Integrated genomics and transcriptomics reveal key events in pancreatic neuroendocrine neoplasm

BACKGROUND: Pancreatic neuroendocrine neoplasm (PanNEN) represents the second most common epithelial neoplasm of the pancreas, characterized by remarkable heterogeneity among its subtypes. This study aimed to comprehensively characterize the molecular landscape of PanNENs and identify key features associated with tumor progression and therapeutic implications. RESULTS: We performed an integrated molecular analysis of 106 PanNEN samples using whole-genome sequencing, whole-exome sequencing, and transcriptome sequencing. PanNEC demonstrated significantly higher mutation burden compared to PanNET, with recurrent mutations in KRAS and TP53. In metastatic PanNET, structural variation rearrangement signatures (RS) emerged as crucial molecular events affecting tumor-related gene expression. Copy number variation (CNV) analysis revealed four distinct PanNET subgroups: chromosomal-scale loss of heterozygosity (LOH), limited CNV events, whole-genome duplication (WGD), and WGD with chromosomal-scale LOH. We proposed a novel evolutionary model for PanNET based on CNV patterns, validated through transcriptomic analysis and clinical sampling. WGD was identified as a pivotal event in PanNET progression, significantly enhancing tumor aggressiveness. Transcriptomic profiling revealed distinct immune signatures associated with RS subtypes and WGD status, with the RS2 subtype showing a particularly favorable immune profile suggesting potential immunotherapy responsiveness. CONCLUSIONS: In summary, our systematic genomic and transcriptomic analyses revealed distinct biological features among PanNEN subtypes and identified a novel CNV-based evolutionary trajectory in PanNET. We demonstrated that structural variation and whole-genome duplication were critical events driving PanNET progression, providing new insights into PanNET biology with potential clinical implications.