Mutation Profile of Aggressive Pheochromocytoma and Paraganglioma with Comparison of TCGA Data

SIMPLE SUMMARY: Pheochromocytomas and paragangliomas (PPGLs) are neuroendocrine tumors arising from chromaffin cells of the adrenal medulla, or extra-adrenal paraganglia, respectively. In PPGLs, germline or somatic mutations in one of the known susceptibility genes are identified in up to 60% patients. Recent WHO classification defines that all PPGLs can have metastatic potential. The term, ‘malignant’ is replaced with ‘metastatic’ in this group of tumors. However, the peculiar genetic events that drive the aggressive behavior, including metastasis in PPGLs are yet poorly understood. We performed targeted next-generation sequencing analysis to characterize the mutation profile in fifteen aggressive PPGL patients and compared accessible data of aggressive PPGLs from The Cancer Genome Atlas (TCGA) with findings of our cohort. This targeted mutational analysis might expand the mutation profile of aggressive PPGLs, and may also be useful in detecting the possible experimental therapeutic options or predicting poor prognosis. ABSTRACT: In pheochromocytoma and paraganglioma (PPGL), germline or somatic mutations in one of the known susceptibility genes are identified in up to 60% patients. However, the peculiar genetic events that drive the aggressive behavior including metastasis in PPGL are poorly understood. We performed targeted next-generation sequencing analysis to characterize the mutation profile in fifteen aggressive PPGL patients and compared accessible data of aggressive PPGLs from The Cancer Genome Atlas (TCGA) with findings of our cohort. A total of 115 germline and 34 somatic variants were identified with a median 0.58 per megabase tumor mutation burden in our cohort. The most frequent mutation was SDHB germline mutation (27%) and the second frequent mutations were somatic mutations for SETD2, NF1, and HRAS (13%, respectively). Patients were subtyped into three categories based on the kind of mutated genes: pseudohypoxia (n = 5), kinase (n = 5), and unknown (n = 5) group. In copy number variation analysis, deletion of chromosome arm 1p harboring SDHB gene was the most frequently observed. In our cohort, SDHB mutation and pseudohypoxia subtype were significantly associated with poor overall survival. In conclusion, subtyping of mutation profile can be helpful in aggressive PPGL patients with heterogeneous prognosis to make relevant follow-up plan and achieve proper treatment.