Pancreatic neuroendocrine neoplasms (PNENs) are biologically and clinically heterogeneous neoplasms in which pathogenic alterations are often indiscernible. Treatments for PNENs are insufficient in part due to lack of alternatives once current options are exhausted. Despite previous efforts to characterize PNENs at the molecular level, there remains a lack of molecular subgroups and molecular features with clinical utility for PNENs. In this work, I describe the identification and characterization of four molecularly distinct subgroups from primary PNEN specimens using whole-exome sequencing, RNA-sequencing and global proteome profiling. A Proliferative subgroup with molecular features of proliferating cells was associated with an inferior overall survival probability. A PDX1-high subgroup consisted of PNENs demonstrating genetic and transcriptomic indications of NRAS or HRAS activation. An Alpha cell-like subgroup, enriched in PNENs with deleterious MEN1 and DAXX mutations, bore transcriptomic similarity to pancreatic α-cells and harbored proteomic cues of dysregulated metabolism involving glutamine and arginine. Lastly, a Stromal/Mesenchymal subgroup exhibited increased expression and activation of the Hippo signaling pathway effectors YAP1 and WWTR1 that are of emerging interest as potentially actionable targets in other cancer types. Whole-genome and whole-transcriptome analysis of PNEN metastases identified novel molecular events likely contributing to pathogenesis, including one case presumably driven by MYCN amplification. In agreement with the findings in primary PNENs, four of the metastatic PNENs displayed a substantial Alpha cell-like subgroup signature and all harboured concurrent mutations in MEN1 and DAXX. Collectively, the identified subgroups present a potential stratification scheme that facilitates the identification of therapeutic vulnerabilities amidst PNEN heterogeneity to improve the effective management of PNENs
