Proteogenomic analysis of lung adenocarcinoma reveals tumor heterogeneity, survival determinants, and therapeutically relevant pathways

Anthony R Soltis; Nicholas W Bateman; Jianfang Liu; Trinh Nguyen; Teri J Franks; Xijun Zhang; Clifton L Dalgard; Coralie Viollet; Stella Somiari; Chunhua Yan; Karen Zeman; William J Skinner; Jerry S H Lee; Harvey B Pollard; Clesson Turner; Emanuel F Petricoin; Daoud Meerzaman; Thomas P Conrads; Hai Hu; APOLLO Research Network; Craig D Shriver; Christopher A Moskaluk; Robert F Browning Jr; Matthew D Wilkerson

doi:10.1016/j.xcrm.2022.100819

Proteogenomic analysis of lung adenocarcinoma reveals tumor heterogeneity, survival determinants, and therapeutically relevant pathways

Cell Rep Med. 2022 Nov 15;3(11):100819. doi: 10.1016/j.xcrm.2022.100819.

Authors

Anthony R Soltis¹, Nicholas W Bateman², Jianfang Liu³, Trinh Nguyen⁴, Teri J Franks⁵, Xijun Zhang¹, Clifton L Dalgard⁶, Coralie Viollet¹, Stella Somiari³, Chunhua Yan⁴, Karen Zeman⁷, William J Skinner⁷, Jerry S H Lee⁸, Harvey B Pollard⁶, Clesson Turner⁹, Emanuel F Petricoin¹⁰, Daoud Meerzaman⁴, Thomas P Conrads¹¹, Hai Hu¹²; APOLLO Research Network; Craig D Shriver¹³, Christopher A Moskaluk¹⁴, Robert F Browning Jr¹⁵, Matthew D Wilkerson¹⁶

Collaborators

APOLLO Research Network:
Rebecca Blackwell, Gauthaman Sukumar, Dagmar Bacikova, Camille Alba, Elisa McGrath, Sraavya Polisetti, Meila Tuck, Alden Chiu, Gabe Peterson, Caroline Larson, Leonid Kvecher, Brenda Deyarmin, Jennifer Kane, Katie Miller, Kelly A. Conrads, Brian L. Hood, Sasha C. Makohon-Moore, Tamara S. Abulez, Elisa Baldelli, Mariaelena Pierobon, Qing-rong Chen, Henry Rodriguez, Sean E. Hanlon, Anthony R. Soltis, Nicholas W. Bateman, Jianfang Liu, Trinh Nguyen, Teri J. Franks, Xijun Zhang, Clifton L. Dalgard, Coralie Viollet, Stella Somiari, Chunhua Yan, Karen Zeman, William J. Skinner, Jerry S. H. Lee, Harvey B. Pollard, Clesson Turner, Emanuel F. Petricoin, Daoud Meerzaman, Thomas P. Conrads, Hai Hu, Craig D. Shriver, Christopher A. Moskaluk, Robert F. Browning Jr., Matthew D. Wilkerson

Affiliations

¹ The American Genome Center, Collaborative Health Initiative Research Program, Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA; Henry M. Jackson Foundation for Military Medicine, Bethesda, MD 20817, USA.
² Henry M. Jackson Foundation for Military Medicine, Bethesda, MD 20817, USA; Women's Health Integrated Research Center, Inova Women's Service Line, Inova Fairfax Medical Campus, Falls Church, VA 22042, USA; Gynecologic Cancer Center of Excellence, Murtha Cancer Center Research Program, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
³ Chan Soon-Shiong Institute of Molecular Medicine at Windber, Windber, PA 15963, USA.
⁴ Center for Biomedical Informatics and Information Technology, National Cancer Institute, Rockville, MD 20850, USA.
⁵ Pulmonary and Mediastinal Pathology, Department of Defense, Joint Pathology Center, Silver Spring, MD 20910, USA.
⁶ The American Genome Center, Collaborative Health Initiative Research Program, Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
⁷ Department of Medicine, Walter Reed National Military Medical Center, Bethesda, MD 20814, USA; John P. Murtha Cancer Center Research Program, Uniformed Services University, Bethesda, MD 20814, USA.
⁸ Henry M. Jackson Foundation for Military Medicine, Bethesda, MD 20817, USA; John P. Murtha Cancer Center Research Program, Uniformed Services University, Bethesda, MD 20814, USA; Lawrence J. Ellison Institute for Transformative Medicine, Los Angeles, CA 90064, USA; Departments of Medicine, Chemical Engineering and Material Sciences, University of Southern California, Los Angeles, CA 90007, USA.
⁹ John P. Murtha Cancer Center Research Program, Uniformed Services University, Bethesda, MD 20814, USA.
¹⁰ Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA 20110, USA.
¹¹ Women's Health Integrated Research Center, Inova Women's Service Line, Inova Fairfax Medical Campus, Falls Church, VA 22042, USA; Gynecologic Cancer Center of Excellence, Murtha Cancer Center Research Program, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
¹² Chan Soon-Shiong Institute of Molecular Medicine at Windber, Windber, PA 15963, USA; John P. Murtha Cancer Center Research Program, Uniformed Services University, Bethesda, MD 20814, USA.
¹³ John P. Murtha Cancer Center Research Program, Uniformed Services University, Bethesda, MD 20814, USA. Electronic address: craig.shriver@usuhs.edu.
¹⁴ Department of Pathology, University of Virginia, Charlottesville, VA 22908, USA. Electronic address: cam5p@virginia.edu.
¹⁵ Department of Medicine, Walter Reed National Military Medical Center, Bethesda, MD 20814, USA; John P. Murtha Cancer Center Research Program, Uniformed Services University, Bethesda, MD 20814, USA. Electronic address: robert.f.browning2.civ@health.mil.
¹⁶ The American Genome Center, Collaborative Health Initiative Research Program, Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA. Electronic address: matthew.wilkerson@usuhs.edu.

Abstract

We present a deep proteogenomic profiling study of 87 lung adenocarcinoma (LUAD) tumors from the United States, integrating whole-genome sequencing, transcriptome sequencing, proteomics and phosphoproteomics by mass spectrometry, and reverse-phase protein arrays. We identify three subtypes from somatic genome signature analysis, including a transition-high subtype enriched with never smokers, a transversion-high subtype enriched with current smokers, and a structurally altered subtype enriched with former smokers, TP53 alterations, and genome-wide structural alterations. We show that within-tumor correlations of RNA and protein expression associate with tumor purity and immune cell profiles. We detect and independently validate expression signatures of RNA and protein that predict patient survival. Additionally, among co-measured genes, we found that protein expression is more often associated with patient survival than RNA. Finally, integrative analysis characterizes three expression subtypes with divergent mutations, proteomic regulatory networks, and therapeutic vulnerabilities. This proteogenomic characterization provides a foundation for molecularly informed medicine in LUAD.

Keywords: TP53; cancer; immune; lung adenocarcinoma; proteogenomics; proteomics; subtype; survival; transcriptomics; whole genome.

Published by Elsevier Inc.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Extramural

MeSH terms

Adenocarcinoma of Lung* / genetics
Humans
Lung Neoplasms* / genetics
Proteogenomics*
Proteomics
RNA / therapeutic use

Substances

RNA