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Proteogenomic Characterization Reveals Therapeutic Vulnerabilities in Lung Adenocarcinoma.
Cell. 2020 Jul 09; 182(1):200-225.e35.Cell

Abstract

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.

Authors+Show Affiliations

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. Electronic address: gillette@broadinstitute.org.Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, 02142, USA. Electronic address: shankha@broadinstitue.org.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.Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, 02142, 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 Medicine and Genetics, Siteman Cancer Center, Washington University in St. Louis, St. Louis, MO 63110, USA.Department of Medicine and Genetics, Siteman Cancer Center, Washington University in St. Louis, St. Louis, MO 63110, 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 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.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 Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY 10016, USA.Department of Medicine and Genetics, Siteman Cancer Center, Washington University in St. Louis, St. Louis, MO 63110, 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.Department of Medicine and Genetics, Siteman Cancer Center, Washington University in St. Louis, St. Louis, MO 63110, USA.Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, 77030, 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.Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, 02142, USA.Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, 02142, USA.Van Andel Research Institute, Grand Rapids, MI, 49503, USA.Institute for Systems Genetics and Department of Medicine, NYU Grossman School of Medicine, New York, NY 10016, USA.Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, 02142, 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 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 Pathology, University of Michigan, Ann Arbor, MI, 48109, USA.Department of Pathology, University of Michigan, Ann Arbor, MI, 48109, USA.Department of Pathology, University of Michigan, Ann Arbor, MI, 48109, USA.Institute for Systems Genetics and Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY 10016, 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.Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, 02142, USA.Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, 02142, USA.Department of Pathology, University of Michigan, Ann Arbor, MI, 48109, USA.Poznan University of Medical Sciences, Poznań, 61-701, Poland; International Institute for Molecular Oncology, Poznań, 60-203, Poland.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.Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.Van Andel Research Institute, Grand Rapids, MI, 49503, 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.Office of Cancer Clinical Proteomics Research, National Cancer Institute, Bethesda, MD, 20892, USA.Office of Cancer Clinical Proteomics Research, National Cancer Institute, Bethesda, MD, 20892, USA.Office of Cancer Clinical Proteomics Research, National Cancer Institute, Bethesda, MD, 20892, 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.Department of Pathology, University of Michigan, Ann Arbor, MI, 48109, USA.Office of Cancer Clinical Proteomics Research, National Cancer Institute, Bethesda, MD, 20892, USA.Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins Medical Institutions, Baltimore, MD, 21224, USA.Van Andel Research Institute, Grand Rapids, MI, 49503, USA.Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, 21702, USA.Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, 02142, USA.Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, 77030, 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.Department of Pathology, University of Michigan, Ann Arbor, MI, 48109, USA.Office of Cancer Clinical Proteomics Research, National Cancer Institute, Bethesda, MD, 20892, USA.Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, 02142, USA.Division of Oncology and Siteman Cancer Center, Washington University School of Medicine in St. Louis, St. Louis, MO, 63110, 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 Pathology, University of Michigan, Ann Arbor, MI, 48109, USA; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, 48109, USA.Department of Medicine and Genetics, Siteman Cancer Center, Washington University in St. Louis, St. Louis, MO 63110, USA.Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, 02142, USA.Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, 02142, USA. Electronic address: scarr@broad.mit.edu.No affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32649874

