Proteogenomic Characterization Reveals Therapeutic Vulnerabilities in Lung Adenocarcinoma

Michael A Gillette; Shankha Satpathy; Song Cao; Saravana M Dhanasekaran; Suhas V Vasaikar; Karsten Krug; Francesca Petralia; Yize Li; Wen-Wei Liang; Boris Reva; Azra Krek; Jiayi Ji; Xiaoyu Song; Wenke Liu; Runyu Hong; Lijun Yao; Lili Blumenberg; Sara R Savage; Michael C Wendl; Bo Wen; Kai Li; Lauren C Tang; Melanie A MacMullan; Shayan C Avanessian; M Harry Kane; Chelsea J Newton; MacIntosh Cornwell; Ramani B Kothadia; Weiping Ma; Seungyeul Yoo; Rahul Mannan; Pankaj Vats; Chandan Kumar-Sinha; Emily A Kawaler; Tatiana Omelchenko; Antonio Colaprico; Yifat Geffen; Yosef E Maruvka; Felipe da Veiga Leprevost; Maciej Wiznerowicz; Zeynep H Gümüş; Rajwanth R Veluswamy; Galen Hostetter; David I Heiman; Matthew A Wyczalkowski; Tara Hiltke; Mehdi Mesri; Christopher R Kinsinger; Emily S Boja; Gilbert S Omenn; Arul M Chinnaiyan; Henry Rodriguez; Qing Kay Li; Scott D Jewell; Mathangi Thiagarajan; Gad Getz; Bing Zhang; David Fenyö; Kelly V Ruggles; Marcin P Cieslik; Ana I Robles; Karl R Clauser; Ramaswamy Govindan; Pei Wang; Alexey I Nesvizhskii; Li Ding; D R Mani; Steven A Carr; Clinical Proteomic Tumor Analysis Consortium

doi:10.1016/j.cell.2020.06.013

Proteogenomic Characterization Reveals Therapeutic Vulnerabilities in Lung Adenocarcinoma

Cell. 2020 Jul 9;182(1):200-225.e35. doi: 10.1016/j.cell.2020.06.013.

Authors

Michael A Gillette¹, Shankha Satpathy², Song Cao³, Saravana M Dhanasekaran⁴, Suhas V Vasaikar⁵, Karsten Krug⁶, Francesca Petralia⁷, Yize Li³, Wen-Wei Liang³, Boris Reva⁷, Azra Krek⁷, Jiayi Ji⁸, Xiaoyu Song⁸, Wenke Liu⁹, Runyu Hong⁹, Lijun Yao³, Lili Blumenberg¹⁰, Sara R Savage¹¹, Michael C Wendl³, Bo Wen¹¹, Kai Li¹¹, Lauren C Tang¹², Melanie A MacMullan¹³, Shayan C Avanessian⁶, M Harry Kane⁶, Chelsea J Newton¹⁴, MacIntosh Cornwell¹⁰, Ramani B Kothadia⁶, Weiping Ma⁷, Seungyeul Yoo⁷, Rahul Mannan⁴, Pankaj Vats⁴, Chandan Kumar-Sinha⁴, Emily A Kawaler⁹, Tatiana Omelchenko¹⁵, Antonio Colaprico¹⁶, Yifat Geffen⁶, Yosef E Maruvka⁶, Felipe da Veiga Leprevost⁴, Maciej Wiznerowicz¹⁷, Zeynep H Gümüş⁷, Rajwanth R Veluswamy¹⁸, Galen Hostetter¹⁴, David I Heiman⁶, Matthew A Wyczalkowski³, Tara Hiltke¹⁹, Mehdi Mesri¹⁹, Christopher R Kinsinger¹⁹, Emily S Boja¹⁹, Gilbert S Omenn²⁰, Arul M Chinnaiyan⁴, Henry Rodriguez¹⁹, Qing Kay Li²¹, Scott D Jewell¹⁴, Mathangi Thiagarajan²², Gad Getz⁶, Bing Zhang¹¹, David Fenyö⁹, Kelly V Ruggles¹⁰, Marcin P Cieslik⁴, Ana I Robles¹⁹, Karl R Clauser⁶, Ramaswamy Govindan²³, Pei Wang⁷, Alexey I Nesvizhskii²⁴, Li Ding³, D R Mani⁶, Steven A Carr²⁵; Clinical Proteomic Tumor Analysis Consortium

