Comprehensive Genomic Profiling of Neuroendocrine Carcinomas of the Gastrointestinal System

Shinichi Yachida; Yasushi Totoki; Michael Noe; 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

Shinichi Yachida
, Yasushi Totoki
, Michael Noe
, 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

Research output: Contribution to journal › Article › Academic › peer-review

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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.

Original language	English
Pages (from-to)	692-711
Number of pages	20
Journal	Cancer Discovery
Volume	12
Issue number	3
Early online date	8 Dec 2021
DOIs	https://doi.org/10.1158/2159-8290.CD-21-0669
Publication status	Published - 1 Mar 2022

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10.1158/2159-8290.CD-21-0669Licence: CC BY-NC-ND

692Final published version, 8.03 MBLicence: CC BY-NC-ND

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Yachida, S., Totoki, Y., Noe, M., Nakatani, Y., Horie, M., Kawasaki, K., Nakamura, H., Saito-Adachi, M., Suzuki, M., Takai, E., Hama, N., Higuchi, R., Hirono, S., Shiba, S., Kato, M., Furukawa, E., Arai, Y., Rokutan, H., Hashimoto, T., ... Shibata, T. (2022). Comprehensive Genomic Profiling of Neuroendocrine Carcinomas of the Gastrointestinal System. Cancer Discovery, 12(3), 692-711. https://doi.org/10.1158/2159-8290.CD-21-0669

@article{9628185cd7974714b62881d5b59e6b9f,

title = "Comprehensive Genomic Profiling of Neuroendocrine Carcinomas of the Gastrointestinal System",

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.",

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

note = "Funding Information: We thank all patients and their families who participated in this study, Y. Kawahara (Osaka University, Osaka, Japan), Y. Shimada (Kyoto University, Kyoto, Japan), J. Shibahara (Kyorin University, Tokyo, Japan), T. Sakatani (Nippon Medical School Hospital, Tokyo, Japan), T. Ushiku (The University of Tokyo, Tokyo, Japan), A. Fukagawa (National Cancer Center Research Institute, Tokyo, Japan) for expert advice, and E. Arakawa, K. Igarashi (National Cancer Center Research Institute, Tokyo, Japan), and M. Oda (Hiroshima University Hospital, Hiroshima, Japan) for expert technical assistance. This work was supported by grants from the National Cancer Center Research and Development Fund (29-A-6 to T. Shibata); Practical Research for Innovative Cancer Control from the Japan Agency for Medical Research and Development (AMED; JP21ck0106558 to S. Yachida; JP21ck0106693 to S. Yachida; JP21ck0106690 to S. Yachida, Y. Totoki, and T. Shibata; JP21ck0106547 to S. Yachida and T. Shibata; JP15ck0106138 and JP16ck0106138 to C. Morizane); Project for Cancer Research and Therapeutic Evolution (P-CREATE) from AMED (JP17cm0106612 to S. Yachida, Y. Totoki, and E. Takai); United States–Japan Cooperative Medical Science Program from AMED (JP20jk0210009 to S. Yachida, T. Kiyono, and T. Shibata); Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University (to S. Yachida); Joint Research Project of the Institute Medical Science, The University of Tokyo (to S. Yachida and T. Shibata); the Takeda Science Foundation (to S. Yachida); the Yasuda Medical Foundation (to S. Yachida); the Mitsubishi Foundation (to S. Yachida); and the Princess Takamatsu Cancer Research Fund (to S. Yachida). The National Cancer Center Research Biobank is supported by the National Cancer Center Research and Development Fund, Japan. Publisher Copyright: {\textcopyright} 2021 The Authors.",

year = "2022",

month = mar,

day = "1",

doi = "10.1158/2159-8290.CD-21-0669",

language = "English",

volume = "12",

pages = "692--711",

journal = "Cancer Discovery",

issn = "2159-8274",

publisher = "American Association for Cancer Research Inc.",

number = "3",

}

Yachida, S, Totoki, Y, Noe, M, Nakatani, Y, Horie, M, Kawasaki, K, Nakamura, H, Saito-Adachi, M, Suzuki, M, Takai, E, Hama, N, Higuchi, R, Hirono, S, Shiba, S, Kato, M, Furukawa, E, Arai, Y, Rokutan, H, Hashimoto, T, Mitsunaga, S, Kanda, M, Tanaka, H, Takata, S, Shimomura, A, Oshima, M, Hackeng, WM, Okumura, T, Okano, K, Yamamoto, M, Yamaue, H, Morizane, C, Arihiro, K, Furukawa, T, Sato, T, Kiyono, T, Brosens, LAA, Wood, LD, Hruban, RH & Shibata, T 2022, 'Comprehensive Genomic Profiling of Neuroendocrine Carcinomas of the Gastrointestinal System', Cancer Discovery, vol. 12, no. 3, pp. 692-711. https://doi.org/10.1158/2159-8290.CD-21-0669

