Department of Cancer Genome Informatics, Graduate School of Medicine, Osaka University, Osaka, Japan.
Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI), Osaka University, Osaka, Japan.
Cancer Discov. 2022 Mar 1;12(3):692-711. doi: 10.1158/2159-8290.CD-21-0669.
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.
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.
胃肠道系统的神经内分泌癌（GIS-NEC）是一种罕见但高度恶性的肿瘤。我们通过全基因组/外显子测序、转录组测序、DNA 甲基化检测和/或 ATAC-seq 分析了 115 例病例，发现 GIS-NEC 与同一部位的神经内分泌肿瘤（GIS-NET）在遗传上是不同的。胰腺神经内分泌癌（Panc-NEC）和非胰腺 GIS-NEC（Nonpanc-NEC）之间也存在明显的基因组差异。基于基因组特征，Panc-NEC 可分为两个亚组（即“导管型”和“腺泡型”）。TP53 和 RB1 的改变在 GIS-NEC 中很常见，大多数 RB1 完整的 Nonpanc-NEC 表现为 CCNE1 或 MYC 的相互排斥扩增。Notch 基因家族的改变是 Nonpanc-NEC 的特征。神经内分泌分化的转录因子，特别是 SOX2 基因，由于启动子区域的高度甲基化，在大多数 GIS-NEC 中过度表达。这项关于 GIS-NEC 基因组改变的综合研究揭示了导致这种非常致命形式的癌症发生的几个关键生物学过程。
GIS-NEC 与 GIS-NET 在遗传学上是不同的。不同器官中发生的 GIS-NEC 具有相似的组织病理学特征，并具有一些共同的基因组特征，但 Panc-NEC 和 Nonpanc-NEC 之间存在相当大的差异。此外，基于基因组和表观基因组特征，Panc-NEC 可分为两个亚组（即“导管型”和“腺泡型”）。本文在本期的特色文章中进行了重点介绍，第 587 页。
Zotero 插件
