基于基因组与蛋白质组联合分析的肺腺癌治疗靶点研究
Proteogenomic Characterization Reveals Therapeutic Vulnerabilities in Lung Adenocarcinoma.
机构信息
Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, 02142, USA; Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Boston, MA, 02115, USA.
Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, 02142, USA.
出版信息
Cell. 2020 Jul 9;182(1):200-225.e35. doi: 10.1016/j.cell.2020.06.013.
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.
为了探索肺腺癌 (LUAD) 的生物学特性并寻找新的治疗机会，我们对 110 个肿瘤和 101 个匹配的正常相邻组织 (NAT) 进行了全面的蛋白质基因组学特征分析，整合了基因组学、表观基因组学、深度规模蛋白质组学、磷酸化蛋白质组学和乙酰化蛋白质组学。多组学聚类揭示了四个亚组，这些亚组由关键驱动突变、国家和性别定义。蛋白质组学和磷酸化蛋白质组学数据阐明了拷贝数异常、体细胞突变和融合下游的生物学特性，并确定了与涉及 KRAS、EGFR 和 ALK 的驱动事件相关的治疗弱点。免疫亚群分析揭示了一个复杂的景观，强化了 STK11 与免疫冷行为的关联，并强调了中性粒细胞脱颗粒的潜在免疫抑制作用。与吸烟相关的 LUAD 与其他环境暴露特征相关，并在 NAT 中表现出场效应。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。这个蛋白质基因组数据集代表了一个独特的公共资源，供寻求更好地理解和治疗肺腺癌的研究人员和临床医生使用。
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