Abstract 3391: Next generation sequencing paves the way for personalized medicine in pheochromocytoma and paraganglioma patients and their families

Abstract

Abstract More than 35% of pheochromocytomas and paragangliomas (PPGL) are thought to occur due to an underlying genetic predisposition. 18 susceptibility genes have been identified for PPGL, which explain app. 30% of familial cases. Further PPGL predisposition genes, however, remain to be discovered. In addition, identification of biomarkers for malignancy also remains a current challenge since histologic assessment does not suffice discrimination of malignant PPGLs. Personalized screening protocols, risk stratification measures and surveillance guidelines are needed for PPGL patients and their family members at risk. We performed panel sequencing for 94 tumor predisposition syndrome (TPS) genes and identified 12 pathogenic germline mutations in 60 PPGL patients. Two of these patients were identified with NF1-mutations although they did not meet the diagnostic criteria for Neurofibromatosis. Thus, TPS gene panel sequencing proved superior to routine Sanger sequencing since mutations were identified in genes that would have routinely been excluded from analysis. Combining results of immunohistochemistry as well as biochemical profiling by measuring Krebs-cycle metabolites and genetic analyses of tumors we were able to reclassify variants of uncertain significance (VUS) as either pathogenic mutations or polymorphisms in several patients. Three incidentally found pathogenic mutations in CHEK2 and MSH2 prompted further analyses such as testing for microsatellite instability in order to evaluate possible effects on PPGL development. For patients in whom no underlying mutation could be detected we performed custom candidate gene panel sequencing of tumor derived-DNA. Whole exome sequencing (WES) was carried out in 15 cases highly suspicious for a genetic background in order to identify new candidate predisposition genes that will further be evaluated in the patient cohort and in functional studies. We will also present guidelines for diagnostics, surveillance and prevention of PPGL for patients and their family members. Citation Format: Laura Gieldon, Susan Richter, Andreas Rump, Karl Hackmann, Andreas Tzschach, Graeme Eisenhofer, Mariola Pęczkowska, Aleksander Prejbisz, Evelin Schröck, Barbara Klink. Next generation sequencing paves the way for personalized medicine in pheochromocytoma and paraganglioma patients and their families [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3391. doi:10.1158/1538-7445.AM2017-3391