Abstract 3403: Genetic analysis of pheochromocytoma
Authors: Ogasawara Tatsuki , Fujii Yoichi , Fujimoto Masanori , Shiozawa Yusuke , Yoshizato Tetsuichi , Suzuki Hiromichi , Yoshida Kenichi , Shiraishi Yuichi , Makishima Hideki , Miyano Satoru , Tanaka Tomoaki , Ogawa Seishi 
Published: August 2019

Abstract
Backgrounds
Pheochromocytomas (PCs) are rare neuroendocrine tumors of the adrenal medulla characterized by excessive production of catecholamines. Although many are benign tumors, some patients show aggressive clinical courses. Despite improved understanding of gene mutations associated with PC, molecular pathogenesis is still unclear in up to 40% of the cases, particularly in those showing aggressive clinical pictures.
Materials & methods
To elucidate the molecular basis of PC, we investigated germline and somatic mutations, as well as copy number abnormalities in a total of 113 Japanese PC cases (JPN cohort), including 5 with aggressive tumors, using whole exome sequencing (WXS) of paired tumor/normal DNA (n=21), followed by targeted capture sequencing of known candidate driver genes (n=92). WXS data from The Cancer Genome Atlas (TCGA) database (n=144) was also analyzed to compare genetic characteristics between benign and aggressive cases with a higher statistical power (total; n=165, aggressive case; n=15).
Results
WXS of 21 Japanese PC cases disclosed 283 single nucleotide variants (SNVs) and 22 insertions and deletions with a median of 13 (range: 1-26) mutations per sample, predominantly showing age-related signatures. The landscape of genetic lesions was largely similar between JPN and TCGA cohorts. Both cohorts being combined, 36% of the cases had somatic mutations in one or more driver genes previously reported in PC. Mutations were most frequently observed in HRAS (12% of cases), followed by NF1 (9%), RET (5%), and EPAS1 genes (3%), suggesting a major role of alterations of RAS/mTOR and hypoxia pathways. Copy number abnormalities (CNAs) were detected in most cases, including del(1p), del(3q), del(17p), and del(22q). As many as 20% of the cases carried a germline variant, frequently detected in either RET, VHL, or NF1, confirming a strong genetic background in PC pathogenesis. EPAS1 mutation, MAML3 fusion gene, and a higher number of somatic mutations were associated with aggressive tumors. Of interest, two aggressive tumors harbored alterations in previously unreported genes, including a somatic PTEN mutation (frameshift) and a germline TP53 variant, respectively.
Conclusion
We disclosed a landscape of 113 PC cases, including a somatic truncating PTEN mutation and a germline TP53 mutation which were newly detected. Somatic EPAS1 mutations and MAML3 fusion genes could be associated with aggressive PC. Molecular pathogenesis is still unclear in 40% of all PC cases, for which a more unbiased analysis with whole genome sequencing is warranted.
Citation Format: Tatsuki Ogasawara, Yoichi Fujii, Masanori Fujimoto, Yusuke Shiozawa, Tetsuichi Yoshizato, Hiromichi Suzuki, Kenichi Yoshida, Yuichi Shiraishi, Hideki Makishima, Satoru Miyano, Tomoaki Tanaka, Seishi Ogawa. Genetic analysis of pheochromocytoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3403.