Mutational profile and genotype/phenotype correlation of non-familial pheochromocytoma and paraganglioma

About 30%–40% of patients with pheochromocytoma (PCC) and paraganglioma (PGL) have underlying germline mutations in certain susceptibility genes despite absent family history of these tumors. Here, we present mutational profile of 101 such patients with PCC/PGL (PPGL) from the highly consanguineous population of Saudi Arabia. Results: Of 101 cases with PPGL, 37/101 (36.6%) had germline mutations. Mutations were detected in 30 cases by PCR and direct Sanger sequencing and in 7 additional cases by NGS. The most commonly mutated gene was SDHB (21/101 cases, 20.8%) and the most common SDHB mutation was c.268C>T, p.R90X occurring in 12/21 (57%) cases. Mutations also occurred in SDHC (4/101, 3.96%), SDHD (3/101, 3%), VHL (2/101, 2%) and MAX (2/101, 2%) genes. The following genes were mutated in 1 patient each (1%), RET, SDHA, SDHAF2, TMEM127 and NF1. Metastatic PPGL occurred in 6/21 cases (28.6%) with SDHB mutations and in 1 case with SDHAF2 mutation. Patients and Methods: DNA was isolated from peripheral blood (53 patients) or from non-tumorous formalin fixed paraffin embedded (FFPE) tissue (48 patients). PCR and direct Sanger sequencing of RET, SDHx, VHL, MAX and TMEM127 genes were performed. Cases without mutations were subjected to whole exome sequencing using next generation sequencing (NGS). Conclusion: About 37% of PPGL without family history of such tumors harbor germline mutations. The most commonly mutated gene is SDHB followed by SDHC, SDHD, VHL, MAX and rarely RET, SDHA, SDHAF2, TMEM127 and NF1. SDHB mutations were associated with metastatic PPGL in more than a quarter of cases.