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Proteogenomic Characterization Reveals Therapeutic Vulnerabilities in Lung Adenocarcinoma
Open accessAbstract
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.
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“Collectively, CPTAC and ICPC collaborators have comprehensively characterized 13 cancer types at the proteogenomics level, with all datasets publicly accessible109–117.”
From A high-stringency blueprint of the human proteome (2020) · cites this paper as [111]
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Metadata
- Authors
- 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., Wen, B., Li, K., Tang, L. C., MacMullan, M. A., Avanessian, S. C., Kane, M. H., Newton, C. J., Cornwell, M., Kothadia, R. B., Ma, W., Yoo, S., Mannan, R., Vats, P., Kumar-Sinha, C., Kawaler, E. A., Omelchenko, T., Colaprico, A., Geffen, Y., Maruvka, Y. E., da Veiga Leprevost, F., Wiznerowicz, M., Gümüş, Z. H., Veluswamy, R. R., Hostetter, G., Heiman, D. I., Wyczalkowski, M. A., Hiltke, T., Mesri, M., Kinsinger, C. R., Boja, E. S., Omenn, G. S., Chinnaiyan, A. M., Rodriguez, H., Li, Q. K., Jewell, S. D., Thiagarajan, M., Getz, G., Zhang, B., Fenyö, D., Ruggles, K. V., Cieslik, M. P., Robles, A. I., Clauser, K. R., Govindan, R., Wang, P., Nesvizhskii, A. I., Ding, L., Mani, D. R., Carr, S. A., Webster, A., Francis, A., Charamut, A., Paulovich, A. G., Perou, A. M., Godwin, A. K., Karnuta, A., Marrero-Oliveras, A., Hindenach, B., Pruetz, B., Kubisa, B., Druker, B. J., Birger, C., Jones, C. D., Valley, D. R., Rohrer, D. C., Zhou, D. C., Chan, D. W., Chesla, D., Clark, D. J., Rykunov, D., Tan, D., Ponomareva, E. V., Duffy, E., Burks, E. J., Schadt, E. E., Bergstrom, E. J., Fedorov, E. S., Malc, E., Wilson, G. D., Chen, H.-Q., Krzystek, H. M., Liu, H., Culpepper, H., Sun, H., Zhang, H., Day, J., Suh, J., Whiteaker, J. R., Eschbacher, J., McGee, J., Ketchum, K. A., Rodland, K. D., Robinson, K., Hoadley, K. A., Suzuki, K., Um, K. S., Elburn, K., Wang, L.-B., Chen, L., Hannick, L., Qi, L., Sokoll, L. J., Wojtyś, M., Domagalski, M. J., Gritsenko, M. A., Beasley, M. B., Monroe, M. E., Ellis, M. J., Dyer, M., Burke, M. C., Borucki, M., Sun, M.-H., Roehrl, M. H., Birrer, M. J., Noble, M., Schnaubelt, M., Vernon, M., Chaikin, M., Krotevich, M., Khan, M., Selvan, M. E., Roche, N., Edwards, N. J., Vatanian, N., Potapova, O., Grady, P., McGarvey, P. B., Mieczkowski, P., Hariharan, P., Madan, R., Thangudu, R. R., Smith, R. D., Welsh, R. J., Zelt, R., Mehra, R., Matteotti, R., Mareedu, S., Payne, S. H., Cottingham, S., Markey, S. P., Chugh, S., Smith, S., Tsang, S., Cai, S., Boca, S. M., Carter, S., Gabriel, S., De Young, S., Stein, S. E., Shankar, S., Krubit, T., Liu, T., Skelly, T., Bauer, T., Velvulou, U., Ozbek, U., Petyuk, V. A., Sovenko, V., Bocik, W. E., Maggio, W. W., Chen, X., Shi, Y., Wu, Y., Hu, Y., Liao, Y., Zhang, Z., & Shi, Z.
- Affiliations
- Broad Institute (US)
- Washington University in St. Louis (US)
- University of Michigan (US)
- The University of Texas MD Anderson Cancer Center (US)
- Icahn School of Medicine at Mount Sinai (US)
- Tisch Cancer Institute (US)
- New York University (US)
- Baylor College of Medicine (US)
- Van Andel Institute (US)
- Memorial Sloan Kettering Cancer Center (US)
- University of Miami (US)
- Poznan University of Medical Sciences (PL)
- National Cancer Institute (US)
- Johns Hopkins University (US)
- Frederick National Laboratory for Cancer Research (US)
- Corresponding author
- Gillette, Michael A.
- Satpathy, Shankha
- Carr, Steven A.
- ORCID
- Gillette, Michael A.
- Satpathy, Shankha
- Cao, Song
- Dhanasekaran, Saravana M.
- Vasaikar, Suhas V.
