TY - JOUR
T1 - Comprehensive Genomic Profiling of Neuroendocrine Carcinomas of the Gastrointestinal System
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
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.
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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U2 - 10.1158/2159-8290.CD-21-0669
DO - 10.1158/2159-8290.CD-21-0669
M3 - Article
C2 - 34880079
AN - SCOPUS:85125965862
SN - 2159-8274
VL - 12
SP - 692
EP - 711
JO - Cancer Discovery
JF - Cancer Discovery
IS - 3
ER -
