Zhou Lulin, Niu Zubiao, Wang Yuqi, Zheng You, Zhu Yichao, Wang Chenxi, Gao Xiaoyan, Gao Lihua, Zhang Wen, Zhang Kaitai, Melino Gerry, Huang Hongyan, Wang Xiaoning, Sun Qiang
School of Medicine, Nankai University, 94 Weijin Road, Tianjin, 300071, China.
Institute of Biotechnology, Research Unit of Cell Death Mechanism, Chinese Academy of Medical Sciences, 20 Dongda Street, Beijing, 100071, China.
Cell Death Discov. 2022 Jan 10;8(1):13. doi: 10.1038/s41420-021-00769-6.
Senescence is believed to be a pivotal player in the onset and progression of tumors as well as cancer therapy. However, the guiding roles of senescence in clinical outcomes and therapy selection for patients with cancer remain obscure, largely due to the absence of a feasible senescence signature. Here, by integrative analysis of single cell and bulk transcriptome data from multiple datasets of gastric cancer patients, we uncovered senescence as a veiled tumor feature characterized by senescence gene signature enriched, unexpectedly, in the noncancerous cells, and further identified two distinct senescence-associated subtypes based on the unsupervised clustering. Patients with the senescence subtype had higher tumor mutation loads and better prognosis as compared with the aggressive subtype. By the machine learning, we constructed a scoring system termed as senescore based on six signature genes: ADH1B, IL1A, SERPINE1, SPARC, EZH2, and TNFAIP2. Higher senescore demonstrated robustly predictive capability for longer overall and recurrence-free survival in 2290 gastric cancer samples, which was independently validated by the multiplex staining analysis of gastric cancer samples on the tissue microarray. Remarkably, the senescore signature served as a reliable predictor of chemotherapeutic and immunotherapeutic efficacies, with high-senescore patients benefited from immunotherapy, while low-senescore patients were responsive to chemotherapy. Collectively, we report senescence as a heretofore unrecognized hallmark of gastric cancer that impacts patient outcomes and therapeutic efficacy.
衰老被认为是肿瘤发生、发展以及癌症治疗中的关键因素。然而，衰老在癌症患者临床结局和治疗选择中的指导作用仍不明确，这主要是由于缺乏可行的衰老特征。在此，通过对来自多个胃癌患者数据集的单细胞和批量转录组数据进行综合分析，我们发现衰老作为一种隐藏的肿瘤特征，其特征是衰老基因特征在非癌细胞中意外富集，并基于无监督聚类进一步确定了两种不同的衰老相关亚型。与侵袭性亚型相比，衰老亚型的患者具有更高的肿瘤突变负荷和更好的预后。通过机器学习，我们基于六个特征基因：ADH1B、IL1A、SERPINE1、SPARC、EZH2和TNFAIP2构建了一个名为senescore的评分系统。较高的senescore对2290例胃癌样本的总生存期和无复发生存期具有强大的预测能力，这在组织芯片上的胃癌样本多重染色分析中得到了独立验证。值得注意的是，senescore特征可作为化疗和免疫治疗疗效的可靠预测指标，高senescore的患者从免疫治疗中获益，而低senescore的患者对化疗有反应。总的来说，我们报告衰老作为一种迄今为止未被认识的胃癌特征，它影响患者的预后和治疗效果。
