Proteotranscriptomic classification and characterization of pancreatic neuroendocrine neoplasms

Pancreatic neuroendocrine neoplasms (PNENs) are biologically and clinically heterogeneous. Here, we use a multi-omics approach to uncover the molecular factors underlying this heterogeneity. Transcriptomic analysis of 84 PNEN specimens, drawn from two cohorts, is substantiated with proteomic profiling and identifies four subgroups: Proliferative, PDX1-high, Alpha cell-like and Stromal/Mesenchymal. The Proliferative subgroup, consisting of both well- and poorly differentiated specimens, is associated with inferior overall survival probability. The PDX1-high and Alpha cell-like subgroups partially resemble previously described subtypes, and we further uncover distinctive metabolism-related features in the Alpha cell-like subgroup. The Stromal/Mesenchymal subgroup exhibits molecular characteristics of YAP1/WWTR1(TAZ) activation suggestive of Hippo signaling pathway involvement in PNENs. Whole-exome sequencing reveals subgroup-enriched mutational differences, supported by activity inference analysis, and identifies hypermorphic proto-oncogene variants in 14.3% of sequenced PNENs. Our study reveals differences in cellular signaling axes that provide potential directions for PNEN patient stratification and treatment strategies. [Display omitted] •Transcriptomic and proteomic variations define 4 subgroups of PNENs•Mutant MEN1/DAXX and metabolic features characterize an Alpha cell-like subgroup•A Stromal/Mesenchymal subgroup has elevated YAP1 and WWTR1 activities•Both well- and poorly differentiated neoplasms comprise a Proliferative subgroup Heterogeneity undermines PNEN management. Yang et al. identify and characterize four subgroups of PNENs with mutational, transcriptomic, and proteomic differences. They report dysregulation in cellular signaling axes that may be further exploited to facilitate patient stratification and treatment strategies.