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-NET) in the same location. Clear genomic differences were also evident between pancreatic NECs (Pant-NEC) and nonpancreatic GIS-NECs (Nonpanc-NEC). 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 RB1 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 overex-pressed 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. SIGNIFICANCE: GIS-NECs are genetically distinct from GIS-NETs. GIS-NECs arising in different organs show similar histopathologic features and share some genomic features, but considerable differences exist between Panc-NECs and Nonpanc-NECs. In addition, Panc-NECs could be classified into two subgroups (i.e., ductal-type and acinar-type) based on genomic and epigenomic features.

Automated summary

Gastrointestinal neuroendocrine carcinoma (GIS-NEC) is a rare but highly malignant tumor that is genetically distinct from gastrointestinal neuroendocrine tumors (GIS-NET). There are clear genomic differences between pancreatic NECs (Pant-NEC) and nonpancreatic GIS-NECs (Nonpanc-NEC). Panc-NECs can be classified into two subgroups based on genomic and epigenomic features.