دورية أكاديمية
A modular master regulator landscape controls cancer transcriptional identity.
| العنوان: | A modular master regulator landscape controls cancer transcriptional identity. |
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| المؤلفون: | Paull EO; Department of Systems Biology, Columbia University Irving Medical Center, New York, NY 10032, USA., Aytes A; Department of Systems Biology, Columbia University Irving Medical Center, New York, NY 10032, USA; Molecular Mechanisms and Experimental Therapeutics in Oncology (ONCOBell), Bellvitge Institute for Biomedical Research, L'Hospitalet de Llobregat, Barcelona 08908, Spain; Program Against Cancer Therapeutics Resistance (ProCURE), Catalan Institute of Oncology, Bellvitge Institute for Biomedical Research, L'Hospitalet de Llobregat, Barcelona 08908, Spain., Jones SJ; Department of Systems Biology, Columbia University Irving Medical Center, New York, NY 10032, USA., Subramaniam PS; Department of Systems Biology, Columbia University Irving Medical Center, New York, NY 10032, USA., Giorgi FM; Department of Pharmacy and Biotechnology, University of Bologna, Bologna 40126, Italy., Douglass EF; Department of Systems Biology, Columbia University Irving Medical Center, New York, NY 10032, USA., Tagore S; Department of Systems Biology, Columbia University Irving Medical Center, New York, NY 10032, USA., Chu B; Department of Systems Biology, Columbia University Irving Medical Center, New York, NY 10032, USA., Vasciaveo A; Department of Systems Biology, Columbia University Irving Medical Center, New York, NY 10032, USA., Zheng S; Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Verhaak R; Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USA., Abate-Shen C; Department of Systems Biology, Columbia University Irving Medical Center, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY 10032, USA; Department of Molecular Pharmacology and Therapeutics, Columbia University Irving Medical Center, New York, NY 10032, USA; Department of Urology, Columbia University Irving Medical Center, New York, NY 10032, USA. Electronic address: ca2319@cumc.columbia.edu., Alvarez MJ; Department of Systems Biology, Columbia University Irving Medical Center, New York, NY 10032, USA; DarwinHealth, Inc. New York, NY 10018, USA. Electronic address: malvarez@darwinhealth.com., Califano A; Department of Systems Biology, Columbia University Irving Medical Center, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY 10032, USA; DarwinHealth, Inc. New York, NY 10018, USA; Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA; Department of Biochemistry & Molecular Biophysics, Columbia University Irving Medical Center, New York, NY 10032, USA; Department of Biomedical Informatics, Columbia University Irving Medical Center, New York, NY 10032, USA. Electronic address: ac2248@columbia.edu. |
| المصدر: | Cell [Cell] 2021 Jan 21; Vol. 184 (2), pp. 334-351.e20. Date of Electronic Publication: 2021 Jan 11. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S. |
| اللغة: | English |
| بيانات الدورية: | Publisher: Cell Press Country of Publication: United States NLM ID: 0413066 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1097-4172 (Electronic) Linking ISSN: 00928674 NLM ISO Abbreviation: Cell Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Cambridge, Ma : Cell Press Original Publication: Cambridge, MIT Press. |
| مواضيع طبية MeSH: | Transcription, Genetic*, Neoplasms/*genetics, Adenocarcinoma/genetics ; Animals ; Cell Line, Tumor ; Colonic Neoplasms/genetics ; Gene Expression Regulation, Neoplastic ; Gene Regulatory Networks ; Genome, Human ; HEK293 Cells ; Humans ; Mice, Nude ; Mutation/genetics ; Reproducibility of Results ; Mice |
| مستخلص: | Despite considerable efforts, the mechanisms linking genomic alterations to the transcriptional identity of cancer cells remain elusive. Integrative genomic analysis, using a network-based approach, identified 407 master regulator (MR) proteins responsible for canalizing the genetics of individual samples from 20 cohorts in The Cancer Genome Atlas (TCGA) into 112 transcriptionally distinct tumor subtypes. MR proteins could be further organized into 24 pan-cancer, master regulator block modules (MRBs), each regulating key cancer hallmarks and predictive of patient outcome in multiple cohorts. Of all somatic alterations detected in each individual sample, >50% were predicted to induce aberrant MR activity, yielding insight into mechanisms linking tumor genetics and transcriptional identity and establishing non-oncogene dependencies. Genetic and pharmacological validation assays confirmed the predicted effect of upstream mutations and MR activity on downstream cellular identity and phenotype. Thus, co-analysis of mutational and gene expression profiles identified elusive subtypes and provided testable hypothesis for mechanisms mediating the effect of genetic alterations. Competing Interests: Declaration of interests A.C. is founder, equity holder, consultant, and director of DarwinHealth Inc., a company that has licensed some of the algorithms used in this manuscript from Columbia University. M.J.A. is Chief Scientific Officer and equity holder at DarwinHealth, Inc. Patent 10,790,040, titled “Virtual Inference of Protein Activity by Regulon Analysis” has issued on Sept. 29, 2020 related to the VIPER method. Columbia University is also an equity holder in DarwinHealth Inc. (Copyright © 2020 Elsevier Inc. All rights reserved.) |
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| معلومات مُعتمدة: | U54 CA209997 United States CA NCI NIH HHS; R01 CA173481 United States CA NCI NIH HHS; S10 OD012351 United States OD NIH HHS; R01 CA196662 United States CA NCI NIH HHS; P30 CA013696 United States CA NCI NIH HHS; U01 CA217858 United States CA NCI NIH HHS; S10 OD021764 United States OD NIH HHS; R35 CA197745 United States CA NCI NIH HHS; R01 CA183929 United States CA NCI NIH HHS |
| فهرسة مساهمة: | Keywords: cancer genetics; cancer systems biology; genomic alteration; integrative genomics; multiomics; network analysis; pan-cancer analysis; transcriptional regulation |
| تواريخ الأحداث: | Date Created: 20210112 Date Completed: 20210826 Latest Revision: 20240402 |
| رمز التحديث: | 20240402 |
| مُعرف محوري في PubMed: | PMC8103356 |
| DOI: | 10.1016/j.cell.2020.11.045 |
| PMID: | 33434495 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1097-4172 |
|---|---|
| DOI: | 10.1016/j.cell.2020.11.045 |