Abstract

Cancer driver events refer to key genetic aberrations that drive oncogenesis; however, their exact molecular mechanisms remain insufficiently understood. Here, our multi-omics pan-cancer analysis uncovers insights into the impacts of cancer drivers by identifying their significant cis-effects and distal trans-effects quantified at the RNA, protein, and phosphoprotein levels. Salient observations include the association of point mutations and copy-number alterations with the rewiring of protein interaction networks, and notably, most cancer genes converge toward similar molecular states denoted by sequence-based kinase activity profiles. A correlation between predicted neoantigen burden and measured T cell infiltration suggests potential vulnerabilities for immunotherapies. Patterns of cancer hallmarks vary by polygenic protein abundance ranging from uniform to heterogeneous. Overall, our work demonstrates the value of comprehensive proteogenomics in understanding the functional states of oncogenic drivers and their links to cancer development, surpassing the limitations of studying individual cancer types.

Original languageEnglish
Pages (from-to)3921-3944.e25
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) under award numbers U24CA210955 , U24CA210985 , U24CA210986 , U24CA210954 , U24CA210967 , U24CA210972 , U24CA210979 , U24CA210993 , U01CA214114 , U01CA214116 , and U01CA214125 as U24CA210972 (D.F., L.D., and S.H.P.), U24CA210979 (G.G. and C.B.), and U24CA270823 (S.S. and M.A.G.), and Contract GR0012005 (L.D.). M.S. is supported by the Asociación Española Contra el Cáncer (AECC) project LABAE20038PORT. E.P.-P., V.R.-S., and K.J.I. are supported by the Spanish Ministry of Science (grants RYC2019-026415-I and PID2019-107043RA-I00). This work was supported by the National Cancer Institute (NCI) Clinical Proteomic Tumor Analysis Consortium (CPTAC) under award numbers U24CA210955, U24CA210985, U24CA210986, U24CA210954, U24CA210967, U24CA210972, U24CA210979, U24CA210993, U01CA214114, U01CA214116, and U01CA214125 as U24CA210972 (D.F. L.D. and S.H.P.), U24CA210979 (G.G. and C.B.), and U24CA270823 (S.S. and M.A.G.), and Contract GR0012005 (L.D.). M.S. is supported by the Asociación Española Contra el Cáncer (AECC) project LABAE20038PORT. E.P.-P. V.R.-S. and K.J.I. are supported by the Spanish Ministry of Science (grants RYC2019-026415-I and PID2019-107043RA-I00). Study conception and design, Y.L. C.K.-S. A.J.L. L.C.C. G.G. and L.D.; performed experiment or data collection, Y.L. Y.G. S.A. M.A.W. Y.S. W.-W.L. N.V.T. F.M.R. K.R.C. D.I.H. Q.Z. F.A. C.B. D.C.Z. and L.-B.W.; computational, multi-omic, and statistical analyses, Y.L. E.P.-P. C.T. M.H.B. T.M.Y. V.S. K.J.I. Y.G. S.C. S.A. Y.A. W.L. E.P.S. M.C.W. W.Z. M.S. V.R.-S. J.L.J. E.M.H. P.P. and A.J.L.; data interpretation and biological analysis, Y.L. E.P.-P. C.T. M.H.B. T.M.Y. Y.G. V.S. K.J.I. S.C. S.A. Y.A. W.L. E.P.S. M.C.W. W.Z. M.S. V.R.-S. J.L.J. E.M.H. P.P. C.K.-S. A.J.L. L.C.C. G.G. and L.D.; data visualization and figure design: Y.L. E.P-P. C.T. M.H.B. T.M.Y. V.S. K.J.I. S.C. M.A.W. C.K.-S. A.J.L. L.C.C. G.G. and L.D; writing – original drafts, Y.L. E.P.-P. C.T. M.H.B. T.M.Y. V.S. K.J.I. S.C. C.K.-S. A.J.L. and L.D.; writing – review and editing, Y.L. E.P.-P. C.T. M.H.B. T.M.Y. V.S. Y.G. K.J.I. S.C. M.C.W. S.M.D. S.S. J.B. A.C. A.I. M.C. C.J.R. D.F. S.H.P. A.I.R. M.A.G. C.K.-S. A.J.L. L.C.C. G.G. and L.D.; supervision: Y.L. A.I.R. C.K.-S. A.J.L. L.C.C. G.G. and L.D.; and administration, Y.L. H.R. A.I.R. G.G. and L.D. Y.G. is a consultant for Oriel Research Therapeutics. T.M.Y. is a co-founder, stockholder, and member of 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. 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. G.G. is also a founder, consultant, and privately held equity in Scorpion Therapeutics.

FundersFunder number
Asociación Española contra el Cáncer
Clinical Proteomic Tumor Analysis ConsortiumU24CA270823, U24CA210955, GR0012005, U24CA210954, U24CA210979, U24CA210967, U24CA210972, U24CA210986, U24CA210985, U24CA210993, U01CA214116, U01CA214114, U01CA214125
MSIDetect
MSMutSig
MinimuMM-Seq
Petra Pharmaceuticals
National Cancer Institute
International Business Machines Corporation
Broad Institute
Ministerio de Ciencia e InnovaciónPID2019-107043RA-I00, RYC2019-026415-I

    Keywords

    • CPTAC
    • cancer hallmark
    • oncogenic driver
    • pan-cancer
    • phosphoproteomics
    • protein complex
    • proteogenomics
    • proteomics
    • therapeutic target

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