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

Abstract

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. <b>Results:</b> 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 <i>SDHB</i> (21/101 cases, 20.8%) and the most common <i>SDHB</i> mutation was c.268C>T, p.R90X occurring in 12/21 (57%) cases. Mutations also occurred in <i>SDHC</i> (4/101, 3.96%), <i>SDHD</i> (3/101, 3%), <i>VHL</i> (2/101, 2%) and <i>MAX</i> (2/101, 2%) genes. The following genes were mutated in 1 patient each (1%), <i>RET, SDHA, SDHAF2, TMEM127</i> and <i>NF1</i>. Metastatic PPGL occurred in 6/21 cases (28.6%) with <i>SDHB</i> mutations and in 1 case with <i>SDHAF2</i> mutation. <b>Patients and Methods:</b> 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 <i>RET, SDHx, VHL, MAX</i> and <i>TMEM127</i> genes were performed. Cases without mutations were subjected to whole exome sequencing using next generation sequencing (NGS). <b>Conclusion:</b> About 37% of PPGL without family history of such tumors harbor germline mutations. The most commonly mutated gene is <i>SDHB</i> followed by <i>SDHC</i>, <i>SDHD, VHL, MAX</i> and rarely <i>RET, SDHA, SDHAF2, TMEM127</i> and <i>NF1</i>. <i>SDHB</i> mutations were associated with metastatic PPGL in more than a quarter of cases.