- Krug, Karsten
- Petralia, Francesca
- Li, Yize
- Liang, Wen-Wei
- Reva, Boris
- Krek, Azra
- Ji, Jiayi
- Song, Xiaoyu
- Liu, Wenke
- Hong, Runyu
- Blumenberg, Lili
- Savage, Sara R.
- Wendl, Michael C.
- Wen, Bo
- Li, Kai
- Tang, Lauren C.
- MacMullan, Melanie A.
- Avanessian, Shayan C.
- Kane, M. Harry
- Cornwell, MacIntosh
- Kothadia, Ramani B.
- Ma, Weiping
- Yoo, Seungyeul
- Mannan, Rahul
- Vats, Pankaj
- Kawaler, Emily A.
- Omelchenko, Tatiana
- Colaprico, Antonio
- Geffen, Yifat
- Maruvka, Yosef E.
- Wiznerowicz, Maciej
- Veluswamy, Rajwanth R.
- Hostetter, Galen
- Heiman, David I.
- Wyczalkowski, Matthew A.
- Hiltke, Tara
- Mesri, Mehdi
- Kinsinger, Christopher R.
- Boja, Emily S.
- Omenn, Gilbert S.
- Chinnaiyan, Arul M.
- Rodriguez, Henry
- Li, Qing Kay
- Jewell, Scott D.
- Thiagarajan, Mathangi
- Getz, Gad
- Zhang, Bing
- Fenyö, David
- Ruggles, Kelly V.
- Cieslik, Marcin P.
- Robles, Ana I.
- Clauser, Karl R.
- Govindan, Ramaswamy
- Wang, Pei
- Nesvizhskii, Alexey I.
- Ding, Li
- Mani, D.R.
- Carr, Steven A.
- Francis, Alicia
- Paulovich, Amanda G.
- Godwin, Andrew K.
- Kubisa, Bartosz
- Druker, Brian J.
- Jones, Corbin D.
- Rohrer, Daniel C.
- Zhou, Daniel Cui
- Chan, Daniel W.
- Clark, David J.
- Rykunov, Dmitry
- Duffy, Elizabeth
- Burks, Eric J.
- Schadt, Eric E.
- Bergstrom, Erik J.
- Malc, Ewa
- Wilson, George D.
- Liu, Hongwei
- Sun, Hua
- Zhang, Hui
- Suh, James
- Whiteaker, Jeffrey R.
- Ketchum, Karen A.
- Rodland, Karin D.
- Hoadley, Katherine A.
- Suzuki, Kei
- Wang, Liang-Bo
- Chen, Lijun
- Hannick, Linda
- Sokoll, Lori J.
- Wojtyś, Małgorzata
- Domagalski, Marcin J.
- Beasley, Mary B.
- Monroe, Matthew E.
- Ellis, Matthew J.
- Dyer, Maureen
- Burke, Meghan C.
- Roehrl, Michael H.
- Birrer, Michael J.
- Noble, Michael
- Schnaubelt, Michael
- Selvan, Myvizhi Esai
- Edwards, Nathan J.
- Potapova, Olga
- McGarvey, Peter B.
- Mieczkowski, Piotr
- Madan, Rashna
- Thangudu, Ratna R.
- Smith, Richard D.
- Mehra, Rohit
- Matteotti, Ronald
- Payne, Samuel H.
- Chugh, Seema
- Smith, Shaleigh
- Cai, Shuang
- Boca, Simina M.
- Gabriel, Stacey
- Stein, Stephen E.
- Shankar, Sunita
- Liu, Tao
- Petyuk, Vladislav A.
- Bocik, William E.
- Chen, Xi
- Shi, Yan
- Wu, Yige
- Hu, Yingwei
- Liao, Yuxing
- Zhang, Zhen
- Shi, Zhiao
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2020-07
- Volume
- 182
- Issue
- 1
- Pages
- 200-225.e35
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC7373300
- OpenAlex
- W3041397352
- Cited by
- 820
- References
- 260
- Citations by year
- 2026: 129 · 2025: 148 · 2024: 143 · 2023: 151 · 2022: 119 · 2021: 112 · 2020: 15
- FWCI
- 58.06
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cell (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion, cc-by-nc-nd)
- Funders
- National Institutes of Health
- National Institute of Environmental Health Sciences
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Oncology › Lung Cancer Research Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- lung adenocarcinoma, proteogenomics, therapeutic vulnerabilities, KRAS, EGFR, anaplastic lymphoma kinase, STK11, neutrophil degranulation, smoking, field effect, copy number alterations, somatic mutations, protein expression signatures, multi-omics clustering
- MeSH terms
- Proteogenomics, Adenocarcinoma of Lung, Adult, Aged, Aged, 80 and over, Female, Humans, Lung Neoplasms, Male, Middle Aged, Mutation, Phenotype, Phosphoproteins, Biomarkers, Tumor, Oncogene Proteins, Fusion, DNA Methylation, Proteome, DNA Copy Number Variations, Carcinogenesis
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