Proteogenomic insights suggest druggable pathways in endometrial carcinoma

Clinical Proteomic Tumor Analysis Consortium

Résultat de rechercheexamen par les pairs

13 Citations (Scopus)

Résumé

We characterized a prospective endometrial carcinoma (EC) cohort containing 138 tumors and 20 enriched normal tissues using 10 different omics platforms. Targeted quantitation of two peptides can predict antigen processing and presentation machinery activity, and may inform patient selection for immunotherapy. Association analysis between MYC activity and metformin treatment in both patients and cell lines suggests a potential role for metformin treatment in non-diabetic patients with elevated MYC activity. PIK3R1 in-frame indels are associated with elevated AKT phosphorylation and increased sensitivity to AKT inhibitors. CTNNB1 hotspot mutations are concentrated near phosphorylation sites mediating pS45-induced degradation of β-catenin, which may render Wnt-FZD antagonists ineffective. Deep learning accurately predicts EC subtypes and mutations from histopathology images, which may be useful for rapid diagnosis. Overall, this study identified molecular and imaging markers that can be further investigated to guide patient stratification for more precise treatment of EC.

Langue d'origineEnglish
Pages (de-à)1586-1605.e15
JournalCancer Cell
Volume41
Numéro de publication9
DOI
Statut de publicationPublished - sept. 11 2023

