https://www.biorxiv.org/content/10.1101/2020.06.12.146811v2
In the wake of the multi-omics era, stratification of cancer entities at multiple molecular levels have become increasingly prominent for diagnostic and therapeutic purposes. By uncovering the diversity within a cancer entity, we can understand inter-tumor heterogeneity as well as the biological mechanism contributing to it. Our study presents an integrative multi-omics approach that classifies pancreatic neuroendocrine neoplasms (PanNENs) subgroups, highlights cell-of-origin distinction, as well as differences in multi-genomic aberration and proteomic changes grounded within these subgroups. We determined that PanNEN tumor methylome profile closely resembles either α-like and β-like cells of Islet of Langerhans. The most aggressive tumor grades of PanNEN contain β-cell features and show hypermethylation of various transcription factors involved in Islet cell differentiation and maintenance. Mutations within MEN1/DAXX/ATRX tumor suppressor genes and overexpression of mTOR pathway proteins are key features of α-like tumors. DNA copy number data further implicates differences in tumor progression mechanism within the α-like tumors. Taken together, our data provides new insights into the PanNEN heterogeneity and further establishes a foundation for future diagnostic and therapy-relevant patient stratification.