학술논문
Gene fusions are frequent in ACTH-secreting neuroendocrine neoplasms of the pancreas, but not in their non-pancreatic counterparts.
Document Type
Academic Journal
Author
Agaimy A; Institute of Pathology, University Hospital Erlangen, Friedrich Alexander University of Erlangen-Nuremberg & Comprehensive Cancer Center, European Metropolitan Area Erlangen-Nuremberg (CCC ER-EMN), Erlangen, Germany. abbas.agaimy@uk-erlangen.de.; Kasajima A; Institute of Pathology, Technical University Munich, Munich, Germany.; Stoehr R; Institute of Pathology, University Hospital Erlangen, Friedrich Alexander University of Erlangen-Nuremberg & Comprehensive Cancer Center, European Metropolitan Area Erlangen-Nuremberg (CCC ER-EMN), Erlangen, Germany.; Haller F; Institute of Pathology, University Hospital Erlangen, Friedrich Alexander University of Erlangen-Nuremberg & Comprehensive Cancer Center, European Metropolitan Area Erlangen-Nuremberg (CCC ER-EMN), Erlangen, Germany.; Schubart C; Institute of Pathology, University Hospital Erlangen, Friedrich Alexander University of Erlangen-Nuremberg & Comprehensive Cancer Center, European Metropolitan Area Erlangen-Nuremberg (CCC ER-EMN), Erlangen, Germany.; Tögel L; Institute of Pathology, University Hospital Erlangen, Friedrich Alexander University of Erlangen-Nuremberg & Comprehensive Cancer Center, European Metropolitan Area Erlangen-Nuremberg (CCC ER-EMN), Erlangen, Germany.; Pfarr N; Institute of Pathology, Technical University Munich, Munich, Germany.; von Werder A; Department of Internal Medicine 2, Technical University Munich, Munich, Germany.; Pavel ME; Department of Medicine 1, Division of Endocrinology, Comprehensive Cancer Center, Erlangen University Hospital, European Metropolitan Area Erlangen-Nuremberg (CCC ER-EMN), Friedrich Alexander University of Erlangen-Nuremberg, Erlangen, Germany.; Sessa F; Unit of Pathology, Department of Medicine and Surgery, University of Insubria, Varese, Italy.; Uccella S; Humanitas University, Pieve Emanuele, Milan, Italy.; Humanitas Research Hospital, Rozzano, Milan, Italy.; La Rosa S; Unit of Pathology, Department of Medicine and Surgery, University of Insubria, Varese, Italy.; Klöppel G; Institute of Pathology, Technical University Munich, Munich, Germany.
Source
Publisher: Springer International Country of Publication: Germany NLM ID: 9423843 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1432-2307 (Electronic) Linking ISSN: 09456317 NLM ISO Abbreviation: Virchows Arch Subsets: MEDLINE
Subject
Language
English
Abstract
Ectopic Cushing syndrome is a rare clinical disorder resulting from excessive adrenocorticotrophic hormone (ACTH) produced by non-pituitary neoplasms, mainly neuroendocrine neoplasms (NENs) of the lung, pancreas, and gastrointestinal tract, and other less common sites. The genetic background of ACTH-producing NENs has not been well studied. Inspired by an index case of ACTH-producing pancreatic NEN carrying a gene fusion, we postulated that ACTH-producing NENs might be enriched for gene fusions. We herein examined 21 ACTH-secreting NENs of the pancreas (10), lung (9), thymus (1), and kidney (1) using targeted RNA sequencing. The tumors were classified according to the most recent WHO classification as NET-G1/typical carcinoid (n = 4), NETG-2/atypical carcinoid (n = 14), and NET-G3 (n = 3). Overall, targeted RNA sequencing was successful in 11 cases (4 of 10 pancreatic tumors, 5 of 9 pulmonary tumors, and in the one renal and one thymic tumor). All four successfully tested pancreatic tumors revealed a gene fusion: two had a EWSR1::BEND2 and one case each had a KMT2A::BCOR and a TFG::ADGRG7 fusion, respectively. EWSR1 rearrangements were confirmed in both tumors with a EWSR1::BEND2 by FISH. Gene fusions were mutually exclusive with ATRX, DAXX, and MEN1 mutations (the most frequently mutated genes in NETs) in all four cases. Using RNA-based variant assessment (n = 16) or via the TSO500 panel (n = 5), no pathogenic BCOR mutations were detected in any of the cases. Taken together, gene fusions were detected in 4/4 (100%) pancreatic versus 0/7 (0%) non-pancreatic tumors, respectively. These results suggest a potential role for gene fusions in triggering the ACTH production in pancreatic NENs presenting with ectopic Cushing syndrome. While the exact mechanisms responsible for the ectopic ACTH secretion are beyond the scope of this study, overexpressed fusion proteins might be involved in promoter-mediated overexpression of pre-ACTH precursors in analogy to the mechanisms postulated for EWSR1::CREB1-mediated paraneoplastic phenomena in certain mesenchymal neoplasms. The genetic background of the ACTH-producing non-pancreatic NENs remains to be further studied.
(© 2023. The Author(s).)
(© 2023. The Author(s).)