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  3. Interpretation of cancer mutations using a multiscale map of protein systems

Interpretation of cancer mutations using a multiscale map of protein systems

  • Science. 2021 Oct;374(6563):eabf3067. doi: 10.1126/science.abf3067.
Fan Zheng  # 1 2,  Marcus R Kelly  # 1 2,  Dana J Ramms 2 3 4,  Marissa L Heintschel 5,  Kai Tao 6 7,  Beril Tutuncuoglu 2 8 9 10,  John J Lee 1,  Keiichiro Ono 1,  Helene Foussard 8 9 10,  Michael Chen 1,  Kari A Herrington 11,  Erica Silva 1,  Sophie N Liu 1,  Jing Chen 1,  Christopher Churas 1,  Nicholas Wilson 1,  Anton Kratz 1 2,  Rudolf T Pillich 1 2,  Devin N Patel 1 2,  Jisoo Park 1 2,  Brent Kuenzi 1 2,  Michael K Yu 1,  Katherine Licon 1 2,  Dexter Pratt 1,  Jason F Kreisberg 1 2,  Minkyu Kim 2 8 9 10,  Danielle L Swaney 2 8 9 10,  Xiaolin Nan 6 7 12,  Stephanie I Fraley 5,  J Silvio Gutkind 2 3 4,  Nevan J Krogan 2 8 9 10,  Trey Ideker 1 2 3 5
Affiliations

Affiliations

  • 1 Division of Genetics, Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA.
  • 2 Cancer Cell Map Initiative (CCMI), La Jolla, CA, USA.
  • 3 Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA.
  • 4 Department of Pharmacology, University of California San Diego, La Jolla, CA 92093, USA.
  • 5 Department of Bioengineering, University of California San Diego, La Jolla, CA 92093, USA.
  • 6 Department of Biomedical Engineering, Oregon Health and Science University, Portland, OR 97239, USA.
  • 7 Center for Spatial Systems Biomedicine, Oregon Health and Science University, Portland, OR 97201, USA.
  • 8 Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158, USA.
  • 9 J. David Gladstone Institutes, San Francisco, CA 94158, USA.
  • 10 Quantitative Biosciences Institute, University of California, San Francisco, CA 94158, USA.
  • 11 Department of Biochemistry and Biophysics Center for Advanced Light Microscopy at UCSF, University of California, San Francisco, CA 94158, USA.
  • 12 Knight Cancer Early Detection Advanced Research Center, Oregon Health and Science University, Portland, OR 97201, USA.
  • # Contributed equally.
PMID: 34591613 DOI: 10.1126/science.abf3067
Abstract

A major goal of Cancer research is to understand how mutations distributed across diverse genes affect common cellular systems, including multiprotein complexes and assemblies. Two challenges—how to comprehensively map such systems and how to identify which are under mutational selection—have hindered this understanding. Accordingly, we created a comprehensive map of Cancer protein systems integrating both new and published multi-omic interaction data at multiple scales of analysis. We then developed a unified statistical model that pinpoints 395 specific systems under mutational selection across 13 Cancer types. This map, called NeST (Nested Systems in Tumors), incorporates canonical processes and notable discoveries, including a PIK3CA-actomyosin complex that inhibits phosphatidylinositol 3-kinase signaling and recurrent mutations in collagen complexes that promote tumor proliferation. These systems can be used as clinical biomarkers and implicate a total of 548 genes in Cancer evolution and progression. This work shows how disparate tumor mutations converge on protein assemblies at different scales.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-15244
    99.95%, PI3Kα抑制剂
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