inpancreaticb-celltumorigenesis.PDFVIP

Endocrine-Related Cancer (2006) 13 1223–1236 Gene expression profiling in insulinomas of Men1 b-cell mutant mice reveals early genetic and epigenetic events involved in pancreatic b-cell tumorigenesis ` 1,2 3 5 5 1 1 S Fontaniere , J Tost , A Wierinckx , J Lachuer , J Lu , N Hussein , F Busato3, I Gut 3, Z-Q Wang 2,4 and C-X Zhang 1 1 ´ ´ ´ ´ ´ Laboratoire Genetique et Cancer, CNRS, UMR5201, Faculte de Medecine, Universite Claude Bernard Lyon 1, 69373 Lyon, France 2International Agency for Research on Cancer (IARC), 69008 Lyon, France 3Centre National de Genotypage, Laboratory for Epigenetics, Cremieux, CP5721, 91057 Evry Cedex, France 4Leibniz Institute for Age Research (FLI), Fritz Lipmann Institute e.V., 07745 Jena, Germany 5ProfilExpert, Neurobiotec Services, 69676 Bron, France (Requests for offprints should be addressed to C-X Zhang; Email: zhang@sante.univ-lyon1.fr) Abstract Mutations of the MEN1 gene lead to the occurrence of multiple endocrine neoplasia type 1 (MEN1). To gain insights into the mechanisms of the tumorigenesis related to MEN1 inactivation, we have used mice in which the Men1 gene was specifically disrupted in pancreatic b-cells. In these mice, we observed full penetrance of insulinoma with defined histological characteristics of tumorigenesis. To identify the genetic factors taking part in the tumour development, we performed gene expression profiling analysis of these insulinomas at different stages. Here, we show that in late stage insulinomas, 56 genes are up-regulated and 194 are down-regulated more than fourfold compared with normal pancreatic islets. Clustering analysis reveals the deregulation of Hox gene family and the genes involved in