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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 β-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 cell proliferation and cell cycle control. The altered expression of  Igf2 ,  Igfbp3  and  Igfbp6  as well as  cyclin A2 ,  B2  and  D2  are confirmed by quantitative RT-PCR, with the overexpression of all the three cyclins found in early stage insulinomas. Moreover, an increased proportion of cyclin A2- and D2-expressing cells and the overexpression of insulin-like growth factor 2 (IGF2) protein are detected in mouse  Men1  insulinomas by immunostaining. Interestingly, the analysis of DNA methylation patterns by quantitative serial pyrosequencing reveals that four specific CpGs in the intragenic differentially methylated region 2 (DMR2) region of the  Igf2  gene known to augment transcription through methylation are significantly hypermethylated in insulinomas of  Men1  β-cell mutant mice at 6 and 10 months of age, even before IGF2 overexpression can be detected. Thus, our data indicate the involvement of both genetic and epigenetic mechanisms in early tumorigenesis of β-cells related to  MEN1  inactivation.

endocrine-related cancer

Gene expression profiling in insulinomas of Men1 β-cell mutant mice reveals early genetic and epigenetic events involved in pancreatic β-cell tumorigenesis