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Epigenetic and transcriptomic characterization reveals progression markers and essential pathways in clear cell renal cell carcinoma

Author

Listed:
  • Yige Wu

    (Washington University in St. Louis
    Washington University in St. Louis)

  • Nadezhda V. Terekhanova

    (Washington University in St. Louis
    Washington University in St. Louis)

  • Wagma Caravan

    (Washington University in St. Louis
    Washington University in St. Louis)

  • Nataly Naser Al Deen

    (Washington University in St. Louis
    Washington University in St. Louis)

  • Preet Lal

    (Washington University in St. Louis)

  • Siqi Chen

    (Washington University in St. Louis
    Washington University in St. Louis)

  • Chia-Kuei Mo

    (Washington University in St. Louis
    Washington University in St. Louis)

  • Song Cao

    (Washington University in St. Louis
    Washington University in St. Louis)

  • Yize Li

    (Washington University in St. Louis
    Washington University in St. Louis)

  • Alla Karpova

    (Washington University in St. Louis
    Washington University in St. Louis)

  • Ruiyang Liu

    (Washington University in St. Louis
    Washington University in St. Louis)

  • Yanyan Zhao

    (Washington University in St. Louis)

  • Andrew Shinkle

    (Washington University in St. Louis
    Washington University in St. Louis)

  • Ilya Strunilin

    (Washington University in St. Louis
    Washington University in St. Louis)

  • Cody Weimholt

    (Washington University in St. Louis)

  • Kazuhito Sato

    (Washington University in St. Louis)

  • Lijun Yao

    (Washington University in St. Louis
    Washington University in St. Louis)

  • Mamatha Serasanambati

    (Washington University in St. Louis)

  • Xiaolu Yang

    (Washington University in St. Louis)

  • Matthew Wyczalkowski

    (Washington University in St. Louis
    Washington University in St. Louis)

  • Houxiang Zhu

    (Washington University in St. Louis
    Washington University in St. Louis)

  • Daniel Cui Zhou

    (Washington University in St. Louis
    Washington University in St. Louis)

  • Reyka G. Jayasinghe

    (Washington University in St. Louis
    Washington University in St. Louis)

  • Daniel Mendez

    (Washington University in St. Louis)

  • Michael C. Wendl

    (Washington University in St. Louis
    Washington University in St. Louis
    Washington University in St. Louis
    Washington University in St. Louis)

  • David Clark

    (Johns Hopkins University)

  • Chelsea Newton

    (Van Andel Institutes)

  • Yijun Ruan

    (The Jackson Laboratory for Genomic Medicine)

  • Melissa A. Reimers

    (Washington University in St. Louis
    Washington University School of Medicine)

  • Russell K. Pachynski

    (Washington University in St. Louis
    Washington University School of Medicine)

  • Chris Kinsinger

    (Office of Cancer Clinical Proteomics Research, National Cancer Institute)

  • Scott Jewell

    (Van Andel Institutes)

  • Daniel W. Chan

    (Johns Hopkins University)

  • Hui Zhang

    (Johns Hopkins University)

  • Aadel A. Chaudhuri

    (Washington University in St. Louis
    Washington University School of Medicine
    Washington University in St. Louis)

  • Milan G. Chheda

    (Washington University in St. Louis
    Washington University School of Medicine)

  • Benjamin D. Humphreys

    (Washington University in St. Louis)

  • Mehdi Mesri

    (Office of Cancer Clinical Proteomics Research, National Cancer Institute)

  • Henry Rodriguez

    (Office of Cancer Clinical Proteomics Research, National Cancer Institute)

  • James J. Hsieh

    (Washington University in St. Louis)

  • Li Ding

    (Washington University in St. Louis
    Washington University in St. Louis
    Washington University in St. Louis
    Washington University in St. Louis)

  • Feng Chen

    (Washington University in St. Louis
    Washington University in St. Louis)

