Epigenetic landscape of pancreatic neuroendocrine tumours reveals distinct cells of origin and means of tumour progression

Recent data suggest that Pancreatic Neuroendocrine Tumours (PanNETs) originate from - or {beta}-cells of the islets of Langerhans. The majority of PanNETs are non-functional 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 - and {beta}-cells. To confirm cell identity, we investigated ARX and PDX1 expression. Based on epigenetic similarities, PanNETs clustered in -like, {beta}-like and intermediate tumours. The epigenetic similarity to -cells progressively decreased in the intermediate tumours, which presented unclear differentiation. Specific transcription factor methylation and expression varied in the respective /{beta}-tumour groups. Depending on DNAme similarity to /{beta}-cells, PanNETs have different mutational spectra, stage of the disease and prognosis, indicating potential means of PanNET progression.