Integrated Genomic Analysis of the Ubiquitin Pathway across Cancer Types

The Cancer Genome Atlas Research Network

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

Abstract

Protein ubiquitination is a dynamic and reversible process of adding single ubiquitin molecules or various ubiquitin chains to target proteins. Here, using multidimensional omic data of 9,125 tumor samples across 33 cancer types from The Cancer Genome Atlas, we perform comprehensive molecular characterization of 929 ubiquitin-related genes and 95 deubiquitinase genes. Among them, we systematically identify top somatic driver candidates, including mutated FBXW7 with cancer-type-specific patterns and amplified MDM2 showing a mutually exclusive pattern with BRAF mutations. Ubiquitin pathway genes tend to be upregulated in cancer mediated by diverse mechanisms. By integrating pan-cancer multiomic data, we identify a group of tumor samples that exhibit worse prognosis. These samples are consistently associated with the upregulation of cell-cycle and DNA repair pathways, characterized by mutated TP53, MYC/TERT amplification, and APC/PTEN deletion. Our analysis highlights the importance of the ubiquitin pathway in cancer development and lays a foundation for developing relevant therapeutic strategies. Ge et al. analyze a cohort of 9,125 TCGA samples across 33 cancer types to provide a comprehensive characterization of the ubiquitin pathway. They detect somatic driver candidates in the ubiquitin pathway and identify a cluster of patients with poor survival, highlighting the importance of this pathway in cancer development.

Original languageEnglish (US)
Pages (from-to)213-226.e3
JournalCell reports
Volume23
Issue number1
DOIs
StatePublished - Apr 3 2018

Bibliographical note

Funding Information:
This study was supported in part by the NIH ( R01CA175486 and U24CA209851 to H.L., R01CA166051 and R01CA181029 to L.M., U54HG003273 , U54HG003067 , U54HG003079 , U24CA143799 , U24CA143835 , U24CA143840 , U24CA143843 , U24CA143845 , U24CA143848 , U24CA143858 , U24CA143866 , U24CA143867 , U24CA143882 , U24CA143883 , U24CA144025 , and P30CA016672 ), the Cancer Prevention and Research Institute of Texas ( RP140462 to H.L. and RP150319 to L.M.), a Stand Up To Cancer Innovative Research Grant (to L.M.), a University of Texas System STARS award (to H.L.), and the US Department of Defense through the Henry M. Jackson Foundation for the Advancement of Military Medicine ( W81XWH-12-2-0050 , HU0001-16-2-0004 ). We thank the MD Anderson high-performance computing core facility for computing and LeeAnn Chastain for editorial assistance. The views expressed in this article are those of the authors and do not reflect the official policy of the U.S. Army, Navy, Air Force, Department of Defense, or government.

Funding Information:
Michael Seiler, Peter G. Smith, Ping Zhu, Silvia Buonamici, and Lihua Yu are employees of H3 Biomedicine, Inc. Parts of this work are the subject of a patent application: WO2017040526 titled “Splice variants associated with neomorphic sf3b1 mutants.” Shouyoung Peng, Anant A. Agrawal, James Palacino, and Teng Teng are employees of H3 Biomedicine, Inc. Andrew D. Cherniack, Ashton C. Berger, and Galen F. Gao receive research support from Bayer Pharmaceuticals. Gordon B. Mills serves on the External Scientific Review Board of Astrazeneca. Anil Sood is on the Scientific Advisory Board for Kiyatec and is a shareholder in BioPath. Jonathan S. Serody receives funding from Merck, Inc. Kyle R. Covington is an employee of Castle Biosciences, Inc. Preethi H. Gunaratne is founder, CSO, and shareholder of NextmiRNA Therapeutics. Christina Yau is a part-time employee/consultant at NantOmics. Franz X. Schaub is an employee and shareholder of SEngine Precision Medicine, Inc. Carla Grandori is an employee, founder, and shareholder of SEngine Precision Medicine, Inc. Robert N. Eisenman is a member of the Scientific Advisory Boards and shareholder of Shenogen Pharma and Kronos Bio. Daniel J. Weisenberger is a consultant for Zymo Research Corporation. Joshua M. Stuart is the founder of Five3 Genomics and shareholder of NantOmics. Marc T. Goodman receives research support from Merck, Inc. Andrew J. Gentles is a consultant for Cibermed. Charles M. Perou is an equity stock holder, consultant, and Board of Directors member of BioClassifier and GeneCentric Diagnostics and is also listed as an inventor on patent applications on the Breast PAM50 and Lung Cancer Subtyping assays. Matthew Meyerson receives research support from Bayer Pharmaceuticals; is an equity holder in, consultant for, and Scientific Advisory Board chair for OrigiMed; and is an inventor of a patent for EGFR mutation diagnosis in lung cancer, licensed to LabCorp. Eduard Porta-Pardo is an inventor of a patent for domainXplorer. Han Liang is a shareholder and scientific advisor of Precision Scientific and Eagle Nebula. Da Yang is an inventor on a pending patent application describing the use of antisense oligonucleotides against specific lncRNA sequence as diagnostic and therapeutic tools. Yonghong Xiao was an employee and shareholder of TESARO, Inc. Bin Feng is an employee and shareholder of TESARO, Inc. Carter Van Waes received research funding for the study of IAP inhibitor ASTX660 through a Cooperative Agreement between NIDCD, NIH, and Astex Pharmaceuticals. Raunaq Malhotra is an employee and shareholder of Seven Bridges, Inc. Peter W. Laird serves on the Scientific Advisory Board for AnchorDx. Joel Tepper is a consultant at EMD Serono. Kenneth Wang serves on the Advisory Board for Boston Scientific, Microtech, and Olympus. Andrea Califano is a founder, shareholder, and advisory board member of DarwinHealth, Inc. and a shareholder and advisory board member of Tempus, Inc. Toni K. Choueiri serves as needed on advisory boards for Bristol-Myers Squibb, Merck, and Roche. Lawrence Kwong receives research support from Array BioPharma. Sharon E. Plon is a member of the Scientific Advisory Board for Baylor Genetics Laboratory. Beth Y. Karlan serves on the Advisory Board of Invitae.

Funding Information:
This study was supported in part by the NIH (R01CA175486 and U24CA209851 to H.L., R01CA166051 and R01CA181029 to L.M., U54HG003273, U54HG003067, U54HG003079, U24CA143799, U24CA143835, U24CA143840, U24CA143843, U24CA143845, U24CA143848, U24CA143858, U24CA143866, U24CA143867, U24CA143882, U24CA143883, U24CA144025, and P30CA016672), the Cancer Prevention and Research Institute of Texas (RP140462 to H.L. and RP150319 to L.M.), a Stand Up To Cancer Innovative Research Grant (to L.M.), a University of Texas System STARS award (to H.L.), and the US Department of Defense through the Henry M. Jackson Foundation for the Advancement of Military Medicine (W81XWH-12-2-0050, HU0001-16-2-0004). We thank the MD Anderson high-performance computing core facility for computing and LeeAnn Chastain for editorial assistance. The views expressed in this article are those of the authors and do not reflect the official policy of the U.S. Army, Navy, Air Force, Department of Defense, or government.

Publisher Copyright:
© 2018 The Authors

Keywords

  • FBXW7
  • The Cancer Genome Atlas
  • biomarker
  • cancer prognosis
  • pan-cancer analysis
  • therapeutic targets
  • tumor subtype
  • ubiquitin pathway

Fingerprint Dive into the research topics of 'Integrated Genomic Analysis of the Ubiquitin Pathway across Cancer Types'. Together they form a unique fingerprint.

Cite this