Decreased expression and promoter methylation of the menin tumor suppressor in pancreatic ductal Adenocarcinoma

Ilaria Cavallari, Silic Benussi Micol, Francesca Rende, Annalisa Martines, Paola Fogar, Daniela Basso, Manuela Della Vella, Sergio Pedrazzoli, James G. Herman, Chieco-Bianchi Luigi Chieco-Bianchi, Giovanni Esposito, Vincenzo Ciminale, Donna A. D'Agostino

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Loss of menin, a tumor suppressor coded by the MENI gene, is a key factor in the pathogenesis of multiple endocrine neoplasia type I and in a percentage of sporadic endocrine tumors of the pancreas and parathyroid glands. This study investigated expression of the menin protein in the normal exocrine pancreas and in pancreatic ductal adenocarcinoma (PDAC), the most common pancreatic tumor. Immunofluorescence (IF) analyses showed that menin is expressed at high levels in normal acinar and duct cells. Examination of 24 clinical samples of PDAC revealed a pronounced decrease in menin expression in all tumors examined. To identify alterations underlying this defect, we searched for disruption and epigenetic silencing of the MENI gene. Analysis of nine laser-microdissected tumors revealed loss of heterozygosity of intragenic (one tumor) or adjacent (three tumors) MENI microsatellite markers. Methylation of CpG sites in the MENI promoter was documented in five of 24 tumors. IF analyses also revealed low to undetectable menin expression in the PDAC cell lines MiaPaCa-2 and Panc-1. Ectopic expression of menin in these cells resulted in a marked alteration of the cell cycle, with an increase in the G1/S+G2 ratio. These findings represent the first evidence that the MENI gene is a target of mutation and methylation in PDAC and that menin influences the cell cycle profile of duct cells.

Original languageEnglish
Pages (from-to)383-396
Number of pages14
JournalGenes Chromosomes and Cancer
Volume48
Issue number5
DOIs
Publication statusPublished - May 2009

Fingerprint

Methylation
Adenocarcinoma
Neoplasms
Fluorescent Antibody Technique
Cell Cycle
Multiple Endocrine Neoplasia Type 1
Exocrine Pancreas
Parathyroid Glands
Acinar Cells
Loss of Heterozygosity
Gene Silencing
Islets of Langerhans
Epigenomics
Microsatellite Repeats
Genes
Lasers
Cell Line
Mutation
Proteins

ASJC Scopus subject areas

  • Cancer Research
  • Genetics
  • Medicine(all)

Cite this

Cavallari, I., Micol, S. B., Rende, F., Martines, A., Fogar, P., Basso, D., ... D'Agostino, D. A. (2009). Decreased expression and promoter methylation of the menin tumor suppressor in pancreatic ductal Adenocarcinoma. Genes Chromosomes and Cancer, 48(5), 383-396. https://doi.org/10.1002/gcc.20650

Decreased expression and promoter methylation of the menin tumor suppressor in pancreatic ductal Adenocarcinoma. / Cavallari, Ilaria; Micol, Silic Benussi; Rende, Francesca; Martines, Annalisa; Fogar, Paola; Basso, Daniela; Vella, Manuela Della; Pedrazzoli, Sergio; Herman, James G.; Luigi Chieco-Bianchi, Chieco-Bianchi; Esposito, Giovanni; Ciminale, Vincenzo; D'Agostino, Donna A.

In: Genes Chromosomes and Cancer, Vol. 48, No. 5, 05.2009, p. 383-396.

Research output: Contribution to journalArticle

Cavallari, I, Micol, SB, Rende, F, Martines, A, Fogar, P, Basso, D, Vella, MD, Pedrazzoli, S, Herman, JG, Luigi Chieco-Bianchi, C-B, Esposito, G, Ciminale, V & D'Agostino, DA 2009, 'Decreased expression and promoter methylation of the menin tumor suppressor in pancreatic ductal Adenocarcinoma', Genes Chromosomes and Cancer, vol. 48, no. 5, pp. 383-396. https://doi.org/10.1002/gcc.20650
Cavallari, Ilaria ; Micol, Silic Benussi ; Rende, Francesca ; Martines, Annalisa ; Fogar, Paola ; Basso, Daniela ; Vella, Manuela Della ; Pedrazzoli, Sergio ; Herman, James G. ; Luigi Chieco-Bianchi, Chieco-Bianchi ; Esposito, Giovanni ; Ciminale, Vincenzo ; D'Agostino, Donna A. / Decreased expression and promoter methylation of the menin tumor suppressor in pancreatic ductal Adenocarcinoma. In: Genes Chromosomes and Cancer. 2009 ; Vol. 48, No. 5. pp. 383-396.
@article{a79a1cea9067427680689c6ee3da7031,
title = "Decreased expression and promoter methylation of the menin tumor suppressor in pancreatic ductal Adenocarcinoma",
abstract = "Loss of menin, a tumor suppressor coded by the MENI gene, is a key factor in the pathogenesis of multiple endocrine neoplasia type I and in a percentage of sporadic endocrine tumors of the pancreas and parathyroid glands. This study investigated expression of the menin protein in the normal exocrine pancreas and in pancreatic ductal adenocarcinoma (PDAC), the most common pancreatic tumor. Immunofluorescence (IF) analyses showed that menin is expressed at high levels in normal acinar and duct cells. Examination of 24 clinical samples of PDAC revealed a pronounced decrease in menin expression in all tumors examined. To identify alterations underlying this defect, we searched for disruption and epigenetic silencing of the MENI gene. Analysis of nine laser-microdissected tumors revealed loss of heterozygosity of intragenic (one tumor) or adjacent (three tumors) MENI microsatellite markers. Methylation of CpG sites in the MENI promoter was documented in five of 24 tumors. IF analyses also revealed low to undetectable menin expression in the PDAC cell lines MiaPaCa-2 and Panc-1. Ectopic expression of menin in these cells resulted in a marked alteration of the cell cycle, with an increase in the G1/S+G2 ratio. These findings represent the first evidence that the MENI gene is a target of mutation and methylation in PDAC and that menin influences the cell cycle profile of duct cells.",
author = "Ilaria Cavallari and Micol, {Silic Benussi} and Francesca Rende and Annalisa Martines and Paola Fogar and Daniela Basso and Vella, {Manuela Della} and Sergio Pedrazzoli and Herman, {James G.} and {Luigi Chieco-Bianchi}, Chieco-Bianchi and Giovanni Esposito and Vincenzo Ciminale and D'Agostino, {Donna A.}",
year = "2009",
month = "5",
doi = "10.1002/gcc.20650",
language = "English",
volume = "48",
pages = "383--396",
journal = "Genes Chromosomes and Cancer",
issn = "1045-2257",
publisher = "Wiley-Liss Inc.",
number = "5",

