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A multiscale functional map of somatic mutations in cancer integrating protein structure and network topology

Author

Listed:
  • Yingying Zhang

    (Cornell University
    Cornell University
    Cornell University)

  • Alden K. Leung

    (Cornell University
    Cornell University)

  • Jin Joo Kang

    (Cornell University
    Cornell University)

  • Yu Sun

    (Cornell University
    Cornell University)

  • Guanxi Wu

    (Cornell University)

  • Le Li

    (Cornell University
    Cornell University)

  • Jiayang Sun

    (Cornell University)

  • Lily Cheng

    (Cornell University)

  • Tian Qiu

    (Cornell University)

  • Junke Zhang

    (Cornell University
    Cornell University)

  • Shayne D. Wierbowski

    (Cornell University
    Cornell University)

  • Shagun Gupta

    (Cornell University
    Cornell University)

  • James G. Booth

    (Cornell University
    Cornell University)

  • Haiyuan Yu

    (Cornell University
    Cornell University)

Abstract

A major goal of cancer biology is to understand the mechanisms driven by somatically acquired mutations. Two distinct methodologies—one analyzing mutation clustering within protein sequences and 3D structures, the other leveraging protein-protein interaction network topology—offer complementary strengths. We present NetFlow3D, a unified, end-to-end 3D structurally-informed protein interaction network propagation framework that maps the multiscale mechanistic effects of mutations. Built upon the Human Protein Structurome, which incorporates the 3D structures of every protein and the binding interfaces of all known protein interactions, NetFlow3D integrates atomic, residue, protein and network-level information: It clusters mutations on 3D protein structures to identify driver mutations and propagates their impacts anisotropically across the protein interaction network, guided by the involved interaction interfaces, to reveal systems-level impacts. Applied to 33 cancer types, NetFlow3D identifies 2 times more 3D clusters and incorporates 8 times more proteins in significantly interconnected network modules compared to traditional methods.

Suggested Citation

  • Yingying Zhang & Alden K. Leung & Jin Joo Kang & Yu Sun & Guanxi Wu & Le Li & Jiayang Sun & Lily Cheng & Tian Qiu & Junke Zhang & Shayne D. Wierbowski & Shagun Gupta & James G. Booth & Haiyuan Yu, 2025. "A multiscale functional map of somatic mutations in cancer integrating protein structure and network topology," Nature Communications, Nature, vol. 16(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-024-54176-3
    DOI: 10.1038/s41467-024-54176-3
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    References listed on IDEAS

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    1. Hongjian Qi & Haicang Zhang & Yige Zhao & Chen Chen & John J. Long & Wendy K. Chung & Yongtao Guan & Yufeng Shen, 2021. "MVP predicts the pathogenicity of missense variants by deep learning," Nature Communications, Nature, vol. 12(1), pages 1-9, December.
    2. Kathryn Tunyasuvunakool & Jonas Adler & Zachary Wu & Tim Green & Michal Zielinski & Augustin Žídek & Alex Bridgland & Andrew Cowie & Clemens Meyer & Agata Laydon & Sameer Velankar & Gerard J. Kleywegt, 2021. "Highly accurate protein structure prediction for the human proteome," Nature, Nature, vol. 596(7873), pages 590-596, August.
    3. Zachary C. Drake & Justin T. Seffernick & Steffen Lindert, 2022. "Protein complex prediction using Rosetta, AlphaFold, and mass spectrometry covalent labeling," Nature Communications, Nature, vol. 13(1), pages 1-9, December.
    4. Fiona M. Behan & Francesco Iorio & Gabriele Picco & Emanuel Gonçalves & Charlotte M. Beaver & Giorgia Migliardi & Rita Santos & Yanhua Rao & Francesco Sassi & Marika Pinnelli & Rizwan Ansari & Sarah H, 2019. "Prioritization of cancer therapeutic targets using CRISPR–Cas9 screens," Nature, Nature, vol. 568(7753), pages 511-516, April.
    5. Mu Gao & Davi Nakajima An & Jerry M. Parks & Jeffrey Skolnick, 2022. "AF2Complex predicts direct physical interactions in multimeric proteins with deep learning," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    6. Michael S. Lawrence & Petar Stojanov & Paz Polak & Gregory V. Kryukov & Kristian Cibulskis & Andrey Sivachenko & Scott L. Carter & Chip Stewart & Craig H. Mermel & Steven A. Roberts & Adam Kiezun & Pe, 2013. "Mutational heterogeneity in cancer and the search for new cancer-associated genes," Nature, Nature, vol. 499(7457), pages 214-218, July.
    7. Yuki Saito & Junji Koya & Mitsugu Araki & Yasunori Kogure & Sumito Shingaki & Mariko Tabata & Marni B. McClure & Kota Yoshifuji & Shigeyuki Matsumoto & Yuta Isaka & Hiroko Tanaka & Takanori Kanai & Sa, 2020. "Landscape and function of multiple mutations within individual oncogenes," Nature, Nature, vol. 582(7810), pages 95-99, June.
    8. John Jumper & Richard Evans & Alexander Pritzel & Tim Green & Michael Figurnov & Olaf Ronneberger & Kathryn Tunyasuvunakool & Russ Bates & Augustin Žídek & Anna Potapenko & Alex Bridgland & Clemens Me, 2021. "Highly accurate protein structure prediction with AlphaFold," Nature, Nature, vol. 596(7873), pages 583-589, August.
    9. Esther Rheinbay & Morten Muhlig Nielsen & Federico Abascal & Jeremiah A. Wala & Ofer Shapira & Grace Tiao & Henrik Hornshøj & Julian M. Hess & Randi Istrup Juul & Ziao Lin & Lars Feuerbach & Radhakris, 2020. "Analyses of non-coding somatic drivers in 2,658 cancer whole genomes," Nature, Nature, vol. 578(7793), pages 102-111, February.
    10. Jedidiah Carlson & Adam E. Locke & Matthew Flickinger & Matthew Zawistowski & Shawn Levy & Richard M. Myers & Michael Boehnke & Hyun Min Kang & Laura J. Scott & Jun Z. Li & Sebastian Zöllner, 2018. "Extremely rare variants reveal patterns of germline mutation rate heterogeneity in humans," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
    11. Konrad J. Karczewski & Laurent C. Francioli & Grace Tiao & Beryl B. Cummings & Jessica Alföldi & Qingbo Wang & Ryan L. Collins & Kristen M. Laricchia & Andrea Ganna & Daniel P. Birnbaum & Laura D. Gau, 2020. "The mutational constraint spectrum quantified from variation in 141,456 humans," Nature, Nature, vol. 581(7809), pages 434-443, May.
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