Comprehensive Genomic Profiling of Neuroendocrine Carcinomas of the Gastrointestinal System-Reference-Cited by-同舟云学术

Comprehensive Genomic Profiling of Neuroendocrine Carcinomas of the Gastrointestinal System

Published:2022-03-01 Issue:3 Volume:12 Page:692-711
ISSN:2159-8274
Container-title:Cancer Discovery
language:en
Short-container-title:

Author:

Yachida Shinichi¹²³^ORCID,Totoki Yasushi⁴^ORCID,Noë Michaël⁵⁶,Nakatani Yoichiro¹^ORCID,Horie Masafumi¹,Kawasaki Kenta⁷,Nakamura Hiromi⁴,Saito-Adachi Mihoko⁴^ORCID,Suzuki Masami¹,Takai Erina¹,Hama Natsuko⁴,Higuchi Ryota⁸,Hirono Seiko⁹,Shiba Satoshi⁴^ORCID,Kato Mamoru¹⁰,Furukawa Eisaku¹⁰,Arai Yasuhito⁴,Rokutan Hirofumi⁴,Hashimoto Taiki¹¹^ORCID,Mitsunaga Shuichi¹²,Kanda Mitsuro¹³^ORCID,Tanaka Hidenori¹^ORCID,Takata So¹^ORCID,Shimomura Ayaka¹⁴,Oshima Minoru¹⁴^ORCID,Hackeng Wenzel M.¹⁵,Okumura Tomoyuki¹⁶,Okano Keiichi¹⁴,Yamamoto Masakazu⁸,Yamaue Hiroki⁹,Morizane Chigusa¹⁷,Arihiro Koji¹⁸,Furukawa Toru¹⁹^ORCID,Sato Toshiro⁷^ORCID,Kiyono Tohru²⁰^ORCID,Brosens Lodewijk A.A.¹⁵^ORCID,Wood Laura D.⁵⁶,Hruban Ralph H.⁵⁶^ORCID,Shibata Tatsuhiro⁴²¹

Affiliation:

1. 1Department of Cancer Genome Informatics, Graduate School of Medicine, Osaka University, Osaka, Japan.

2. 2Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI), Osaka University, Osaka, Japan.

3. 3Division of Genomic Medicine, National Cancer Center Research Institute, Tokyo, Japan.

4. 4Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan.

5. 5Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland.

6. 6Sol Goldman Pancreatic Cancer Research Center, Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, Maryland.

7. 7Department of Organoid Medicine, Keio University School of Medicine, Tokyo, Japan.

8. 8Department of Surgery, Institute of Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan.

9. 9Second Department of Surgery, Wakayama Medical University, Wakayama, Japan.

10. 10Department of Bioinformatics, National Cancer Center Research Institute, Tokyo, Japan.

11. 11Department of Diagnostic Pathology, National Cancer Center Hospital, Tokyo, Japan.

12. 12Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Chiba, Japan.

13. 13Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Aichi, Japan.

14. 14Department of Gastroenterological Surgery, Faculty of Medicine, Kagawa University, Kagawa, Japan.

15. 15Department of Pathology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.

16. 16Department of Surgery and Science, Faculty of Medicine, Academic Assembly, University of Toyama, Toyama, Japan.

17. 17Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan.

18. 18Department of Anatomical Pathology, Hiroshima University Hospital, Hiroshima, Japan.

19. 19Department of Investigative Pathology, Tohoku University Graduate School of Medicine, Miyagi, Japan.

20. 20Project for Prevention of HPV-Related Cancer, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Chiba, Japan.

21. 21Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.

Abstract

AbstractThe 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

Funder

AMED

Cancer Research and Therapeutic Evolution

Publisher

American Association for Cancer Research (AACR)

Link

https://aacrjournals.org/cancerdiscovery/article-pdf/12/3/692/3199833/692.pdf

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