}

TY - JOUR

T1 - Decreased expression and promoter methylation of the menin tumor suppressor in pancreatic ductal Adenocarcinoma

AU - Cavallari, Ilaria

AU - Micol, Silic Benussi

AU - Rende, Francesca

AU - Martines, Annalisa

AU - Fogar, Paola

AU - Basso, Daniela

AU - Vella, Manuela Della

AU - Pedrazzoli, Sergio

AU - Herman, James G.

AU - Luigi Chieco-Bianchi, Chieco-Bianchi

AU - Esposito, Giovanni

AU - Ciminale, Vincenzo

AU - D'Agostino, Donna A.

PY - 2009/5

Y1 - 2009/5

N2 - Loss of menin, a tumor suppressor coded by the MENI gene, is a key factor in the pathogenesis of multiple endocrine neoplasia type I and in a percentage of sporadic endocrine tumors of the pancreas and parathyroid glands. This study investigated expression of the menin protein in the normal exocrine pancreas and in pancreatic ductal adenocarcinoma (PDAC), the most common pancreatic tumor. Immunofluorescence (IF) analyses showed that menin is expressed at high levels in normal acinar and duct cells. Examination of 24 clinical samples of PDAC revealed a pronounced decrease in menin expression in all tumors examined. To identify alterations underlying this defect, we searched for disruption and epigenetic silencing of the MENI gene. Analysis of nine laser-microdissected tumors revealed loss of heterozygosity of intragenic (one tumor) or adjacent (three tumors) MENI microsatellite markers. Methylation of CpG sites in the MENI promoter was documented in five of 24 tumors. IF analyses also revealed low to undetectable menin expression in the PDAC cell lines MiaPaCa-2 and Panc-1. Ectopic expression of menin in these cells resulted in a marked alteration of the cell cycle, with an increase in the G1/S+G2 ratio. These findings represent the first evidence that the MENI gene is a target of mutation and methylation in PDAC and that menin influences the cell cycle profile of duct cells.

AB - Loss of menin, a tumor suppressor coded by the MENI gene, is a key factor in the pathogenesis of multiple endocrine neoplasia type I and in a percentage of sporadic endocrine tumors of the pancreas and parathyroid glands. This study investigated expression of the menin protein in the normal exocrine pancreas and in pancreatic ductal adenocarcinoma (PDAC), the most common pancreatic tumor. Immunofluorescence (IF) analyses showed that menin is expressed at high levels in normal acinar and duct cells. Examination of 24 clinical samples of PDAC revealed a pronounced decrease in menin expression in all tumors examined. To identify alterations underlying this defect, we searched for disruption and epigenetic silencing of the MENI gene. Analysis of nine laser-microdissected tumors revealed loss of heterozygosity of intragenic (one tumor) or adjacent (three tumors) MENI microsatellite markers. Methylation of CpG sites in the MENI promoter was documented in five of 24 tumors. IF analyses also revealed low to undetectable menin expression in the PDAC cell lines MiaPaCa-2 and Panc-1. Ectopic expression of menin in these cells resulted in a marked alteration of the cell cycle, with an increase in the G1/S+G2 ratio. These findings represent the first evidence that the MENI gene is a target of mutation and methylation in PDAC and that menin influences the cell cycle profile of duct cells.

UR - http://www.scopus.com/inward/record.url?scp=65349191230&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=65349191230&partnerID=8YFLogxK

U2 - 10.1002/gcc.20650

DO - 10.1002/gcc.20650

M3 - Article

C2 - 19170121

AN - SCOPUS:65349191230

VL - 48

SP - 383

EP - 396

JO - Genes Chromosomes and Cancer

JF - Genes Chromosomes and Cancer

SN - 1045-2257

IS - 5

ER -