期刊
CANCER DISCOVERY
卷 12, 期 3, 页码 692-711出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-21-0669
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资金
- National Cancer Center Research and Development Fund [29-A-6]
- Practical Research for Innovative Cancer Control from the Japan Agency for Medical Research and Development (AMED) [JP21ck0106558, JP21ck0106693, JP21ck0106690, JP21ck0106547, JP15ck0106138, JP16ck0106138]
- Project for Cancer Research and Therapeutic Evolution (P-CREATE) from AMED [JP17cm0106612]
- United States-Japan Cooperative Medical Science Program from AMED [JP20jk0210009]
- Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University
- Joint Research Project of the Institute Medical Science, The University of Tokyo
- Takeda Science Foundation
- Yasuda Medical Foundation
- Mitsubishi Foundation
- Princess Takamatsu Cancer Research Fund
- National Cancer Center Research and Development Fund, Japan
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.
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.
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