title: MEN1 in pancreatic endocrine tumors: analysis of gene and protein status in 169 sporadic neoplasms reveals alterations in the vast majority of cases.
abstract: Pancreatic endocrine tumors (PETs) may be part of hereditary multiple endocrine neoplasia type 1 (MEN1) syndrome. While MEN1 gene mutation is the only ascertained genetic anomaly described in PETs, no data exist on the cellular localization of MEN1-encoded protein, menin, in normal pancreas and PETs. A total of 169 PETs were used to assess the i) MEN1 gene mutational status in 100 clinically sporadic PETs by direct DNA sequencing, ii) immunohistochemical expression of menin in normal pancreas and 140 PETs, including 71 cases screened for gene mutations, and iii) correlation of these findings with clinical-pathological parameters. Twenty-seven PETs showed mutations that were somatic in 25 patients and revealed to be germline in 2 patients. Menin immunostaining showed strong nuclear and very faint cytoplasmic signal in normal islet cells, whereas it displayed abnormal location and expression levels in 80% of tumors. PETs harboring MEN1 truncating mutations lacked nuclear protein, and most PETs with MEN1 missense mutations showed a strong cytoplasmic positivity for menin. Menin was also misplaced in a significant number of cases lacking MEN1 mutations. In conclusion, the vast majority of PETs showed qualitative and/or quantitative alterations in menin localization. In 30% of cases, this was associated with MEN1 mutations affecting sequences involved in nuclear localization or protein-protein interaction. In cases lacking MEN1 mutations, the alteration of one of the menin interactors may have prevented its proper localization, as suggested by recent data showing that menin protein shuttles between the nucleus and cytoplasm and also affects the subcellular localization of its interactors.
authors.affiliation: ARC-NET Research Center Department of Pathology, University of Verona, Policlinico G.B. Rossi c/o Piastra Odontoiatrica, Piazzale L.A. Scuro 10, Verona, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Corbo
authors.forename: Irene
authors.initials: I
authors.lastname: Dalai
authors.forename: Maria
authors.initials: M
authors.lastname: Scardoni
authors.forename: Stefano
authors.initials: S
authors.lastname: Barbi
authors.forename: Stefania
authors.initials: S
authors.lastname: Beghelli
authors.forename: Samantha
authors.initials: S
authors.lastname: Bersani
authors.forename: Luca
authors.initials: L
authors.lastname: Albarello
authors.forename: Claudio
authors.initials: C
authors.lastname: Doglioni
authors.forename: Christina
authors.initials: C
authors.lastname: Schott
authors.forename: Paola
authors.initials: P
authors.lastname: Capelli
authors.forename: Marco
authors.initials: M
authors.lastname: Chilosi
authors.forename: Letizia
authors.initials: L
authors.lastname: Boninsegna
authors.forename: Karl-Friedrich
authors.initials: KF
authors.lastname: Becker
authors.forename: Massimo
authors.initials: M
authors.lastname: Falconi
authors.forename: Aldo
authors.initials: A
authors.lastname: Scarpa
mesh_terms: D000328:Adult; D015153:Blotting, Western; D002454:Cell Differentiation; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D008875:Middle Aged; D018761:Multiple Endocrine Neoplasia Type 1 / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C105373:MEN1 protein, human; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger