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

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

医化学

研究成果: Article › 査読

66 被引用数 (Scopus)

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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.

本文言語	English
ページ（範囲）	692-711
ページ数	20
ジャーナル	Cancer Discovery
巻	12
号	3
DOI	https://doi.org/10.1158/2159-8290.CD-21-0669
出版ステータス	Published - 2022 3月 1

ASJC Scopus subject areas

腫瘍学

UN SDG

この成果は、次の持続可能な開発目標に貢献しています

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10.1158/2159-8290.CD-21-0669

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Yachida, S., Totoki, Y., Noë, 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

Yachida, S, Totoki, Y, Noë, 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

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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.",

author = "Shinichi Yachida and Yasushi Totoki and Micha{\"e}l No{\"e} 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",

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AU - Yachida, Shinichi

AU - Totoki, Yasushi

AU - Noë, Michaël

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

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.

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.

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Comprehensive Genomic Profiling of Neuroendocrine Carcinomas of the Gastrointestinal System

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