Epigenetically regulated gene expression profiles decipher four molecular subtypes with prognostic and therapeutic implications in gastric cancer.

IF 5.7 2区 医学 Q1 Medicine
Siyuan Weng, Minghao Li, Jinhai Deng, Hui Xu, Yuqing Ren, Zhaokai Zhou, Libo Wang, Yuyuan Zhang, Zhe Xing, Lifeng Li, Zaoqu Liu, Xinwei Han
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Abstract

Background: Gastric cancer (GC) is one of the most common malignant tumors of the digestive tract which seriously endangers the health of human beings worldwide. Transcriptomic deregulation by epigenetic mechanisms plays a crucial role in the heterogeneous progression of GC. This study aimed to investigate the impact of epigenetically regulated genes on the prognosis, immune microenvironment, and potential treatment of GC.

Results: Under the premise of verifying significant co-regulation of the aberrant frequencies of microRNA (miRNA) correlated (MIRcor) genes and DNA methylation-correlated (METcor) genes. Four GC molecular subtypes were identified and validated by comprehensive clustering of MIRcor and METcor GEPs in 1521 samples from five independent multicenter GC cohorts: cluster 1 was characterized by up-regulated cell proliferation and transformation pathways, with good prognosis outcomes, driven by mutations, and was sensitive to 5-fluorouracil and paclitaxel; cluster 2 performed moderate prognosis and benefited more from apatinib and cisplatin; cluster 3 was featured by an up-regulated ligand-receptor formation-related pathways, poor prognosis, an immunosuppression phenotype with low tumor purity, resistant to chemotherapy (e.g., 5-fluorouracil, paclitaxel, and cisplatin), and targeted therapy drug (apatinib) and sensitive to dasatinib; cluster 4 was characterized as an immune-activating phenotype, with advanced tumor stages, benefit more from immunotherapy and displayed worst prognosis.

Conclusions: According to the epigenetically regulated GEPs, we developed four robust GC molecular subtypes, which facilitated the understanding of the epigenetic mechanisms underlying GC heterogeneity, offering an optimized decision-making and surveillance platform for GC patients.

表观遗传调控的基因表达谱破译四种分子亚型与胃癌的预后和治疗意义。
背景:胃癌是消化道最常见的恶性肿瘤之一,严重危害人类健康。表观遗传机制的转录组失调在GC的异质性进展中起着至关重要的作用。本研究旨在探讨表观遗传调控基因对胃癌预后、免疫微环境和潜在治疗的影响。结果:在验证microRNA (miRNA)相关基因(MIRcor)和DNA甲基化相关基因(METcor)异常频率显著共调控的前提下。通过对来自5个独立多中心GC队列的1521个样本进行MIRcor和METcor GEPs的综合聚类,鉴定并验证了4种GC分子亚型:聚类1的特点是细胞增殖和转化途径上调,受突变驱动,预后良好,对5-氟尿嘧啶和紫杉醇敏感;第2组预后中等,从阿帕替尼和顺铂中获益较多;集群3的特点是配体受体形成相关通路上调,预后差,肿瘤纯度低,免疫抑制表型,对化疗(如5-氟尿嘧啶、紫杉醇、顺铂)耐药,对靶向治疗药物(阿帕替尼)敏感,对达沙替尼敏感;集群4的特征是免疫激活表型,肿瘤分期晚期,免疫治疗获益更多,预后最差。结论:根据表观遗传调控的GEPs,我们开发了四种强大的GC分子亚型,促进了对GC异质性的表观遗传机制的理解,为GC患者提供了优化的决策和监测平台。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Clinical Epigenetics
Clinical Epigenetics Biochemistry, Genetics and Molecular Biology-Developmental Biology
CiteScore
8.90
自引率
5.30%
发文量
150
审稿时长
12 weeks
期刊介绍: Clinical Epigenetics, the official journal of the Clinical Epigenetics Society, is an open access, peer-reviewed journal that encompasses all aspects of epigenetic principles and mechanisms in relation to human disease, diagnosis and therapy. Clinical trials and research in disease model organisms are particularly welcome.
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