Whole exome sequencing for the investigation of novel genetic causes of metastatic Pheochromocytomas and Paragangliomas

Abstract

Pheochromocytomas and Paragangliomas are neuroendocrine tumors derived from chromaffin cells. Approximately 15-20% of Pheochromocytomas and Paragangliomas are classified as metastatic, defined by the presence of tumor in non-chromaffin tissues. To date, at least 20 susceptibility genes for PPGLs have been reported. Germline pathogenic variants in SDHB gene are the most well-established risk factor to predict metastatic disease in 40-50% of cases. In our Institution, germline genetic alterations in SDHB were found in 25% of the cases, SDHD 3%, NF1 3%, SDHA 3% and MET 3%. Therefore, 63% of the metastatic Pheochromocytomas and Paragangliomas of our cohort remain without genetic diagnosis after investigation using a gene target sequencing panel by massive parallel sequencing. The aim of this project is to investigate novel genetic causes of metastatic Pheochromocytomas and Paragangliomas. The specific aims are: 1) to perform whole exome sequencing of germline and tumor DNA of 20 patients with metastatic pheochromocytoma or paraganglioma; 2) to correlate the genetic findings with clinical and follow-up data; 3) to perform functional studies to evaluate the pathogenicity of the rare and in silico deleterious germline variants in new candidate genes. (AU)