title: Aberrant Menin expression is an early event in pancreatic neuroendocrine tumorigenesis.
abstract: Pancreatic neuroendocrine tumors (PanNETs) are the second most common pancreatic malignancy and cause significant morbidity and mortality. Neuroendocrine microadenomas have been proposed as a potential precursor lesion for sporadic PanNETs. In this study, we applied telomere-specific fluorescent in situ hybridization (FISH) to a series of well-characterized sporadic neuroendocrine microadenomas and investigated the prevalence of alterations in known PanNET driver genes (MEN1 and ATRX/DAXX) in these same tumors using immunohistochemistry for the encoded proteins. We identified aberrant Menin expression in 14 of 19 (74%) microadenomas, suggesting that alterations in Menin, at least a subset of which was likely due to somatic mutation, are early events in pancreatic neuroendocrine tumorigenesis. In contrast, none of the microadenomas met criteria for the alternative lengthening of telomeres phenotype (ALT) based on telomere FISH, a phenotype that is strongly correlated to ATRX or DAXX mutations. Two of 13 microadenomas (15%) were noted to have very rare abnormal bright telomere foci on FISH, suggestive of early ALT, but these lesions did not show loss of ATRX or DAXX protein expression by immunohistochemistry. Overall, these data suggest that loss of Menin is an early event in pancreatic neuroendocrine tumorigenesis and that ATRX/DAXX loss and ALT are relatively late events.
authors.affiliation: Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Department of Pathology, University Medical Center Utrecht, Utrecht 3584, CX, the Netherlands.
authors.forename: Wenzel M
authors.initials: WM
authors.lastname: Hackeng
authors.affiliation: Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Department of Pathology, University Medical Center Utrecht, Utrecht 3584, CX, the Netherlands.
authors.forename: Lodewijk A A
authors.initials: LA
authors.lastname: Brosens
authors.affiliation: Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Poruk
authors.affiliation: Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Department of Pathology, University Medical Center Utrecht, Utrecht 3584, CX, the Netherlands.
authors.forename: Michaël
authors.initials: M
authors.lastname: Noë
authors.affiliation: Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
authors.forename: Waki
authors.initials: W
authors.lastname: Hosoda
authors.affiliation: Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
authors.forename: Justin S
authors.initials: JS
authors.lastname: Poling
authors.affiliation: Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Rizzo
authors.affiliation: Department of Pathology, College of Medicine, University of Florida, Gainesville, FL 32610-0275, USA.
authors.forename: Martha
authors.initials: M
authors.lastname: Campbell-Thompson
authors.affiliation: Department of Pathology, College of Medicine, University of Florida, Gainesville, FL 32610-0275, USA; Department of Pediatrics, College of Medicine, University of Florida, Gainesville, FL 32610-0275, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Atkinson
authors.affiliation: Department of Pathology, Technical University Munich, 81675 Munich, Germany.
authors.forename: Björn
authors.initials: B
authors.lastname: Konukiewitz
authors.affiliation: Department of Pathology, Technical University Munich, 81675 Munich, Germany.
authors.forename: Günter
authors.initials: G
authors.lastname: Klöppel
authors.affiliation: Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Heaphy
authors.affiliation: Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
authors.forename: Alan K
authors.initials: AK
authors.lastname: Meeker
authors.affiliation: Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. Electronic address: ldwood@jhmi.edu.
authors.forename: Laura D
authors.initials: LD
authors.lastname: Wood
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000032:analysis; D000236:Adenoma / Q000737:chemistry / Q000235:genetics* / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics*; D056970:Co-Repressor Proteins; D004265:DNA Helicases / Q000032:analysis; D018450:Disease Progression; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D018832:Molecular Chaperones; D009154:Mutation; D018358:Neuroendocrine Tumors / Q000737:chemistry / Q000235:genetics* / Q000473:pathology; D009687:Nuclear Proteins / Q000032:analysis; D010190:Pancreatic Neoplasms / Q000737:chemistry / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000032:analysis / Q000235:genetics*; D059505:Telomere Homeostasis; D047368:Tumor Burden; D000075924:X-linked Nuclear Protein
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; D056970:Co-Repressor Proteins; C106985:DAXX protein, human; C105373:MEN1 protein, human; D018832:Molecular Chaperones; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D004265:DNA Helicases; C092332:ATRX protein, human; D000075924:X-linked Nuclear Protein
keywords: ATRX; DAXX; Menin; Microadenoma; PanNET; Tumorigenesis