Multi-omic profiling of peritoneal metastases in gastric cancer identifies molecular subtypes and therapeutic vulnerabilities
Multi-omic profiling of peritoneal metastases in gastric cancer identifies molecular subtypes and therapeutic vulnerabilities
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DOI：
10.1038/s43018-021-00240-6
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发表时间：
2021-08-16
期刊：
影响因子：
22.7
通讯作者：
Mano, Hiroyuki
中科院分区：
文献类型：
--
作者：
Tanaka, Yosuke;Chiwaki, Fumiko;Mano, Hiroyuki
腹膜转移是无法治愈的进展期胃癌（GC）的标志，目前尚无根治性治疗方法，其分子特征尚未得到广泛研究。在这里，我们提出了一个全面的多组学分析的恶性腹水样本和相应的肿瘤细胞系从98例，包括全基因组测序，RNA测序，DNA甲基化和增强子景观。我们发现，与原发性GC相比，受体酪氨酸激酶和丝裂原活化蛋白激酶途径的改变频率更高;此外，大约一半的基因改变可能通过靶向治疗进行治疗。我们的分析还将腹水播散型胃癌分为两种不同的分子亚型：一种在ELF 3、KLF 5和EHF基因座处显示活性超级增强子（SE），另一种亚型通过SMAD 3 SE激活和转录增强子因子TEF-1（TEAD 1）的高表达携带转化生长因子-β（TGF-β）途径激活。在TGF-β亚型中，抑制TEAD通路可以避免治疗耐药性，这表明这种亚型的难治性GC.Tanaka及其同事对胃癌腹膜转移进行了全面的多组学表征，以确定分子亚型和可行的治疗靶点。
Peritoneal metastasis, a hallmark of incurable advanced gastric cancer (GC), presently has no curative therapy and its molecular features have not been examined extensively. Here we present a comprehensive multi-omic analysis of malignant ascitic fluid samples and their corresponding tumor cell lines from 98 patients, including whole-genome sequencing, RNA sequencing, DNA methylation and enhancer landscape. We identify a higher frequency of receptor tyrosine kinase and mitogen-activated protein kinase pathway alterations compared to primary GC; moreover, approximately half of the gene alterations are potentially treatable with targeted therapy. Our analyses also stratify ascites-disseminated GC into two distinct molecular subtypes: one displaying active super enhancers (SEs) at the ELF3, KLF5 and EHF loci, and a second subtype bearing transforming growth factor-beta (TGF-beta) pathway activation through SMAD3 SE activation and high expression of transcriptional enhancer factor TEF-1 (TEAD1). In the TGF-beta subtype, inhibition of the TEAD pathway circumvents therapy resistance, suggesting a potential molecular-guided therapeutic strategy for this subtype of intractable GC.Tanaka and colleagues perform a comprehensive multi-omic characterization of peritoneal metastasis of gastric cancer to define molecular subtypes and actionable therapeutic targets.