Collaborators

Clinical Proteomic Tumor Analysis Consortium:
Alex Webster, Alicia Francis, Alyssa Charamut, Amanda G Paulovich, Amy M Perou, Andrew K Godwin, Andrii Karnuta, Annette Marrero-Oliveras, Barbara Hindenach, Barbara Pruetz, Bartosz Kubisa, Brian J Druker, Chet Birger, Corbin D Jones, Dana R Valley, Daniel C Rohrer, Daniel Cui Zhou, Daniel W Chan, David Chesla, David J Clark, Dmitry Rykunov, Donghui Tan, Elena V Ponomareva, Elizabeth Duffy, Eric J Burks, Eric E Schadt, Erik J Bergstrom, Eugene S Fedorov, Ewa Malc, George D Wilson, Hai-Quan Chen, Halina M Krzystek, Hongwei Liu, Houston Culpepper, Hua Sun, Hui Zhang, Jacob Day, James Suh, Jeffrey R Whiteaker, Jennifer Eschbacher, John McGee, Karen A Ketchum, Karin D Rodland, Karna Robinson, Katherine A Hoadley, Kei Suzuki, Ki Sung Um, Kim Elburn, Liang-Bo Wang, Lijun Chen, Linda Hannick, Liqun Qi, Lori J Sokoll, Małgorzata Wojtyś, Marcin J Domagalski, Marina A Gritsenko, Mary B Beasley, Matthew E Monroe, Matthew J Ellis, Maureen Dyer, Meghan C Burke, Melissa Borucki, Meng-Hong Sun, Michael H Roehrl, Michael J Birrer, Michael Noble, Michael Schnaubelt, Michael Vernon, Michelle Chaikin, Mikhail Krotevich, Munziba Khan, Myvizhi Esai Selvan, Nancy Roche, Nathan J Edwards, Negin Vatanian, Olga Potapova, Pamela Grady, Peter B McGarvey, Piotr Mieczkowski, Pushpa Hariharan, Rashna Madan, Ratna R Thangudu, Richard D Smith, Robert J Welsh, Robert Zelt, Rohit Mehra, Ronald Matteotti, Sailaja Mareedu, Samuel H Payne, Sandra Cottingham, Sanford P Markey, Seema Chugh, Shaleigh Smith, Shirley Tsang, Shuang Cai, Simina M Boca, Sonya Carter, Stacey Gabriel, Stephanie De Young, Stephen E Stein, Sunita Shankar, Tanya Krubit, Tao Liu, Tara Skelly, Thomas Bauer, Uma Velvulou, Umut Ozbek, Vladislav A Petyuk, Volodymyr Sovenko, William E Bocik, William W Maggio, Xi Chen, Yan Shi, Yige Wu, Yingwei Hu, Yuxing Liao, Zhen Zhang, Zhiao Shi

Affiliations

¹ 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.
² Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, 02142, USA. Electronic address: shankha@broadinstitue.org.
³ Department of Medicine and Genetics, Siteman Cancer Center, Washington University in St. Louis, St. Louis, MO 63110, USA.
⁴ Department of Pathology, University of Michigan, Ann Arbor, MI, 48109, USA.
⁵ Department of Translational Molecular Pathology, MD Anderson Cancer Center, Houston, TX, 77030, USA.
⁶ Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, 02142, USA.
⁷ 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.
⁸ Department of Population Health Science and Policy; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
⁹ Institute for Systems Genetics and Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY 10016, USA.
¹⁰ Institute for Systems Genetics and Department of Medicine, NYU Grossman School of Medicine, New York, NY 10016, USA.
¹¹ Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, 77030, USA.
¹² Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, 02142, USA; Department of Biological Sciences, Columbia University, New York, NY, 10027, USA.
¹³ 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.
¹⁴ Van Andel Research Institute, Grand Rapids, MI, 49503, USA.
¹⁵ Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
¹⁶ Department of Public Health Sciences, University of Miami, Miller School of Medicine, Miami, FL, 33136, USA.
¹⁷ Poznan University of Medical Sciences, Poznań, 61-701, Poland; International Institute for Molecular Oncology, Poznań, 60-203, Poland.
¹⁸ Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
¹⁹ Office of Cancer Clinical Proteomics Research, National Cancer Institute, Bethesda, MD, 20892, USA.
²⁰ Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, 48109, USA.
²¹ Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins Medical Institutions, Baltimore, MD, 21224, USA.
²² Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, 21702, USA.
²³ Division of Oncology and Siteman Cancer Center, Washington University School of Medicine in St. Louis, St. Louis, MO, 63110, USA.
²⁴ 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.
²⁵ Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, 02142, USA. Electronic address: scarr@broad.mit.edu.

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.

Keywords: CPTAC; acetylation; adenocarcinoma; genomics; lung cancer; mass spectrometry; phosphorylation; protein; proteogenomics; proteomics.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Adenocarcinoma of Lung / drug therapy*
Adenocarcinoma of Lung / genetics*
Adenocarcinoma of Lung / immunology
Adult
Aged
Aged, 80 and over
Biomarkers, Tumor / metabolism
Carcinogenesis / genetics
Carcinogenesis / pathology
DNA Copy Number Variations / genetics
DNA Methylation / genetics
Female
Humans
Lung Neoplasms / drug therapy*
Lung Neoplasms / genetics*
Lung Neoplasms / immunology
Male
Middle Aged
Mutation / genetics
Oncogene Proteins, Fusion
Phenotype
Phosphoproteins / metabolism
Proteogenomics*
Proteome / metabolism

Substances

Biomarkers, Tumor
Oncogene Proteins, Fusion
Phosphoproteins
Proteome

Abstract

Publication types

MeSH terms

Substances

Grants and funding