Comprehensive Genomic Profiling of Neuroendocrine Carcinomas of the Gastrointestinal System

Shinichi Yachida, Yasushi Totoki, Michaël Noë, Yoichiro Nakatani, Masafumi Horie, Kenta Kawasaki, Hiromi Nakamura, Mihoko Saito-Adachi, Masami Suzuki, Erina Takai, Natsuko Hama, Ryota Higuchi, Seiko Hirono, Satoshi Shiba, Mamoru Kato, Eisaku Furukawa, Yasuhito Arai, Hirofumi Rokutan, Taiki Hashimoto, Shuichi MitsunagaMitsuro Kanda, Hidenori Tanaka, So Takata, Ayaka Shimomura, Minoru Oshima, Wenzel M. Hackeng, Tomoyuki Okumura, Keiichi Okano, Masakazu Yamamoto, Hiroki Yamaue, Chigusa Morizane, Koji Arihiro, Toru Furukawa, Toshiro Sato, Tohru Kiyono, Lodewijk A.A. Brosens, Laura D. Wood, Ralph H. Hruban, Tatsuhiro Shibata

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

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 (Panc-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 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. 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.

Original languageEnglish
Pages (from-to)692-711
Number of pages20
JournalCancer Discovery
Volume12
Issue number3
DOIs
Publication statusPublished - 2022 Mar 1

ASJC Scopus subject areas

  • Oncology

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