Abstract
Background Pheochromocytomas (PCCs) show the highest degree of heritability in human neoplasms. However, despite the wide number of alterations until now reported in PCCs, it is likely that other susceptibility genes remain still unknown, especially for those PCCs not clearly syndromic. Methods Whole exome sequencing of tumor DNA was performed on a set of twelve PCCs clinically defined as sporadic. Results About 50% of PCCs examined had somatic mutations on the known susceptibility VHL, NF1, and RET genes. In addition to these driver events, mutations on SYNE1, ABCC10, and RAD54B genes were also detected. Moreover, extremely rare germline variants were present in half of the sporadic PCC samples analyzed, in particular variants of MAX and SAMD9L were detected in the germline of cases wild-type for mutations in the known susceptibility genes. Conclusions Additional somatic passenger mutations can be associated with known susceptibility VHL, NF1, and RET genes in PCCs, and a wide number of germline variants with still unknown clinical significance can be detected in these patients. Therefore, many efforts should be aimed to better define the pathogenetic role of all these germline variants for discovering novel potential therapeutic targets for this disease still orphan of effective treatments.
Highlights
Pheochromocytomas (PCCs) are rare tumors of the autonomic nervous system that arise from the chromaffin tissue of the adrenal medulla [1]
von Hippel Lindau (VHL) missense mutations were identified in two cases: a p.S65A identified in N51, a mutation already reported in PCC (COSM144970), and a p.Y98H in N56, a mutation reported in ClinVar and HMGD as pathogenic in association with Von Hippel-Lindau syndrome
We performed whole exome sequencing on a set of twelve PCCs, clinically defined as sporadic, and we found that 50% of PCCs examined had somatic mutations on the known susceptibility VHL, neurofibromatosis type 1 (NF1), and RET genes
Summary
Pheochromocytomas (PCCs) are rare tumors of the autonomic nervous system that arise from the chromaffin tissue of the adrenal medulla [1]. About 50% of PCCs examined had somatic mutations on the known susceptibility VHL, NF1, and RET genes. In addition to these driver events, mutations on SYNE1, ABCC10, and RAD54B genes were detected. Extremely rare germline variants were present in half of the sporadic PCC samples analyzed, in particular variants of MAX and SAMD9L were detected in the germline of cases wild-type for mutations in the known susceptibility genes. Additional somatic passenger mutations can be associated with known susceptibility VHL, NF1, and RET genes in PCCs, and a wide number of germline variants with still unknown clinical significance can be detected in these patients. Many efforts should be aimed to better define the pathogenetic role of all these germline variants for discovering novel potential therapeutic targets for this disease still orphan of effective treatments
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