TY - JOUR

T1 - Comprehensive Genomic Profiling of Neuroendocrine Carcinomas of the Gastrointestinal System

AU - Yachida, Shinichi

AU - Totoki, Yasushi

AU - Noe, Michael

AU - Nakatani, Yoichiro

AU - Horie, Masafumi

AU - Kawasaki, Kenta

AU - Nakamura, Hiromi

AU - Saito-Adachi, Mihoko

AU - Suzuki, Masami

AU - Takai, Erina

AU - Hama, Natsuko

AU - Higuchi, Ryota

AU - Hirono, Seiko

AU - Shiba, Satoshi

AU - Kato, Mamoru

AU - Furukawa, Eisaku

AU - Arai, Yasuhito

AU - Rokutan, Hirofumi

AU - Hashimoto, Taiki

AU - Mitsunaga, Shuichi

AU - Kanda, Mitsuro

AU - Tanaka, Hidenori

AU - Takata, So

AU - Shimomura, Ayaka

AU - Oshima, Minoru

AU - Hackeng, Wenzel M

AU - Okumura, Tomoyuki

AU - Okano, Keiichi

AU - Yamamoto, Masakazu

AU - Yamaue, Hiroki

AU - Morizane, Chigusa

AU - Arihiro, Koji

AU - Furukawa, Toru

AU - Sato, Toshiro

AU - Kiyono, Tohru

AU - Brosens, Lodewijk A A

AU - Wood, Laura D

AU - Hruban, Ralph H

AU - Shibata, Tatsuhiro

N1 - Funding Information: We thank all patients and their families who participated in this study, Y. Kawahara (Osaka University, Osaka, Japan), Y. Shimada (Kyoto University, Kyoto, Japan), J. Shibahara (Kyorin University, Tokyo, Japan), T. Sakatani (Nippon Medical School Hospital, Tokyo, Japan), T. Ushiku (The University of Tokyo, Tokyo, Japan), A. Fukagawa (National Cancer Center Research Institute, Tokyo, Japan) for expert advice, and E. Arakawa, K. Igarashi (National Cancer Center Research Institute, Tokyo, Japan), and M. Oda (Hiroshima University Hospital, Hiroshima, Japan) for expert technical assistance. This work was supported by grants from the National Cancer Center Research and Development Fund (29-A-6 to T. Shibata); Practical Research for Innovative Cancer Control from the Japan Agency for Medical Research and Development (AMED; JP21ck0106558 to S. Yachida; JP21ck0106693 to S. Yachida; JP21ck0106690 to S. Yachida, Y. Totoki, and T. Shibata; JP21ck0106547 to S. Yachida and T. Shibata; JP15ck0106138 and JP16ck0106138 to C. Morizane); Project for Cancer Research and Therapeutic Evolution (P-CREATE) from AMED (JP17cm0106612 to S. Yachida, Y. Totoki, and E. Takai); United States–Japan Cooperative Medical Science Program from AMED (JP20jk0210009 to S. Yachida, T. Kiyono, and T. Shibata); Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University (to S. Yachida); Joint Research Project of the Institute Medical Science, The University of Tokyo (to S. Yachida and T. Shibata); the Takeda Science Foundation (to S. Yachida); the Yasuda Medical Foundation (to S. Yachida); the Mitsubishi Foundation (to S. Yachida); and the Princess Takamatsu Cancer Research Fund (to S. Yachida). The National Cancer Center Research Biobank is supported by the National Cancer Center Research and Development Fund, Japan. Publisher Copyright: © 2021 The Authors.

PY - 2022/3/1

Y1 - 2022/3/1

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85125965862

U2 - 10.1158/2159-8290.CD-21-0669

DO - 10.1158/2159-8290.CD-21-0669

M3 - Article

C2 - 34880079

SN - 2159-8274

VL - 12

SP - 692

EP - 711

JO - Cancer Discovery

JF - Cancer Discovery

IS - 3

ER -

Comprehensive Genomic Profiling of Neuroendocrine Carcinomas of the Gastrointestinal System

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