title: Hypermethylation of the IGF2 differentially methylated region 2 is a specific event in insulinomas leading to loss-of-imprinting and overexpression.
abstract: 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.
authors.affiliation: Laboratory for Epigenetics CEA-Institut de Génomique, Centre National de Génotypage, 91000 Evry, France.
authors.forename: Emelyne
authors.initials: E
authors.lastname: Dejeux
authors.forename: Robert
authors.initials: R
authors.lastname: Olaso
authors.forename: Bertrand
authors.initials: B
authors.lastname: Dousset
authors.forename: Anne
authors.initials: A
authors.lastname: Audebourg
authors.forename: Ivo G
authors.initials: IG
authors.lastname: Gut
authors.forename: Benoit
authors.initials: B
authors.lastname: Terris
authors.forename: Jörg
authors.initials: J
authors.lastname: Tost
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation / Q000502:physiology*; D005260:Female; D015408:Gastrinoma / Q000145:classification / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D018392:Genomic Imprinting / Q000235:genetics*; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000235:genetics* / Q000378:metabolism; D007340:Insulinoma / Q000145:classification / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009928:Organ Specificity / Q000235:genetics; D010190:Pancreatic Neoplasms / Q000145:classification / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000502:physiology; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; C094335:H19 long non-coding RNA; C035170:IGF2 protein, human; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; D007335:Insulin-Like Growth Factor II