Citation

Gillette, Michael A., et al. "Proteogenomic Characterization Reveals Therapeutic Vulnerabilities in Lung Adenocarcinoma." Cell, vol. 182, no. 1, 2020, pp. 200-225.e35.
Gillette MA, Satpathy S, Cao S, et al. Proteogenomic Characterization Reveals Therapeutic Vulnerabilities in Lung Adenocarcinoma. Cell. 2020;182(1):200-225.e35.
Gillette, M. A., Satpathy, S., Cao, S., Dhanasekaran, S. M., Vasaikar, S. V., Krug, K., Petralia, F., Li, Y., Liang, W. W., Reva, B., Krek, A., Ji, J., Song, X., Liu, W., Hong, R., Yao, L., Blumenberg, L., Savage, S. R., Wendl, M. C., ... Carr, S. A. (2020). Proteogenomic Characterization Reveals Therapeutic Vulnerabilities in Lung Adenocarcinoma. Cell, 182(1), 200-e35. https://doi.org/10.1016/j.cell.2020.06.013
Gillette MA, et al. Proteogenomic Characterization Reveals Therapeutic Vulnerabilities in Lung Adenocarcinoma. Cell. 2020 Jul 9;182(1):200-225.e35. PubMed PMID: 32649874.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Proteogenomic Characterization Reveals Therapeutic Vulnerabilities in Lung Adenocarcinoma. AU - Gillette,Michael A, AU - Satpathy,Shankha, AU - Cao,Song, AU - Dhanasekaran,Saravana M, AU - Vasaikar,Suhas V, AU - Krug,Karsten, AU - Petralia,Francesca, AU - Li,Yize, AU - Liang,Wen-Wei, AU - Reva,Boris, AU - Krek,Azra, AU - Ji,Jiayi, AU - Song,Xiaoyu, AU - Liu,Wenke, AU - Hong,Runyu, AU - Yao,Lijun, AU - Blumenberg,Lili, AU - Savage,Sara R, AU - Wendl,Michael C, AU - Wen,Bo, AU - Li,Kai, AU - Tang,Lauren C, AU - MacMullan,Melanie A, AU - Avanessian,Shayan C, AU - Kane,M Harry, AU - Newton,Chelsea J, AU - Cornwell,MacIntosh, AU - Kothadia,Ramani B, AU - Ma,Weiping, AU - Yoo,Seungyeul, AU - Mannan,Rahul, AU - Vats,Pankaj, AU - Kumar-Sinha,Chandan, AU - Kawaler,Emily A, AU - Omelchenko,Tatiana, AU - Colaprico,Antonio, AU - Geffen,Yifat, AU - Maruvka,Yosef E, AU - da Veiga Leprevost,Felipe, AU - Wiznerowicz,Maciej, AU - Gümüş,Zeynep H, AU - Veluswamy,Rajwanth R, AU - Hostetter,Galen, AU - Heiman,David I, AU - Wyczalkowski,Matthew A, AU - Hiltke,Tara, AU - Mesri,Mehdi, AU - Kinsinger,Christopher R, AU - Boja,Emily S, AU - Omenn,Gilbert S, AU - Chinnaiyan,Arul M, AU - Rodriguez,Henry, AU - Li,Qing Kay, AU - Jewell,Scott D, AU - Thiagarajan,Mathangi, AU - Getz,Gad, AU - Zhang,Bing, AU - Fenyö,David, AU - Ruggles,Kelly V, AU - Cieslik,Marcin P, AU - Robles,Ana I, AU - Clauser,Karl R, AU - Govindan,Ramaswamy, AU - Wang,Pei, AU - Nesvizhskii,Alexey I, AU - Ding,Li, AU - Mani,D R, AU - Carr,Steven A, AU - ,, PY - 2019/11/05/received PY - 2020/03/06/revised PY - 2020/06/03/accepted PY - 2020/7/11/entrez PY - 2020/7/11/pubmed PY - 2020/7/11/medline KW - CPTAC KW - acetylation KW - adenocarcinoma KW - genomics KW - lung cancer KW - mass spectrometry KW - phosphorylation KW - protein KW - proteogenomics KW - proteomics SP - 200 EP - 225.e35 JF - Cell JO - Cell VL - 182 IS - 1 N2 - 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. SN - 1097-4172 UR - https://www.unboundmedicine.com/medline/citation/32649874/Proteogenomic_Characterization_Reveals_Therapeutic_Vulnerabilities_in_Lung_Adenocarcinoma L2 - https://linkinghub.elsevier.com/retrieve/pii/S0092-8674(20)30744-3 DB - PRIME DP - Unbound Medicine ER -
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