Distinguishing metastatic from non-metastatic pheochromocytomas and paragangliomas using genetic alterations

Background: Pheochromocytomas (PCCs) and paragangliomas (PGLs) are rare neuroendocrine tumors and collectively known as PPGLs. The prognosis of metastatic PPGLs is much poorer than that of non-metastatic PPGLs. But currently there is no applicable criterion to distinguish one from the other at initial diagnosis. We aimed to identify different germline and somatic mutations between metastatic and non-metastatic PPGLs. Methods: Whole exome sequencing was performed to identify germline and somatic mutations in the blood and tumor tissues of 10 metastatic and 10 non-metastatic PPGL patients. Results: The germline mutant frequencies of 20 genes were significantly different in metastatic PPGLs than non-metastatic ones, including BRCA2 and CLCA2. Somatic MYO6, ACOT8, OTOP2, and DCAF8L2 were identified as recurrently mutant genes in metastatic rather than non-metastatic PPGLs. Enrichment analysis revealed that histone methylation, especially the methylation of lysine residue, was exclusively altered in metastatic PPGLs. In addition, MUC family members have the highest mutation rate in PPGLs. Conclusion: The frequencies of germline or somatic mutant genes are different between metastatic and non-metastatic PPGLs. Patients with PPGLs should receive WES to evaluate their metastatic potential.