Proteogenomic Characterization Reveals Therapeutic Vulnerabilities in Lung Adenocarcinoma.,Cell

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Proteogenomic Characterization Reveals Therapeutic Vulnerabilities in Lung Adenocarcinoma.
Cell ( IF 45.5 ) Pub Date : 2020-07-09 , DOI: 10.1016/j.cell.2020.06.013
Michael A Gillette ₁ , Shankha Satpathy ₂ , Song Cao ₃ , Saravana M Dhanasekaran ₄ , Suhas V Vasaikar ₅ , Karsten Krug ₂ , Francesca Petralia ₆ , Yize Li ₃ , Wen-Wei Liang ₃ , Boris Reva ₆ , Azra Krek ₆ , Jiayi Ji ₇ , Xiaoyu Song ₇ , Wenke Liu ₈ , Runyu Hong ₈ , Lijun Yao ₃ , Lili Blumenberg ₉ , Sara R Savage ₁₀ , Michael C Wendl ₃ , Bo Wen ₁₀ , Kai Li ₁₀ , Lauren C Tang ₁₁ , Melanie A MacMullan ₁₂ , Shayan C Avanessian ₂ , M Harry Kane ₂ , Chelsea J Newton ₁₃ , MacIntosh Cornwell ₉ , Ramani B Kothadia ₂ , Weiping Ma ₆ , Seungyeul Yoo ₆ , Rahul Mannan ₄ , Pankaj Vats ₄ , Chandan Kumar-Sinha ₄ , Emily A Kawaler ₈ , Tatiana Omelchenko ₁₄ , Antonio Colaprico ₁₅ , Yifat Geffen ₂ , Yosef E Maruvka ₂ , Felipe da Veiga Leprevost ₄ , Maciej Wiznerowicz ₁₆ , Zeynep H Gümüş ₆ , Rajwanth R Veluswamy ₁₇ , Galen Hostetter ₁₃ , David I Heiman ₂ , Matthew A Wyczalkowski ₃ , Tara Hiltke ₁₈ , Mehdi Mesri ₁₈ , Christopher R Kinsinger ₁₈ , Emily S Boja ₁₈ , Gilbert S Omenn ₁₉ , Arul M Chinnaiyan ₄ , Henry Rodriguez ₁₈ , Qing Kay Li ₂₀ , Scott D Jewell ₁₃ , Mathangi Thiagarajan ₂₁ , Gad Getz ₂ , Bing Zhang ₁₀ , David Fenyö ₈ , Kelly V Ruggles ₉ , Marcin P Cieslik ₄ , Ana I Robles ₁₈ , Karl R Clauser ₂ , Ramaswamy Govindan ₂₂ , Pei Wang ₆ , Alexey I Nesvizhskii ₂₃ , Li Ding ₃ , D R Mani ₂ , Steven A Carr ₂ ,

Affiliation

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.
Department of Medicine and Genetics, Siteman Cancer Center, Washington University in St. Louis, St. Louis, MO 63110, USA.
Department of Pathology, University of Michigan, Ann Arbor, MI, 48109, USA.
Department of Translational Molecular Pathology, MD Anderson Cancer Center, Houston, TX, 77030, USA.
Department of Genetics and Genomic Sciences, Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Department of Population Health Science and Policy; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
Institute for Systems Genetics and Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY 10016, USA.
Institute for Systems Genetics and Department of Medicine, NYU Grossman School of Medicine, New York, NY 10016, USA.
Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, 77030, USA.
Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, 02142, USA; Department of Biological Sciences, Columbia University, New York, NY, 10027, USA.
Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, 02142, USA; Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, CA, 90089, USA.
Van Andel Research Institute, Grand Rapids, MI, 49503, USA.
Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
Department of Public Health Sciences, University of Miami, Miller School of Medicine, Miami, FL, 33136, USA.
Poznan University of Medical Sciences, Poznań, 61-701, Poland; International Institute for Molecular Oncology, Poznań, 60-203, Poland.
Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Office of Cancer Clinical Proteomics Research, National Cancer Institute, Bethesda, MD, 20892, USA.
Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, 48109, USA.
Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins Medical Institutions, Baltimore, MD, 21224, USA.
Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, 21702, USA.
Division of Oncology and Siteman Cancer Center, Washington University School of Medicine in St. Louis, St. Louis, MO, 63110, USA.
Department of Pathology, University of Michigan, Ann Arbor, MI, 48109, USA; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, 48109, USA.

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.

中文翻译：

蛋白质基因组学特征揭示了肺腺癌的治疗脆弱性。

为了探索肺腺癌（LUAD）的生物学特性并确定新的治疗机会，我们对 110 例肿瘤和 101 例匹配的正常邻组织（NAT）进行了全面的蛋白质基因组学表征，并结合了基因组学、表观基因组学、深度蛋白质组学、磷酸化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、体细胞突变和融合下游的生物学，并确定了与涉及 KRAS、EGFR 和 ALK 的驱动事件相关的治疗脆弱性。免疫亚型揭示了复杂的景观，加强了 STK11 与免疫感冒行为的关联，并强调了中性粒细胞脱颗粒的潜在免疫抑制作用。吸烟相关的 LUAD 显示与其他环境暴露特征和 NAT 中的场效应相关。匹配的 NAT 可以鉴定具有潜在诊断和治疗效用的差异表达蛋白。该蛋白质基因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。

更新日期：2020-07-09

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