Comprehensive Genomic Profiling of Neuroendocrine Carcinomas of the Gastrointestinal System.

The neuroendocrine carcinoma of the gastrointestinal system (GIS-NEC) is a rare but highly malignant neoplasm. We analyzed 115 cases using whole-genome/exome sequencing, transcriptome sequencing, DNA methylation assays, and/or ATAC-seq and found GIS-NECs to be genetically distinct from neuroendocrine tumors (GIS-NETs) in the same location. Clear genomic differences were also evident between pancreatic NECs (Panc-NECs) and non-pancreatic GIS-NECs (Nonpanc-NECs). Panc-NECs could be classified into two subgroups (i.e., 'Ductal-type' and 'Acinar-type') based on genomic features. Alterations in TP53 and RB1 proved common in GIS-NECs and most Nonpanc-NECs with intact Rb demonstrated mutually exclusive amplification of CCNE1 or MYC. Alterations of the Notch gene family were characteristic of Nonpanc-NECs. Transcription factors for neuroendocrine differentiation, especially the SOX2 gene, appeared overexpressed in most GIS-NECs due to hypermethylation of the promoter region. This first comprehensive study of genomic alterations in GIS-NECs uncovered several key biological processes underlying genesis of this very lethal form of cancer.