Multiomics in primary and metastatic breast tumors from the AURORA US network finds microenvironment and epigenetic drivers of metastasis

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  • Garcia-Recio, S
    • University of North Carolina at Chapel Hill
  • Hinoue, T
    • Other Affiliation: Van Andel Institute, Grand Rapids, MI, United States
  • Wheeler, G.L
    • Other Affiliation: Nationwide Children’s Hospital, Columbus, OH, United States
  • Kelly, B.J
    • Other Affiliation: Nationwide Children’s Hospital, Columbus, OH, United States
  • Garrido-Castro, A.C
    • Other Affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, United States
  • Pascual, T
    • University of North Carolina at Chapel Hill
  • De Cubas, A.A
    • Other Affiliation: Vanderbilt University Medical Center, Nashville, TN, United States, Vanderbilt University Medical Center, Nashville, TN, United States
  • Xia, Y
    • University of North Carolina at Chapel Hill
  • Felsheim, B.M
    • University of North Carolina at Chapel Hill
  • McClure, M.B
    • University of North Carolina at Chapel Hill
  • Rajkovic, A
    • Other Affiliation: Nationwide Children’s Hospital, Columbus, OH, United States
  • Karaesmen, E
    • Other Affiliation: Nationwide Children’s Hospital, Columbus, OH, United States
  • Smith, M.A
    • University of North Carolina at Chapel Hill
  • Fan, C
    • University of North Carolina at Chapel Hill
  • Ericsson, P.I.G
    • Other Affiliation: Vanderbilt University Medical Center, Nashville, TN, United States
  • Sanders, M.E
    • Other Affiliation: Vanderbilt University Medical Center, Nashville, TN, United States
  • Creighton, C.J
    • Other Affiliation: Baylor College of Medicine, Houston, TX, United States
  • Bowen, J
    • Other Affiliation: Nationwide Children’s Hospital, Columbus, OH, United States
  • Leraas, K
    • Other Affiliation: Nationwide Children’s Hospital, Columbus, OH, United States
  • Burns, R.T
    • Other Affiliation: Translational Breast Cancer Research Consortium, Baltimore, United States
  • Coppens, S
    • Other Affiliation: Nationwide Children’s Hospital, Columbus, OH, United States
  • Wheless, A
    • University of North Carolina at Chapel Hill
  • Rezk, S
    • University of North Carolina at Chapel Hill
  • Garrett, A.L
    • University of North Carolina at Chapel Hill
  • Parker, J.S
    • University of North Carolina at Chapel Hill
  • Foy, K.K
    • Other Affiliation: Van Andel Institute, Grand Rapids, MI, United States
  • Shen, H
    • Other Affiliation: Van Andel Institute, Grand Rapids, MI, United States
  • Park, B.H
    • Other Affiliation: Vanderbilt University Medical Center, Nashville, TN, United States
  • Krop, I
    • Other Affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, United States
  • Anders, C
    • Other Affiliation: Duke University, Durham, NC, United States
  • Gastier-Foster, J
    • Other Affiliation: Nationwide Children’s Hospital, Columbus, OH, United States
  • Rimawi, M.F
    • Other Affiliation: Baylor College of Medicine, Houston, TX, United States
  • Nanda, R
    • Other Affiliation: University of Chicago, Chicago, IL, United States
  • Lin, N.U
    • Other Affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, United States
  • Isaacs, C.
    • Other Affiliation: Georgetown University, Washington, DC, United States
  • Marcom, P.K.
    • Other Affiliation: Duke University, Durham, NC, United States
  • Storniolo, A.M.
    • Other Affiliation: Indiana University School of Medicine, Indianapolis, IN, United States
  • Couch, F.J.
    • Other Affiliation: Mayo Clinic, Rochester, MN, United States
  • Chandran, U.
    • Other Affiliation: UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, United States
  • Davis, M.
    • Other Affiliation: UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, United States
  • Silverstein, J.
    • Other Affiliation: UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, United States
  • Ropelewski, A.
    • Other Affiliation: Pittsburgh Supercomputing Center, Carnegie Mellon University, Pittsburgh, PA, United States
  • Liu, M.C.
    • Other Affiliation: Mayo Clinic, Rochester, MN, United States
  • Hilsenbeck, S.G.
    • Other Affiliation: Baylor College of Medicine, Houston, TX, United States
  • Norton, L.
    • Other Affiliation: Memorial Sloan Kettering Cancer Center, New York, NY, United States
  • Richardson, A.L.
    • Other Affiliation: Johns Hopkins University, Baltimore, MD, United States
  • Symmans, W.F.
    • Other Affiliation: MD Anderson Cancer Center, Houston, TX, United States
  • Wolff, A.C.
    • Other Affiliation: Johns Hopkins University, Baltimore, MD, United States
  • Davidson, N.E.
    • Other Affiliation: Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA, United States
  • Carey, L.A.
    • University of North Carolina at Chapel Hill
  • Lee, A.V.
    • Other Affiliation: UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, United States
  • Balko, J.M.
    • Other Affiliation: Vanderbilt University Medical Center, Nashville, TN, United States
  • Hoadley, K.A.
    • University of North Carolina at Chapel Hill
  • Laird, P.W.
    • Other Affiliation: Van Andel Institute, Grand Rapids, MI, United States
  • Mardis, E.R.
    • Other Affiliation: Nationwide Children’s Hospital, Columbus, OH, United States
  • King, T.A.
    • Other Affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, United States
  • De Cubas, A.A.
    • Other Affiliation: Vanderbilt University Medical Center, Nashville, TN, United States
  • Perou, C.M.
    • University of North Carolina at Chapel Hill
  • AURORA US Network
Abstract
  • The AURORA US Metastasis Project was established with the goal to identify molecular features associated with metastasis. We assayed 55 females with metastatic breast cancer (51 primary cancers and 102 metastases) by RNA sequencing, tumor/germline DNA exome and low-pass whole-genome sequencing and global DNA methylation microarrays. Expression subtype changes were observed in ~30% of samples and were coincident with DNA clonality shifts, especially involving HER2. Downregulation of estrogen receptor (ER)-mediated cell–cell adhesion genes through DNA methylation mechanisms was observed in metastases. Microenvironment differences varied according to tumor subtype; the ER+/luminal subtype had lower fibroblast and endothelial content, while triple-negative breast cancer/basal metastases showed a decrease in B and T cells. In 17% of metastases, DNA hypermethylation and/or focal deletions were identified near HLA-A and were associated with reduced expression and lower immune cell infiltrates, especially in brain and liver metastases. These findings could have implications for treating individuals with metastatic breast cancer with immune- and HER2-targeting therapies.
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  • Article
Rights statement
  • In Copyright
License
  • Attribution 4.0 International
Journal title
  • Nature Cancer
Journal volume
  • 4
Journal issue
  • 1
Page start
  • 128
Page end
  • 147
Language
  • English
Version
  • Publisher
Funder
  • National Center for Advancing Translational Sciences, NCATS
  • National Institutes of Health, NIH: UL1TR002489
  • Vanderbilt-Ingram Cancer Center, VICC: P30 CA68485
  • Breast Cancer Research Foundation, BCRF: ELFF-14-002
  • National Cancer Institute, NCI: 2P50CA098131-17, P30-CA016086-45, P50-CA058223
  • National Human Genome Research Institute, NHGRI: phs000178
ISSN
  • 2662-1347
Publisher
  • Nature Research

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