PMID- 35861986 OWN - NLM STAT- MEDLINE DCOM- 20220725 LR - 20230703 IS - 1479-683X (Electronic) IS - 0804-4643 (Print) IS - 0804-4643 (Linking) VI - 187 IP - 1 DP - 2022 Jul 1 TI - Novel GLCCI1-BRAF fusion drives kinase signaling in a case of pheochromocytomatosis. PG - 185-196 LID - 10.1530/EJE-21-0797 [doi] AB - INTRODUCTION: Recurrent and metastatic pheochromocytoma (PCC) are rare advanced endocrine neoplasms with limited treatment options. Insight into the pathogenic molecular alterations in patients with advanced PCC can provide therapeutic options for precisely targeting dysregulated pathways. OBJECTIVE: We report the discovery and characterization of a novel BRAF-containing fusion transcript and its downstream molecular alterations in a patient with recurrent PCC with peritoneal seeding (pheochromocytomatosis). METHODS: We reviewed the medical record of a patient with pheochromocytomatosis. A comprehensive pan-cancer molecular profiling using next-generation sequencing (NGS) as well as confirmatory real-time-quantitative PCR were performed on surgical specimens. BRAF rearrangement and downstream molecular changes were assayed using fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC), respectively. Western blot was used to assess the in vitro activation of the mitogen-activated protein kinase (MAPK) signaling pathway and the EMT markers in transfected HEK-293 cells. RESULTS: The NGS analysis of a specimen from a 72-year-old female patient with pheochromocytomatosis showed an in-frame fusion of exon 3 of Glucocorticoid Induced 1 (GLCCI1) to exon 9 of BRAF. The upstream auto-inhibitory domain of BRAF was excluded from the GLCCI1-BRAF fusion; however, the downstream BRAF kinase domain was intact. A BRAF rearrangement was confirmed via a BRAF-specific break-apart FISH assay. Four separate tumor foci harbored GLCCI1-BRAF fusion. IHC demonstrated increased phosphorylated MEK. HEK-293 cells transfected with the GLCCI1-BRAF fusion demonstrated increased phosphorylated MEK as well as higher expression of EMT markers SNAI1 and ZEB1 in vitro. CONCLUSION: We demonstrate a novel pathogenic gene fusion of GLCCI1 with the oncogenic kinase domain of BRAF, resulting in an activation of the MAPK signaling pathway and EMT markers. Thus, this patient may benefit from clinically available MEK and/or BRAF inhibitors when systemic therapy is indicated. SUMMARY STATEMENT: This report is the first of GLCCI1 fused to BRAF in a human neoplasm and only the second BRAF-containing fusion transcript in PCC. Detailed molecular characterization of PCC can be a valuable tool in managing patients with recurrent PCC and pheochromocytomatosis that represents a significant clinical challenge. CI - (c) European Society of Endocrinology 2022. FAU - Green, Benjamin L AU - Green BL AUID- ORCID: 0000-0002-5772-198X AD - Surgical Oncology Program, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA. FAU - Grant, Robert R C AU - Grant RRC AUID- ORCID: 0000-0002-1152-5959 AD - Surgical Oncology Program, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA. FAU - Richie, Christopher T AU - Richie CT AD - Genetic Engineering and Viral Vector Core, Intramural Research Program, Biomedical Research Center, National Institute on Drug Abuse, Baltimore, Maryland, USA. FAU - Chatterjee, Bishwanath AU - Chatterjee B AD - Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA. FAU - Sampaio De Melo, Michelly AU - Sampaio De Melo M AD - Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA. FAU - Barr, Frederic G AU - Barr FG AD - Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA. FAU - Pacak, Karel AU - Pacak K AD - Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA. FAU - Agarwal, Sunita K AU - Agarwal SK AD - Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA. FAU - Nilubol, Naris AU - Nilubol N AUID- ORCID: 0000-0002-7348-7804 AD - Surgical Oncology Program, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA. LA - eng GR - Z99 CA999999/ImNIH/Intramural NIH HHS/United States GR - ZIA BC011286/ImNIH/Intramural NIH HHS/United States PT - Case Reports PT - Journal Article PT - Review PL - England TA - Eur J Endocrinol JT - European journal of endocrinology JID - 9423848 RN - 0 (Glucocorticoids) RN - EC 2.7.11.1 (BRAF protein, human) RN - EC 2.7.11.1 (Proto-Oncogene Proteins B-raf) RN - EC 2.7.12.2 (Mitogen-Activated Protein Kinase Kinases) SB - IM MH - Aged MH - Female MH - *Glucocorticoids MH - HEK293 Cells MH - Humans MH - In Situ Hybridization, Fluorescence/methods MH - Mitogen-Activated Protein Kinase Kinases/genetics/metabolism MH - Neoplasm Recurrence, Local MH - *Proto-Oncogene Proteins B-raf/genetics MH - Signal Transduction PMC - PMC9347184 MID - NIHMS1813021 COIS- The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported. EDAT- 2022/07/22 06:00 MHDA- 2022/07/26 06:00 PMCR- 2023/07/01 CRDT- 2022/07/21 11:24 PHST- 2022/07/21 11:24 [entrez] PHST- 2022/07/22 06:00 [pubmed] PHST- 2022/07/26 06:00 [medline] PHST- 2023/07/01 00:00 [pmc-release] AID - 10.1530/EJE-21-0797 [doi] PST - ppublish SO - Eur J Endocrinol. 2022 Jul 1;187(1):185-196. doi: 10.1530/EJE-21-0797.