Tong Zhou, Wang Lin, Shi Weiwei, Zeng Yanwu, Zhang Hangyu, Liu Lulu, Zheng Yi, Chen Chunlei, Xia Weiliang, Fang Weijia, Zhao Peng
Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Front Med (Lausanne). 2021 May 5;8:620988. doi: 10.3389/fmed.2021.620988. eCollection 2021.
Data on inter-tumoral heterogeneity and clonal evolution of pancreatic neuroendocrine neoplasms (panNENs) with liver metastasis are limited. The aim of this study was to explore different patterns of clonal evolution of pancreatic neuroendocrine neoplasms with liver metastasis and the possible distinctive signaling pathways involved between G2 neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs). Tumor tissues of five patients (10 samples) with pancreatic neuroendocrine neoplasms with synchronous liver metastasis were analyzed using next-generation sequencing. PyClone, Gene Ontology, and Reactome pathway enrichment analysis were also applied. Mutated genes varied in individuals, reflecting the inter-tumoral heterogeneity of panNENs. The distribution of subclones varied during tumor metastasis, and different clonal evolution patterns were revealed between NETs and NECs. Gene Ontology and Reactome analyses revealed that in both NETs and NECs, signaling pathways and biological processes shared similarities and differences in the primary and metastatic lesions. In addition, the signaling pathway features were different between NETs and NECs. In the primary lesions, epigenetic changes and post-transcriptional modifications participated in NETs, while FGFR signaling, EGFR signaling, and NTRK2 signaling were largely involved in NECs. Although DNA repair and TP53 regulation were both involved in the metastatic lesions, most of the signaling pathways and biological processes disrupted by the mutated genes were different. Our study revealed spatial inter-tumoral heterogeneity and temporal clonal evolution in PanNENs, providing potential therapeutic targets for further prospective clinical trials.
关于伴有肝转移的胰腺神经内分泌肿瘤（panNENs）的肿瘤间异质性和克隆进化的数据有限。本研究的目的是探索伴有肝转移的胰腺神经内分泌肿瘤的不同克隆进化模式，以及G2神经内分泌肿瘤（NETs）和神经内分泌癌（NECs）之间可能涉及的独特信号通路。使用二代测序分析了5例伴有同步肝转移的胰腺神经内分泌肿瘤患者的肿瘤组织（10个样本）。还应用了PyClone、基因本体论和Reactome通路富集分析。个体中突变基因各不相同，反映了panNENs的肿瘤间异质性。亚克隆的分布在肿瘤转移过程中有所变化，并且在NETs和NECs之间揭示了不同的克隆进化模式。基因本体论和Reactome分析表明，在NETs和NECs中，原发灶和转移灶中的信号通路和生物学过程既有相似之处也有不同之处。此外，NETs和NECs之间的信号通路特征也不同。在原发灶中，表观遗传变化和转录后修饰参与了NETs，而FGFR信号、EGFR信号和NTRK2信号在NECs中大量涉及。虽然DNA修复和TP53调节都参与了转移灶，但大多数被突变基因破坏的信号通路和生物学过程是不同的。我们的研究揭示了panNENs中的空间肿瘤间异质性和时间克隆进化，为进一步的前瞻性临床试验提供了潜在的治疗靶点。
