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Multi-omic profiling of peritoneal metastases in gastric cancer identifies molecular subtypes and therapeutic vulnerabilities
Nature Cancer ( IF 22.7 ) Pub Date : 2021-08-16 , DOI: 10.1038/s43018-021-00240-6
Yosuke Tanaka 1 , Fumiko Chiwaki 2 , Shinya Kojima 1 , Masahito Kawazu 1 , Masayuki Komatsu 2 , Toshihide Ueno 1 , Satoshi Inoue 1 , Shigeki Sekine 3 , Keisuke Matsusaki 4 , Hiromichi Matsushita 5 , Narikazu Boku 6 , Yae Kanai 7 , Yasushi Yatabe 3 , Hiroki Sasaki 2 , Hiroyuki Mano 1
Affiliation  

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-β (TGF-β) pathway activation through SMAD3 SE activation and high expression of transcriptional enhancer factor TEF-1 (TEAD1). In the TGF-β subtype, inhibition of the TEAD pathway circumvents therapy resistance, suggesting a potential molecular-guided therapeutic strategy for this subtype of intractable GC.



中文翻译:

胃癌腹膜转移的多组学分析识别分子亚型和治疗脆弱性

腹膜转移是无法治愈的晚期胃癌 (GC) 的标志,目前尚无治愈性疗法,其分子特征尚未得到广泛研究。在这里,我们对来自 98 名患者的恶性腹水样本及其相应的肿瘤细胞系进行了全面的多组学分析,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改变的频率更高;此外,大约一半的基因改变可以通过靶向治疗进行治疗。我们的分析还将腹水播散的 GC 分为两种不同的分子亚型:一种在ELF3KLF5处显示活性超级增强剂 (SE)EHF基因座,以及第二个亚型,通过SMAD3 SE 激活和转录增强因子 TEF-1 (TEAD1) 的高表达来激活转化生长因子-β (TGF-β) 途径。在 TGF-β 亚型中,TEAD 通路的抑制可以规避治疗耐药性,这表明这种顽固性 GC 亚型的潜在分子指导治疗策略。

更新日期:2021-08-16
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