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¹ Laboratory for Epigenetics CEA-Institut de Génomique, Centre National de Génotypage, 91000 Evry, France
² Gene Expression Team, Department of Translational Research, CEA-Institut de Génomique, Centre National de Génotypage, 91000 Evry, France
³ Service de chirurgie digestive et endocrinienne
⁴ Service d'Anatomie et de Cytologie Pathologique, Hôpital Cochin, AP-HP, Université Paris Descartes, 75014 Paris, France
⁵ Institut Cochin de Génétique Moléculaire, Université Paris V René Descartes, CNRS (UMR 8104), 75014 Paris, France
⁶ Department of Translational Research, CEA-Institut de Génomique, Centre National de Génotypage, 91000 Evry, France
⁷ Institut National de la Santé et de la Recherche Médicale U567, 75014 Paris, France

(Correspondence should be addressed to J Tost, Laboratory for Epigenetics, CEA-Institut de Génomique, Centre National de Génotypage, Bâtiment G2, 2 rue Gaston Crémieux, CP 5721, 91057 Evry Cedex, France; Email: tost{at}cng.fr)

Prediction of the evolution of endocrine pancreatic tumors remains difficult based on histological criteria alone. We have previously demonstrated that epigenetic changes are an early event in a mouse model developing insulinomas. Particularly, overexpression of the imprinted IGF2 was caused by the hypermethylation of CpGs in the differentially methylated region 2 (DMR2). Here, we investigated whether IGF2 hypermethylation is also observed in human insulinomas and whether this alteration is common to other human endocrine tumors of the pancreas and the digestive tract. We analyzed the methylation status of 40 CpGs located in the DMR0 and DMR2 of the IGF2 as well as in the H19 DMR by pyrosequencing in a cohort of 62 patients with pancreatic or small intestine endocrine tumors. Altered methylation patterns were observed in all tumor types for the different regions of IGF2, but not for H19. However, hypermethylation of the IGF2 DMR2 was specific for insulinomas and did not occur in any of the other types of tumors which were characterized by a loss of methylation in this region. Gain of methylation in the IGF2 DMR2 in insulinomas correlated with loss-of-imprinting and promoter 4 mediated overexpression of IGF2 at the RNA and protein level. Furthermore, a decreasing degree of methylation in the different regions of IGF2 correlated well with increasing degree of malignancy according to the WHO classification of pancreatic endocrine tumors (PETs), suggesting that methylation of IGF2 might be a useful biomarker for classification and staging of PETs.