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 Mitsunaga; Mitsuro 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

doi:10.1158/2159-8290.CD-21-0669

Comprehensive Genomic Profiling of Neuroendocrine Carcinomas of the Gastrointestinal System

Cancer Discov. 2022 Mar 1;12(3):692-711. doi: 10.1158/2159-8290.CD-21-0669.

Authors

Shinichi Yachida^#^{1

2

3}, Yasushi Totoki^#⁴, Michaël Noë^#^{5

6}, Yoichiro Nakatani^#¹, Masafumi Horie^#¹, Kenta Kawasaki⁷, Hiromi Nakamura⁴, Mihoko Saito-Adachi⁴, Masami Suzuki¹, Erina Takai¹, Natsuko Hama⁴, Ryota Higuchi⁸, Seiko Hirono⁹, Satoshi Shiba⁴, Mamoru Kato¹⁰, Eisaku Furukawa¹⁰, Yasuhito Arai⁴, Hirofumi Rokutan⁴, Taiki Hashimoto¹¹, Shuichi Mitsunaga¹², Mitsuro Kanda¹³, Hidenori Tanaka¹, So Takata¹, Ayaka Shimomura¹⁴, Minoru Oshima¹⁴, Wenzel M Hackeng¹⁵, Tomoyuki Okumura¹⁶, Keiichi Okano¹⁴, Masakazu Yamamoto⁸, Hiroki Yamaue⁹, Chigusa Morizane¹⁷, Koji Arihiro¹⁸, Toru Furukawa¹⁹, Toshiro Sato⁷, Tohru Kiyono²⁰, Lodewijk A A Brosens¹⁵, Laura D Wood^{5

6}, Ralph H Hruban^{5

6}, Tatsuhiro Shibata^{4

21}

Affiliations

¹ Department of Cancer Genome Informatics, Graduate School of Medicine, Osaka University, Osaka, Japan.
² Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI), Osaka University, Osaka, Japan.
³ Division of Genomic Medicine, National Cancer Center Research Institute, Tokyo, Japan.
⁴ Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan.
⁵ Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland.
⁶ Sol Goldman Pancreatic Cancer Research Center, Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, Maryland.
⁷ Department of Organoid Medicine, Keio University School of Medicine, Tokyo, Japan.
⁸ Department of Surgery, Institute of Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan.
⁹ Second Department of Surgery, Wakayama Medical University, Wakayama, Japan.
¹⁰ Department of Bioinformatics, National Cancer Center Research Institute, Tokyo, Japan.
¹¹ Department of Diagnostic Pathology, National Cancer Center Hospital, Tokyo, Japan.
¹² Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Chiba, Japan.
¹³ Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Aichi, Japan.
¹⁴ Department of Gastroenterological Surgery, Faculty of Medicine, Kagawa University, Kagawa, Japan.
¹⁵ Department of Pathology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
¹⁶ Department of Surgery and Science, Faculty of Medicine, Academic Assembly, University of Toyama, Toyama, Japan.
¹⁷ Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan.
¹⁸ Department of Anatomical Pathology, Hiroshima University Hospital, Hiroshima, Japan.
¹⁹ Department of Investigative Pathology, Tohoku University Graduate School of Medicine, Miyagi, Japan.
²⁰ Project for Prevention of HPV-Related Cancer, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Chiba, Japan.
²¹ Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.

^# Contributed equally.

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. This article is highlighted in the In This Issue feature, p. 587.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Carcinoma, Neuroendocrine* / genetics
Exome
Exome Sequencing
Humans
Infant, Newborn
Neuroendocrine Tumors* / genetics
Neuroendocrine Tumors* / pathology
Pancreas / pathology

Abstract

Publication types

MeSH terms

Grants and funding