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Gut 胃腺癌腹膜转移的多重分析确定了预测治疗反应的新靶点和分子亚型。

影响因子：31.793 DOI：10.1136/gutjnl-2018-318070

作者： Wang R,Song S,Harada K,Ghazanfari Amlashi F,Badgwell B,Pizzi MP,Xu Y,Zhao W,Dong X,Jin J,Wang Y,Scott A,Ma L,Huo L,Vicente D,Blum Murphy M,Shanbhag N,Tatlonghari G,Thomas I,Rogers J,Kobayashi M,Vykoukal J,Estrella JS,Roy-Chowdhuri S,Han G,Zhang S,Mao X,Song X,Zhang J,Gu J,Johnson RL,Calin GA,Peng G,Lee JS,Hanash SM,Futreal A,Wang Z,Wang L,Ajani JA 发表时间：2020-07-10 10:03:24

from：《GUT》

keywords： Wang RSong SHarada KGhazanfari Amlashi FBadgwell BPizzi MPXu YZhao WDong XJin JWang YScott AMa LHuo LVicente DBlum Murphy MShanbhag NTatlonghari GThomas IRogers JKobayashi MVykoukal JEstrella JSRoy-Chowdhuri SHan GZhang SMao XSong XZhang JGu JJohnson RLCalin GAPeng GLee JSHanash SMFutreal AWang ZWang LAjani JA

关键词：癌症遗传学胃癌胃肠道癌症基因表达突变

Abstract

OBJECTIVE:Peritoneal carcinomatosis (PC) occurs frequently in patients with gastric adenocarcinoma (GAC) and confers a poor prognosis. Multiplex profiling of primary GACs has been insightful but the underpinnings of PC's development/progression remain largely unknown. We characterised exome/transcriptome/immune landscapes of PC cells from patients with GAC aiming to identify novel therapeutic targets. DESIGN:We performed whole-exome sequencing (WES) and whole transcriptome sequencing (RNA-seq) on 44 PC specimens (43 patients with PC) including an integrative analysis of WES, RNA-seq, immune profile, clinical and pathological phenotypes to dissect the molecular pathogenesis, identifying actionable targets and/or biomarkers and comparison with TCGA primary GACs. RESULTS:We identified distinct alterations in PC versus primary GACs, such as more frequent CDH1 and TAF1 mutations, 6q loss and chr19 gain. Alterations associated with aggressive PC phenotypes emerged with increased mutations in TP53, CDH1, TAF1 and KMT2C, higher level of 'clock-like' mutational signature, increase in whole-genome doublings, chromosomal instability (particularly, copy number losses), reprogrammed microenvironment, enriched cell cycle pathways, MYC activation and impaired immune response. Integrated analysis identified two main molecular subtypes: 'mesenchymal-like' and 'epithelial-like' with discriminating response to chemotherapy (31% vs 71%). Patients with the less responsive 'mesenchymal-like' subtype had high expression of immune checkpoint T-Cell Immunoglobulin And Mucin Domain-Containing Protein 3 (TIM-3), its ligand galectin-9, V-domain Ig suppressor of T cell activation (VISTA) and transforming growth factor-β as potential therapeutic immune targets. CONCLUSIONS:We have uncovered the unique mutational landscape, copy number alteration and gene expression profile of PC cells and defined PC molecular subtypes, which correlated with PC therapy resistance/response. Novel targets and immune checkpoint proteins have been identified with a potential to be translated into clinics.

摘要

目的: 胃腺癌 (GAC) 患者常发生腹膜癌病 (PC)，预后较差。原发性GACs的多重分析具有洞察力，但PC的发展/进展的基础在很大程度上仍然未知。我们表征了GAC患者PC细胞的外显子组/转录组/免疫景观，旨在确定新的治疗靶点。设计: 我们对 44 例PC标本 (43 例PC患者) 进行了全外显子组测序 (WES) 和全转录组测序 (RNA-seq)，包括WES的整合分析，RNA-seq、免疫谱、临床和病理表型分析分子发病机制，确定可操作的靶点和/或生物标志物，并与TCGA原发性GACs进行比较。结果: 我们发现了PC与原发性GACs的明显改变，如更频繁的CDH1 和TAF1 突变、 6q丢失和chr19 增益。与侵袭性PC表型相关的改变随着TP53 、CDH1 、TAF1 和KMT2C突变的增加而出现，更高水平的 “时钟样” 突变标记，全基因组倍增增加，染色体不稳定 (特别是拷贝数丢失) 、重编程微环境、丰富的细胞周期通路、MYC激活和免疫应答受损。综合分析确定了两种主要的分子亚型: '间质样' 和 '上皮样'，对化疗有区分反应 (31% vs 71%)。Pa t ien t s wi t h t he反应迟钝的 '间充质样' 子t型高表达免疫抑制蛋白t T细胞免疫球蛋白和黏蛋白结构域t-Con t ining Pro t ein 3 (T IM-3)，i t s配体galec t in-9，T细胞的V结构域Ig抑制因子ac t iva t离子 (VIS T A) 和t ransforming生长t h fac t或-β 为po t en t al t herapeu t ic免疫t arge t s。结论: 我们揭示了PC细胞独特的突变景观、拷贝数改变和基因表达谱，并确定了与PC治疗抵抗/反应相关的PC分子亚型。新的靶点和免疫检查点蛋白已经被确定，有可能被翻译成诊所。

期刊介绍

《GUT》 (点击进入期刊详情)

英文简介 : Gut, a leading international journal in gastroenterology has an established reputation for publishing first class clinical research of the alimentary tract, the liver, biliary tree and pancreas.

中文简介 : （来自Google、百度翻译）《肠道》是国际领先的胃肠病学杂志，以发表消化道、肝脏、胆道和胰腺的一流临床研究而享有盛誉。

CIRCULATION RESEARCH 期刊中科院评价数据

新中科院分区

大类(学科)	小类(学科)	学科排名
医学	GASTROENTEROLOGY & HEPATOLOGY (胃肠肝病学)	3/80

新发布的期刊年发文量

年度总发文量	年度论文发表量	年度综述发表量
195	188	7

总被引频次 :43400

特征因子 : 0.068140

影响因子趋势图

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