Abstract

Identifying tumor-cell-specific markers and elucidating their epigenetic regulation and spatial heterogeneity provides mechanistic insights into cancer etiology. Here, we perform snRNA-seq and snATAC-seq in 34 and 28 human clear cell renal cell carcinoma (ccRCC) specimens, respectively, with matched bulk proteogenomics data. By identifying 20 tumor-specific markers through a multi-omics tiered approach, we reveal an association between higher ceruloplasmin (CP) expression and reduced survival. CP knockdown, combined with spatial transcriptomics, suggests a role for CP in regulating hyalinized stroma and tumor-stroma interactions in ccRCC. Intratumoral heterogeneity analysis portrays tumor cell-intrinsic inflammation and epithelial-mesenchymal transition (EMT) as two distinguishing features of tumor subpopulations. Finally, BAP1 mutations are associated with widespread reduction of chromatin accessibility, while PBRM1 mutations generally increase accessibility, with the former affecting five times more accessible peaks than the latter. These integrated analyses reveal the cellular architecture of ccRCC, providing insights into key markers and pathways in ccRCC tumorigenesis.

Suggested Citation

  • Yige Wu & Nadezhda V. Terekhanova & Wagma Caravan & Nataly Naser Al Deen & Preet Lal & Siqi Chen & Chia-Kuei Mo & Song Cao & Yize Li & Alla Karpova & Ruiyang Liu & Yanyan Zhao & Andrew Shinkle & Ilya , 2023. "Epigenetic and transcriptomic characterization reveals progression markers and essential pathways in clear cell renal cell carcinoma," Nature Communications, Nature, vol. 14(1), pages 1-25, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37211-7
    DOI: 10.1038/s41467-023-37211-7
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    1. Ghislaine Scelo & Yasser Riazalhosseini & Liliana Greger & Louis Letourneau & Mar Gonzàlez-Porta & Magdalena B. Wozniak & Mathieu Bourgey & Patricia Harnden & Lars Egevad & Sharon M. Jackson & Mehran , 2014. "Variation in genomic landscape of clear cell renal cell carcinoma across Europe," Nature Communications, Nature, vol. 5(1), pages 1-13, December.
    2. Melusine Bleu & Swann Gaulis & Rui Lopes & Kathleen Sprouffske & Verena Apfel & Sjoerd Holwerda & Marco Pregnolato & Umut Yildiz & Valentina Cordoʹ & Antonella F. M. Dost & Judith Knehr & Walter Carbo, 2019. "PAX8 activates metabolic genes via enhancer elements in Renal Cell Carcinoma," Nature Communications, Nature, vol. 10(1), pages 1-10, December.
    3. Johanna C. Scheuermann & Andrés Gaytán de Ayala Alonso & Katarzyna Oktaba & Nga Ly-Hartig & Robert K. McGinty & Sven Fraterman & Matthias Wilm & Tom W. Muir & Jürg Müller, 2010. "Histone H2A deubiquitinase activity of the Polycomb repressive complex PR-DUB," Nature, Nature, vol. 465(7295), pages 243-247, May.
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    Cited by:

    1. Tao Liu & Shuang Chai & Mingyang Li & Xu Chen & Yutao Xie & Zehui Zhao & Jingjing Xie & Yunpeng Yu & Feng Gao & Feng Zhu & Lihua Yang, 2024. "A nanoparticle-based sonodynamic therapy reduces Helicobacter pylori infection in mouse without disrupting gut microbiota," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    2. Akihiko Fukagawa & Natsuko Hama & Yasushi Totoki & Hiromi Nakamura & Yasuhito Arai & Mihoko Saito-Adachi & Akiko Maeshima & Yoshiyuki Matsui & Shinichi Yachida & Tetsuo Ushiku & Tatsuhiro Shibata, 2023. "Genomic and epigenomic integrative subtypes of renal cell carcinoma in a Japanese cohort," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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