Laura Gieldon1,2,3,4, Jimmy Rusdian Masjkur5, Susan Richter6, Roland Därr7,8, Marcos Lahera9, Daniela Aust2,3,4,10,11, Silke Zeugner10, Andreas Rump1, Karl Hackmann1,2,3,4, Andreas Tzschach1, Andrzej Januszewicz12, Aleksander Prejbisz12, Graeme Eisenhofer5,6, Evelin Schrock1,2,3,4, Mercedes Robledo13,14, Barbara Klink1,2,3,4. 1. Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany. 2. German Cancer Consortium (DKTK), Dresden, Germany. 3. German Cancer Research Center (DKFZ), Heidelberg, Germany. 4. National Center for Tumor Diseases (NCT) Partner Site Dresden, Dresden, Germany. 5. Department of Internal Medicine III, University Hospital Carl Gustav Carus at TU Dresden, Dresden, Germany. 6. Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus at TU Dresden, Dresden, Germany. 7. Department of Cardiology and Angiology I, Heart Center Freiburg University, Freiburg, Germany. 8. Department of Medicine IV, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany. 9. Endocrinology and Nutrition Department, La Princesa University Hospital, Madrid, Spain. 10. Institute for Pathology, University Hospital Carl Gustav Carus at TU Dresden, Dresden, Germany. 11. Tumor- and Normal Tissuebank of the University Cancer Center/NCT-Standort Dresden, University Hospital Carl Gustav Carus at TU Dresden, Dresden, Germany. 12. Department of Hypertension, Institute of Cardiology, Warsaw, Poland. 13. Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre, Madrid, Spain. 14. Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.
Abstract
OBJECTIVE: Our objective was to improve molecular diagnostics in patients with hereditary pheochromocytoma and paraganglioma (PPGL) by using next-generation sequencing (NGS) multi-gene panel analysis. Derived from this study, we here present three cases that were diagnosed with NF1 germline mutations but did not have a prior clinical diagnosis of neurofibromatosis type 1 (NF1). DESIGN: We performed genetic analysis of known tumor predisposition genes, including NF1, using a multi-gene NGS enrichment-based panel applied to a total of 1029 PPGL patients. We did not exclude genes known to cause clinically defined syndromes such as NF1 based on missing phenotypic expression as is commonly practiced. METHODS: Genetic analysis was performed using NGS (TruSight Cancer Panel/customized panel by Illumina) for analyzing patients' blood and tumor samples. Validation was carried out by Sanger sequencing. RESULTS: Within our cohort, three patients, who were identified to carry pathogenic NF1 germline mutations, attracted attention, since none of the patients had a clinical suspicion of NF1 and one of them was initially suspected to have MEN2A syndrome due to co-occurrence of a medullary thyroid carcinoma. In these cases, one splice site, one stop and one frameshift mutation in NF1 were identified. CONCLUSIONS: Since phenotypical presentation of NF1 is highly variable, we suggest analysis of the NF1 gene also in PPGL patients who do not meet diagnostic NF1 criteria. Co-occurrence of medullary thyroid carcinoma and PPGL was found to be a clinical decoy in NF1 diagnostics. These observations underline the value of multi-gene panel NGS for PPGL patients.
OBJECTIVE: Our objective was to improve molecular diagnostics in patients with hereditary pheochromocytoma and paraganglioma (PPGL) by using next-generation sequencing (NGS) multi-gene panel analysis. Derived from this study, we here present three cases that were diagnosed with NF1 germline mutations but did not have a prior clinical diagnosis of neurofibromatosis type 1 (NF1). DESIGN: We performed genetic analysis of known tumor predisposition genes, including NF1, using a multi-gene NGS enrichment-based panel applied to a total of 1029 PPGL patients. We did not exclude genes known to cause clinically defined syndromes such as NF1 based on missing phenotypic expression as is commonly practiced. METHODS: Genetic analysis was performed using NGS (TruSight Cancer Panel/customized panel by Illumina) for analyzing patients' blood and tumor samples. Validation was carried out by Sanger sequencing. RESULTS: Within our cohort, three patients, who were identified to carry pathogenic NF1 germline mutations, attracted attention, since none of the patients had a clinical suspicion of NF1 and one of them was initially suspected to have MEN2A syndrome due to co-occurrence of a medullary thyroid carcinoma. In these cases, one splice site, one stop and one frameshift mutation in NF1 were identified. CONCLUSIONS: Since phenotypical presentation of NF1 is highly variable, we suggest analysis of the NF1 gene also in PPGL patients who do not meet diagnostic NF1 criteria. Co-occurrence of medullary thyroid carcinoma and PPGL was found to be a clinical decoy in NF1 diagnostics. These observations underline the value of multi-gene panel NGS for PPGL patients.
Authors: Haizhou Lou; Chongya Zhai; Liu Gong; Hong Pan; Hongming Pan; Yihong Zhang; Mei Yang; Zimin Hu Journal: J Int Med Res Date: 2020-08 Impact factor: 1.671