Proteogenomic Characterization Reveals Therapeutic Vulnerabilities in Lung Adenocarcinoma
Proteogenomic Characterization Reveals Therapeutic Vulnerabilities in Lung Adenocarcinoma
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DOI：
10.1016/j.cell.2020.06.013
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发表时间：
2020-07-09
期刊：
影响因子：
64.5
通讯作者：
Carr, Steven A.
中科院分区：
文献类型：
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作者：
Gillette, Michael A.;Satpathy, Shankha;Carr, Steven A.
为了探索肺腺癌（LUAD）的生物学并确定新的治疗机会，我们对110例肿瘤和101例匹配的正常邻近组织（NAT）进行了全面的蛋白质组学表征，包括基因组学，表观基因组学，深层次蛋白质组学，磷酸蛋白质组学和乙酰蛋白质组学。多组学聚类揭示了由关键驱动突变、国家和性别定义的四个亚组。蛋白质组学和磷酸化蛋白质组学数据阐明了拷贝数畸变、体细胞突变和融合的下游生物学，并确定了与涉及KRAS、EGFR和ALK的驱动事件相关的治疗漏洞。免疫分型揭示了一个复杂的景观，加强了STK11与免疫冷行为的关联，并强调了中性粒细胞脱粒的潜在免疫抑制作用。吸烟相关的LUAD表现出相关性与其他环境暴露的签名和现场效应在NAT。匹配的NAT允许鉴定具有潜在诊断和治疗效用的差异表达蛋白。该蛋白质组学数据集为寻求更好地了解和治疗肺腺癌的研究人员和临床医生提供了独特的公共资源。
To explore the biology of lung adenocarcinoma (LUAD) and identify new therapeutic opportunities, we performed comprehensive proteogenomic characterization of 110 tumors and 101 matched normal adjacent tissues (NATs) incorporating genomics, epigenomics, deep-scale proteomics, phosphoproteomics, and acetylproteomics. Multi-omics clustering revealed four subgroups defined by key driver mutations, country, and gender. Proteomic and phosphoproteomic data illuminated biology downstream of copy number aberrations, somatic mutations, and fusions and identified therapeutic vulnerabilities associated with driver events involving KRAS, EGFR, and ALK. Immune subtyping revealed a complex landscape, reinforced the association of STK11 with immune-cold behavior, and underscored a potential immunosuppressive role of neutrophil degranulation. Smoking-associated LUADs showed correlation with other environmental exposure signatures and a field effect in NATs. Matched NATs allowed identification of differentially expressed proteins with potential diagnostic and therapeutic utility. This proteogenomics dataset represents a unique public resource for researchers and clinicians seeking to better understand and treat lung adenocarcinomas.