PT  - JOURNAL ARTICLE
AU  - Annunziata Di Domenico
AU  - Christodoulos P. Pipinikas
AU  - Renaud Sylvain Maire
AU  - Konstantin Bräutigam
AU  - Cedric Simillion
AU  - Matthias S. Dettmer
AU  - Erik Vassella
AU  - Christina Thirlwell
AU  - Aurel Perren
AU  - Ilaria Marinoni
TI  - Epigenetic landscape of pancreatic neuroendocrine tumours reveals distinct cells of origin and means of tumour progression
AID  - 10.1101/2020.04.08.029785
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.04.08.029785
4099  - http://biorxiv.org/content/early/2020/04/08/2020.04.08.029785.short
4100  - http://biorxiv.org/content/early/2020/04/08/2020.04.08.029785.full
AB  - 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.