Financement

The Clinical Proteomic Tumor Analysis Consortium (CPTAC) is supported by the National Cancer Institute of the National Institutes of Health under award numbers U24CA210955, U24CA210985, U24CA210986, U24CA210954, U24CA210967, U24CA210972, U24CA210979, U24CA210993, U01CA214114, U01CA214116, U01CA214125, U24CA271012, U24CA271076, U24CA271114, and contracts from Leidos (S21-167 and 21X164Q); by NCI grant T32CA203690; by grant RR160027 from the Cancer Prevention & Research Institutes of Texas (CPRIT); and by funding from the McNair Medical Institute at The Robert and Janice McNair Foundation. B.Z. and M.E. are Cancer Prevention & Research Institutes of Texas Scholars in Cancer Research and McNair Medical Institute Scholars. The Pacific Northwest National Laboratory (PNNL) proteomics work described herein was performed in the Environmental Molecular Sciences Laboratory (grid.436923.9), a US Department of Energy (DOE) National Scientific User Facility located at PNNL in Richland, WA. PNNL is a multi-program national laboratory operated by the Battelle Memorial Institute for the DOE under contract DE-AC05-76RL01830. This work was also supported by a US Department of Defense funding DOD BC220523. Study conception & design: Y.D. L.K. M.A.G. M.L.A. K.D.R. B.Z. T.L. and D.F.; Performed experiment or data collection: M.A.G. Y.H. Y.W. I.K. C.T. W.B. X.G. R.C.A. L.C. B.D. M.F. A.G.K. A.T.K. Y. Li, and T. Lin; Computation & statistical analysis: Y.D. L.K. B.R. R.H. R.J.L. W.L. I.J. W.M. T.O. V.A.P. D.R. S.R.S. J.T. J.M.W. Y. Wu, M.A.W. and D.R.M.; Data interpretation & biological analysis: Y.D. L.K. M.A.G. Y.H. B.R. R.H. Y.W. I.K. R.J.L. C.T. W.L. E.A. J.B. L.C. R.K.C. A.C. T.D. E.G.D. D.D. K.D. S.M.D. P.D. T.L.F. C.E.H. T.H. G.H. M.J. S.D.J. I.J. C.K. P.K. A.J.L. R.L. J.T.L. Y. Liao, T.M.L. J.A.M. R.P.M. R.M. W.M. M.M. M.E.M. J.M. R.J.M. M.D.N. C.N. T.O. G.S.O. S.H.P. V.A.P. A.I.R. H.R. K.V.R. D.R. S.R.S. A.A.S. T.S. Z.S. J.T. M.Ta. M.Th. J.M.W. K.K.W. B.W. C.M.W. Y. Wu, M.A.W. X.Y. X.Z. R.Z. D.M. A.M.C. R.D.S. A.I.N. P.W. M.W. L.D. D.R.M. H.Z. M.L.A. K.D.R. B.Z. T.L. and D.F.; Writing—Original drafts: Y.D. L.K. M.A.G. Y.H. B.R. R.H. Y.W. I.K. R.J.L. C.T. M.W. D.R.M. H.Z. M.L.A. K.D.R. B.Z. T.L. and D.F.; Writing—Review & editing: Y.D. L.K. M.A.G. Y.H. B.R. R.H. Y.W. I.K. R.J.L. C.T. W.B. W.L. X.G. E.A. R.C.A. J.B. L.C. R.K.C. A.C. T.D. E.G.D. D.D. K.D. S.M.D. P.D. B.D. T.L.F. M.F. C.E.H. T.H. G.H. M.J. S.D.J. I.J. A.G.K. A.T.K. C.K. P.K. A.J.L. R.L. J.T.L. Y. Li, Y. Liao, T.M.L. T. Lin, J.A.M. R.P.M. R.M. W.M. M.M. M.E.M. J.M. R.J.M. M.D.N. C.N. T.O. G.S.O. S.H.P. V.A.P. A.I.R. H.R. K.V.R. D.R. S.R.S. A.A.S. T.S. Z.S. J.T. M. Ta. M. Th. J.M.W. K.K.W. B.W. C.M.W. Y. Wu, M.A.W. X.Y. X.Z. R.Z. D.M. A.M.C. R.D.S. A.I.N. P.W. M.W. L.D. D.R.M. H.Z. M.L.A. K.D.R. B.Z. T.L. and D.F.; Supervision: M.W. D.R.M. H.Z. M.L.A. K.D.R. B.Z. T.L. and D.F.; Administration: M.L.A. K.D.R. B.Z. T.L. and D.F. The authors declare no competing interests. The Clinical Proteomic Tumor Analysis Consortium (CPTAC) is supported by the National Cancer Institute of the National Institutes of Health under award numbers U24CA210955 , U24CA210985 , U24CA210986 , U24CA210954 , U24CA210967 , U24CA210972 , U24CA210979 , U24CA210993 , U01CA214114 , U01CA214116 , U01CA214125 , U24CA271012 , U24CA271076 , U24CA271114 , and contracts from Leidos ( S21-167 and 21X164Q ); by NCI grant T32CA203690 ; by grant RR160027 from the Cancer Prevention & Research Institutes of Texas ( CPRIT ); and by funding from the McNair Medical Institute at The Robert and Janice McNair Foundation . B.Z. and M.E. are Cancer Prevention & Research Institutes of Texas Scholars in Cancer Research and McNair Medical Institute Scholars. The Pacific Northwest National Laboratory (PNNL) proteomics work described herein was performed in the Environmental Molecular Sciences Laboratory (grid.436923.9), a US Department of Energy (DOE) National Scientific User Facility located at PNNL in Richland, WA. PNNL is a multi-program national laboratory operated by the Battelle Memorial Institute for the DOE under contract DE-AC05-76RL01830. This work was also supported by a US Department of Defense funding DOD BC220523 .

Bailleurs de fondsNuméro du bailleur de fonds
Clinical Proteomic Tumor Analysis Consortium
Janice McNair Foundation
McNair Medical Institute
National Scientific User Facility
National Institutes of HealthS21-167, U24CA210955, U24CA210954, U24CA210979, U24CA210967, U24CA210972, U24CA210986, U24CA210985, U24CA271012, U24CA210993, U24CA271076, U01CA214116, U01CA214114, U01CA214125, 21X164Q, U24CA271114
U.S. Department of DefenseDOD BC220523
U.S. Department of EnergyDE-AC05-76RL01830
National Cancer InstituteT32CA203690, RR160027
Battelle
Cancer Prevention and Research Institute of Texas
Pacific Northwest National Laboratory

    ASJC Scopus Subject Areas

    • Oncology
    • Cancer Research

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