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.

Original languageEnglish
Pages (from-to)3945-3967.e26
JournalCell
Volume186
Issue number18
DOIs
StatePublished - 31 Aug 2023
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2023 The Authors

Funding

This work was supported by the National Cancer Institute (NCI) Clinical Proteomic Tumor Analysis Consortium (CPTAC) grants U24CA210955 , U24CA210985 , U24CA210986 , U24CA210954 , U24CA210967 , U24CA210972 , U24CA210979 , U24CA210993 , U01CA214114 , U01CA214116 , U24 CA270823 , U24CA270823 , U01CA271402 , U24CA271075 , R35CA197588 , and U01CA214125 . In addition, this project has been funded in part with Federal funds from the National Cancer Institute , National Institutes of Health , under contract no. 75N91019D00024 , Task Order 75N91020F00029 , as well as P01CA206978. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. We thank the Pattern Team at the Broad Institute for figure design. Schematic figures and the graphical abstract were created using BioRender.com . This work was supported by the National Cancer Institute (NCI) Clinical Proteomic Tumor Analysis Consortium (CPTAC) grants U24CA210955, U24CA210985, U24CA210986, U24CA210954, U24CA210967, U24CA210972, U24CA210979, U24CA210993, U01CA214114, U01CA214116, U24 CA270823, U24CA270823, U01CA271402, U24CA271075, R35CA197588, and U01CA214125. In addition, this project has been funded in part with Federal funds from the National Cancer Institute, National Institutes of Health, under contract no. 75N91019D00024, Task Order 75N91020F00029, as well as P01CA206978. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. We thank the Pattern Team at the Broad Institute for figure design. Schematic figures and the graphical abstract were created using BioRender.com. Study conception and design, Y.G. S.A. F.A. G.G. and L.D.; performed experiment or data collection, Y.G. S.A. Y.A. J.L.J. Y.L. C.B. D.I.H. Q.Z. A.C. F.A. K.R.C. D.R.M. S.B. and M.T.; computational, multi-omic, and statistical analyses, Y.G. S.A. Y.A. T.M.Y. Y.S. J.L.J. A.G. Ö.B. Y.L. E.H. L.-B.W. Y.E.M. N.J.H. A.K. K.K. and F.A.; data interpretation and biological analysis, Y.G. S.A. Y.A. T.M.Y. Y.S. J.L.J. A.G. Y.E.M. N.J.H. F.A. L.C.C. G.G. and L.D.; writing – original drafts, Y.G. S.A. Y.A. M. Miller, T.M.Y. Y.S. J.L.J. A.G. F.A. and G.G.; writing – review & editing, Y.G. S.A. Y.A. M. Miller, T.M.Y. Y.S. J.L.J. A.G. Ö.B. C.B. D.I.H. Y.E.M. N.J.H. K.R.C. S.S. S.H.P. M.A.G. S.M.D. A.I.R. S.A.C. A.J.L. F.A. L.C.C. L.D. and G.G.; supervision, Y.G. A.I.R. F.A. L.C.C. L.D. and G.G.; administration, Y.G. M. Mesri, H.R. A.I.R. L.D. and G.G. Y.G. is a consultant for Oriel Research Therapeutics. T.M.Y. is a co-founder, stockholder, and on the board of directors of DESTROKE, Inc. an early-stage start-up developing mobile technology for automated clinical stroke detection. J.L.J. has received consulting fees from Scorpion Therapeutics and Volastra Therapeutics. Y.E.M. is a consultant for ForseeGenomics and is also an inventor on patent applications filed by the Broad Institute related to MSMuTect, MSMutSig, and MSIDetect. N.J.H. is a consultant for MorphoSys. F.A. is an inventor on a patent application related to SignatureAnalyzer-GPU and has been an employee of Illumina, Inc. since 8 November 2021. L.C.C. is a founder and member of the board of directors of Agios Pharmaceuticals and is a founder of Petra Pharmaceuticals. L.C.C. is an inventor on patents (pending) for Combination Therapy for PI3K-associated Disease or Disorder, and The Identification of Therapeutic Interventions to Improve Response to PI3K Inhibitors for Cancer Treatment. L.C.C. is a co-founder and shareholder in Faeth Therapeutics. G.G. receives research funds from IBM, Pharmacyclics, and Ultima Genomics, and is also an inventor on patent applications filed by the Broad Institute related to MSMuTect, MSMutSig, POLYSOLVER, SignatureAnalyzer-GPU, MSIDetect, and MinimuMM-Seq. He is also a founder, consultant, and privately held equity in Scorpion Therapeutics.

FundersFunder number
Clinical Proteomic Tumor Analysis ConsortiumU24 CA270823, U24CA210955, U24CA210954, U24CA210979, U24CA210967, R35CA197588, U24CA210972, U24CA271075, U24CA210986, U24CA210985, U24CA210993, U01CA214116, U01CA271402, U01CA214114, U01CA214125
MSIDetect
MSMutSig
MinimuMM-Seq
Petra Pharmaceuticals
U.S. Government
National Institutes of Health75N91019D00024, P01CA206978, 75N91020F00029
U.S. Department of Health and Human Services
National Cancer Institute
International Business Machines Corporation
Broad Institute

    Keywords

    • CPTAC
    • DNA damage response
    • genomics
    • mass spectrometry
    • metabolism
    • pan-cancer
    • post-translational modifications
    • proteomics
    • transcriptomics

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