% of PCC and 7.1% of PGL.
• HRAS-mutated PPGLs clustered together and showed altered gene expression compared to wild-type tumors.
• HRAS mutations were not found with known susceptibility gene mutations; all HRAS-mutated cases were benign.

Conclusions:

• HRAS mutations are a significant driver event in benign PPGLs lacking other known susceptibility mutations.
• HRAS-mutated PPGLs share molecular characteristics with NF1- and RET-mutated tumors, indicating kinase-signaling pathway activation.