Molecular classification reveals the diverse genetic and prognostic features of gastric cancer: A multi-omics consensus ensemble clustering
Molecular classification reveals the diverse genetic and prognostic features of gastric cancer: A multi-omics consensus ensemble clustering
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DOI：
10.1016/j.biopha.2021.112222
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发表时间：
2021-10-01
影响因子：
7.5
通讯作者：
Chen, Wei
中科院分区：
文献类型：
--
作者：
Hu, Xianyu;Wang, Zhenglin;Chen, Wei
背景：在全球范围内，胃癌（GC）是第五大常见肿瘤。有必要确定新的分子亚型，以指导患者选择特定的靶向治疗益处。方法：使用多组学数据，包括转录组学rna测序（mRNA、LncRNA、miRNA）、DNA甲基化和基因突变在TCGA-STAD队列中进行聚类。使用r中的“MOVICS”软件包执行10种经典聚类算法来识别具有不同分子特征的患者。使用单样本基因集富集分析来评估激活的信号通路。比较了基因突变、拷贝数改变和肿瘤突变负担的差异分布，并评估了免疫治疗和化疗的潜在反应。结果：10种聚类算法均能识别出CS1和CS2两种分子亚型。与CS2组相比，CS1组患者的平均总生存时间（28.5个月对68.9个月，P = 0.016）和无进展生存时间（19.0个月对63.9个月，P = 0.008）较短。CS1组细胞外相关生物过程活化程度较高，而CS2组细胞周期相关通路活化程度增强。在CS2组中观察到明显更高的总突变数和新抗原，以及TTN、MUC16和ARID1A的特异性突变。在CS2组中也观察到较高的免疫细胞浸润，反映了潜在的免疫治疗益处。此外，CS2组对5-氟尿嘧啶、顺铂和紫杉醇也有应答。在外部队列GSE62254、GSE26253、GSE15459和GSE84437中成功验证了CS1组和CS2组之间临床结果的相似多样性。结论：通过十种聚类算法对五组学数据进行综合分析，研究结果为GC亚型提供了新的见解。这些可以根据特定的分子特征提供潜在的临床治疗靶点。
Background: Globally, gastric cancer (GC) is the fifth most common tumor. It is necessary to identify novel molecular subtypes to guide patient selection for specific target therapeutic benefits. Methods: Multi-omics data, including transcriptomics RNA-sequencing (mRNA, LncRNA, miRNA), DNA methylation, and gene mutations in the TCGA-STAD cohort were used for the clustering. Ten classical clustering algorithms were executed to recognize patients with different molecular features using the "MOVICS" package in R. The activated signaling pathways were evaluated using the single-sample gene set enrichment analysis. The differential distribution of gene mutations, copy number alterations, and tumor mutation burden was compared, and potential responses to immunotherapy and chemotherapy were also assessed. Results: Two molecular subtypes (CS1 and CS2) were recognized by ten clustering algorithms with consensus ensembles. Patients in the CS1 group had a shorter average overall survival time (28.5 vs. 68.9 months, P = 0.016), and progression-free survival (19.0 vs. 63.9 months, P = 0.008) as compared to those in the CS2 group. Extracellular associated biological process activation was higher in the CS1 group, while the CS2 group displayed the enhanced activation of cell cycle-associated pathways. Significantly higher total mutation numbers and neoantigens were observed in the CS2 group, along with specific mutations in TTN, MUC16, and ARID1A. Higher infiltration of immunocytes was also observed in the CS2 group, reflective of the potential immunotherapeutic benefits. Moreover, the CS2 group could also respond to 5-fluorouracil, cisplatin, and paclitaxel. The similar diversity in clinical outcomes between CS1 and CS2 groups was successfully validated in the external cohorts, GSE62254, GSE26253, GSE15459, and GSE84437. Conclusion: The findings provided novel insights into the GC subtypes through integrative analysis of five -omics data by ten clustering algorithms. These could provide potential clinical therapeutic targets based on the specific molecular features.