Comprehensive Genomic Profiling of Neuroendocrine Carcinomas of the Gastrointestinal System

Shinichi Yachida(Osaka City University), Yasushi Totoki(National Cancer Research Institute), Michaël Noë(Johns Hopkins University), Yoichiro Nakatani(Osaka City University), Masafumi Horie(Osaka City University), Kenta Kawasaki(Keio University), Hiromi Nakamura(National Cancer Research Institute), Mihoko Saito-Adachi(National Cancer Research Institute), Masami Suzuki(Osaka City University), Erina Takai(Osaka City University), Natsuko Hama(National Cancer Research Institute), Ryota Higuchi(Tokyo Women's Medical University), Seiko Hirono(Wakayama Medical University), Satoshi Shiba(National Cancer Research Institute), Mamoru Kato(National Cancer Research Institute), Eisaku Furukawa(National Cancer Research Institute), Yasuhito Arai(National Cancer Research Institute), Hirofumi Rokutan(National Cancer Research Institute), Taiki Hashimoto(National Cancer Centre Japan), Shuichi Mitsunaga(National Cancer Center Hospital East), Mitsuro Kanda(Nagoya University), Hidenori Tanaka(Osaka City University), So Takata(Osaka City University), Ayaka Shimomura(Kagawa University), Minoru Oshima(Kagawa University), Wenzel M. Hackeng(Utrecht University), Tomoyuki Okumura(University of Toyama), Keiichi Okano(Kagawa University), Masakazu Yamamoto(Tokyo Women's Medical University), Hiroki Yamaue(Wakayama Medical University), Chigusa Morizane(National Cancer Centre Japan), Koji Arihiro(Hiroshima University Hospital), Toru Furukawa(Tohoku University), Toshiro Sato(Keio University), Tohru Kiyono(Chiba Cancer Center), Lodewijk A.A. Brosens(Utrecht University), Laura D. Wood(Johns Hopkins University), Ralph H. Hruban(Johns Hopkins University), Tatsuhiro Shibata(National Cancer Research Institute), Pathologie Groep Brosens, Cancer, Pathologie Pathologen staf
Utrecht University Repository (Utrecht University)
March 1, 2022
Cited by 116Open Access
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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.

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