MON-195 Genetic Analysis and Clinical Characteristics of Hereditary Paraganglioma and Pheochromocytoma Syndrome in Korean Population

Abstract

Listen

Translate article

Pheochromocytoma (PCC) and paragangliomas (PGL), rare neuroendocrine tumor originating from the chromaffin cells together referred as PPGL, are acknowledged to be more than 40% hereditary, related to germline mutations of susceptibility gene. With the advancement of genetic analysis technique, including next-generation sequencing (NGS), there has been attempts to classify PPGL into molecular clusters - Pseudohypoxic, Wnt signaling, and Kinase signaling PPGL. With NGS being applied to clinical setting only recently in Korea, we aimed to review the result of genetic analysis, including NGS, and investigate its association with clinical characteristics in Korean PPGL patients. We reviewed medical records of patients with PPGL in Severance hospital enrolled between January of 2006 to October of 2019. We gathered clinical phenotype by reviewing medical records of the patients who underwent targeted NGS from March of 2017 to October of 2019 using Severance hospital’s endocrine panel or who had known germline mutations of related genes. Family gene analysis was recommended for family members of patients with significant gene mutations. Among 78 patients with PPGL, 58 patients underwent targeted NGS results or had prediagnosed mutations. Thirty-three patients (62.1%) had clinically significant germline mutation. In patients with hereditary PPGL, there were higher likelihood of family history and presence of other tumors. There were significant differences in the type of PPGLs, percentage of family history, metastasis rate and the presence of other tumors among 3 molecular clusters - pseudohypoxic TCA cycle-related, pseudohypoxic VHL/EPAS1-related and kinase-signaling group. Twenty-seven different germline mutations from 11 genes (SDHB, RET, VHL, EPAS1, NF1, KIF1B, MAX, SDHA, SDHC, SDHD, and TMEM127) were found, SDHB mutation being the most common. Four of them were novel mutations; EPAS1 c.1250G>A (p.Gly417Glu), NF1 c.6215delA (p.His2072LeufsTer10), NF1 c.6777del (p.Gly2260fs), and SDHC exon 2-6 duplication. In conclusion, we report the prevalence of germline mutations in Korean PPGL patients, and the rate of hereditary PPGL is estimated to be as high as 62.1%. NGS is a good and accessible tool for genetic analysis in patients with PPGLs, and further research on molecular classification will lead to precision medicine.