ABSTRACT
Recent data suggest that Pancreatic Neuroendocrine Tumours (PanNETs) originate from α- or β-cells of the islets of Langerhans. The majority of PanNETs are nonfunctional and do not express cell-type specific hormones. We examined whether tumour DNA methylation (DNAme) profiling combined with genomic data could identify cell of origin and reveal pathways involved in PanNET progression. We analysed genome-wide DNAme data of 125 PanNETs and sorted α- and β-cells. To confirm cell identity, we investigated ARX and PDX1 expression. Based on epigenetic similarities, PanNETs clustered in α-like, β-like and intermediate tumours. The epigenetic similarity to α-cells progressively decreased in the intermediate tumours, which presented unclear differentiation. Specific transcription factor methylation and expression varied in the respective α/β-tumour groups. Depending on DNAme similarity to α/β-cells, PanNETs have different mutational spectra, stage of the disease and prognosis, indicating potential means of PanNET progression.
Footnotes
Grant support: Marie Heim-Vögtlin SNF (PMPDP3_164484) and Tumour Forschung Bern to Ilaria Marinoni. Swiss Cancer League (KLS-4227-08-2017) to Aurel Perren. Cancer Research UK and Experimental Cancer Medicine Centre to Christina Thirlwell and Christodoulos Pipinikas.