Multiplex profiling of peritoneal metastases from gastric adenocarcinoma identified novel targets and molecular subtypes that predict treatment response
Multiplex profiling of peritoneal metastases from gastric adenocarcinoma identified novel targets and molecular subtypes that predict treatment response
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DOI：
10.1136/gutjnl-2018-318070
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发表时间：
2020-01-01
期刊：
影响因子：
24.5
通讯作者：
Ajani, Jaffer A.
中科院分区：
文献类型：
--
作者：
Wang, Ruiping;Song, Shumei;Ajani, Jaffer A.
目的探讨腹膜癌病（PC）在胃腺癌（GAC）患者中的发生及预后。原发性GACs的多重分析已经很有见地，但PC发展/进展的基础仍然很大程度上未知。我们对来自GAC患者的PC细胞的外显子组/转录组/免疫景观进行了表征，旨在确定新的治疗靶点。设计我们对44个PC标本进行了全外显子组测序（WES）和全转录组测序（RNA-seq）（43例PC患者），包括WES、RNA-seq、免疫谱、临床和病理表型的综合分析，以剖析分子发病机制，结果我们鉴定了PC与原发性GACs的不同改变，例如更频繁的CDH 1和TAF 1突变，6 q丢失和chr 19增加。与侵袭性PC表型相关的改变伴随着TP 53、CDH 1、TAF 1和KMT 2C中突变的增加、更高水平的“时钟样”突变特征、全基因组双链增加、染色体不稳定性（特别是拷贝数损失）、重编程微环境、丰富的细胞周期途径、MYC活化和受损的免疫应答而出现。综合分析确定了两种主要的分子亚型：“间充质样”和“上皮样”，对化疗有区别的反应（31%对71%）。具有较低反应性的“间充质样”亚型的患者具有高表达的免疫检查点T细胞免疫调节蛋白和含粘蛋白结构域蛋白3（TIM-3）、其配体半乳糖凝集素9、T细胞活化的V结构域Ig抑制因子（VISTA）和转化生长因子β作为潜在的治疗免疫靶点。PC细胞的拷贝数改变和基因表达谱以及定义的PC分子亚型，其与PC治疗抵抗/应答相关。新的靶点和免疫检查点蛋白已被确定，有可能被转化为临床。
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 lg suppressor of T cell activation (VISTA) and transforming growth factor-beta 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.