Pan-cancer analysis of post-translational modifications reveals shared patterns of protein regulation

Yifat Geffen; Shankara Anand; Yo Akiyama; Tomer M Yaron; Yizhe Song; Jared L Johnson; Akshay Govindan; Özgün Babur; Yize Li; Emily Huntsman; Liang-Bo Wang; Chet Birger; David I Heiman; Qing Zhang; Mendy Miller; Yosef E Maruvka; Nicholas J Haradhvala; Anna Calinawan; Saveliy Belkin; Alexander Kerelsky; Karl R Clauser; Karsten Krug; Shankha Satpathy; Samuel H Payne; D R Mani; Michael A Gillette; Saravana M Dhanasekaran; Mathangi Thiagarajan; Mehdi Mesri; Henry Rodriguez; Ana I Robles; Steven A Carr; Alexander J Lazar; François Aguet; Lewis C Cantley; Li Ding; Gad Getz; Clinical Proteomic Tumor Analysis Consortium

doi:10.1016/j.cell.2023.07.013

Pan-cancer analysis of post-translational modifications reveals shared patterns of protein regulation

Cell. 2023 Aug 31;186(18):3945-3967.e26. doi: 10.1016/j.cell.2023.07.013. Epub 2023 Aug 14.

Authors

Yifat Geffen¹, Shankara Anand², Yo Akiyama², Tomer M Yaron³, Yizhe Song⁴, Jared L Johnson³, Akshay Govindan⁴, Özgün Babur⁵, Yize Li⁴, Emily Huntsman³, Liang-Bo Wang⁴, Chet Birger², David I Heiman², Qing Zhang², Mendy Miller², Yosef E Maruvka⁶, Nicholas J Haradhvala², Anna Calinawan⁷, Saveliy Belkin², Alexander Kerelsky³, Karl R Clauser², Karsten Krug², Shankha Satpathy², Samuel H Payne⁸, D R Mani², Michael A Gillette⁹, Saravana M Dhanasekaran¹⁰, Mathangi Thiagarajan¹¹, Mehdi Mesri¹², Henry Rodriguez¹², Ana I Robles¹², Steven A Carr², Alexander J Lazar¹³, François Aguet¹⁴, Lewis C Cantley¹⁵, Li Ding¹⁶, Gad Getz¹⁷; Clinical Proteomic Tumor Analysis Consortium

Collaborators

Clinical Proteomic Tumor Analysis Consortium:
Eunkyung An, Meenakshi Anurag, Jasmin Bavarva, Michael J Birrer, Özgün Babur, Song Cao, Michele Ceccarelli, Daniel W Chan, Arul M Chinnaiyan, Hanbyul Cho, Shrabanti Chowdhury, Marcin P Cieslik, Antonio Colaprico, Steven A Carr, Felipe da Veiga Leprevost, Corbin Day, Marcin J Domagalski, Yongchao Dou, Brian J Druker, Nathan Edwards, Matthew J Ellis, David Fenyo, Steven M Foltz, Alicia Francis, Tania J Gonzalez Robles, Sara J C Gosline, Zeynep H Gümüş, Tara Hiltke, Runyu Hong, Galen Hostetter, Yingwei Hu, Chen Huang, Antonio Iavarone, Eric J Jaehnig, Scott D Jewel, Jiayi Ji, Wen Jiang, Lizabeth Katsnelson, Karen A Ketchum, Iga Kolodziejczak, Chandan Kumar-Sinha, Karsten Krug, Jonathan T Lei, Wen-Wei Liang, Yuxing Liao, Caleb M Lindgren, Tao Liu, Wenke Liu, Weiping Ma, Wilson McKerrow, Mehdi Mesri, D R Mani, Alexey I Nesvizhskii, Chelsea Newton, Robert Oldroyd, Gilbert S Omenn, Amanda G Paulovich, Francesca Petralia, Pietro Pugliese, Boris Reva, Karin D Rodland, Kelly V Ruggles, Dmitry Rykunov, Fernanda Martins Rodrigues, Sara R Savage, Eric E Schadt, Michael Schnaubelt, Tobias Schraink, Zhiao Shi, Richard D Smith, Xiaoyu Song, Vasileios Stathias, Erik P Storrs, Stephan Schürer, Myvizhi Esai Selvan, Jimin Tan, Nadezhda V Terekhanova, Ratna R Thangudu, Nicole Tignor, Mathangi Thiagarajan, Joshua M Wang, Pei Wang, Ying Cindy Wang, Bo Wen, Maciej Wiznerowicz, Yige Wu, Matthew A Wyczalkowski, Lijun Yao, Xinpei Yi, Lijun Yao, Bing Zhang, Hui Zhang, Xu Zhang, Zhen Zhang, Daniel Cui Zhou

Affiliations

¹ Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA; Cancer Center and Department of Pathology, Massachusetts General Hospital, Boston, MA 02115, USA.
² Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA.
³ Weill Cornell Medical College, Meyer Cancer Center, New York, NY 10021, USA.
⁴ Washington University School of Medicine, St. Louis, MO 63110, USA.
⁵ Department of Computer Science, University of Massachusetts Boston, Boston, MA 02125, USA.
⁶ Biotechnology and Food Engineering, Lokey Center for Life Science and Engineering, Technion, Israel Institute of Technology, Haifa, Israel.
⁷ Department of Genetic and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
⁸ Department of Biology, Brigham Young University, Provo, UT 84602, USA.
⁹ Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA; Harvard Medical School, Boston, MA 02115, USA.
¹⁰ Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
¹¹ Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
¹² Office of Cancer Clinical Proteomics Research, National Cancer Institute, Rockville, MD 20850, USA.
¹³ Departments of Pathology & Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
¹⁴ Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA. Electronic address: faguet@illumina.com.
¹⁵ Weill Cornell Medical College, Meyer Cancer Center, New York, NY 10021, USA. Electronic address: lewis_cantley@dfci.harvard.edu.
¹⁶ Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: lding@wustl.edu.
¹⁷ Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA; Cancer Center and Department of Pathology, Massachusetts General Hospital, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA. Electronic address: gadgetz@broadinstitute.org.

PMID: 37582358
PMCID: PMC10680287 (available on 2024-08-31)
DOI: 10.1016/j.cell.2023.07.013

Abstract

Post-translational modifications (PTMs) play key roles in regulating cell signaling and physiology in both normal and cancer cells. Advances in mass spectrometry enable high-throughput, accurate, and sensitive measurement of PTM levels to better understand their role, prevalence, and crosstalk. Here, we analyze the largest collection of proteogenomics data from 1,110 patients with PTM profiles across 11 cancer types (10 from the National Cancer Institute's Clinical Proteomic Tumor Analysis Consortium [CPTAC]). Our study reveals pan-cancer patterns of changes in protein acetylation and phosphorylation involved in hallmark cancer processes. These patterns revealed subsets of tumors, from different cancer types, including those with dysregulated DNA repair driven by phosphorylation, altered metabolic regulation associated with immune response driven by acetylation, affected kinase specificity by crosstalk between acetylation and phosphorylation, and modified histone regulation. Overall, this resource highlights the rich biology governed by PTMs and exposes potential new therapeutic avenues.

Keywords: CPTAC; DNA damage response; genomics; mass spectrometry; metabolism; pan-cancer; post-translational modifications; proteomics; transcriptomics.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Acetylation
Histones / metabolism
Humans
Neoplasms* / genetics
Neoplasms* / metabolism
Phosphorylation
Protein Processing, Post-Translational*
Proteomics* / methods

Substances

Histones

Abstract

Publication types

MeSH terms

Substances

Grants and funding