机构：[1]Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.[2]Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH, USA.[3]Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA.[4]Department of Systems Biology, Herbert Irving Comprehensive Center, Columbia University, New York, NY, USA.[5]Department of Biomedical Informatics, Columbia University, New York, NY, USA.[6]Center for Cancer Systems Biology (CCSB), Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.[7]Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.[8]Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.[9]Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China.[10]Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA.[11]Research Center for Healthcare Data Science, Zhejiang Lab, Hangzhou, Zhejiang, China.[12]Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China.[13]Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, OH, USA.[14]Biosciences and Biotechnology Division, Physical and Life Sciences Directorate, Lawrence Livermore National Lab, Livermore, CA, USA.[15]Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA.[16]Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH, USA.[17]Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.
Technological and computational advances in genomics and interactomics have made it possible to identify how disease mutations perturb protein-protein interaction (PPI) networks within human cells. Here, we show that disease-associated germline variants are significantly enriched in sequences encoding PPI interfaces compared to variants identified in healthy participants from the projects 1000 Genomes and ExAC. Somatic missense mutations are also significantly enriched in PPI interfaces compared to noninterfaces in 10,861 tumor exomes. We computationally identified 470 putative oncoPPIs in a pan-cancer analysis and demonstrate that oncoPPIs are highly correlated with patient survival and drug resistance/sensitivity. We experimentally validate the network effects of 13 oncoPPIs using a systematic binary interaction assay, and also demonstrate the functional consequences of two of these on tumor cell growth. In summary, this human interactome network framework provides a powerful tool for prioritization of alleles with PPI-perturbing mutations to inform pathobiological mechanism- and genotype-based therapeutic discovery.
基金：
This work was supported by National Institutes of Health (NIH)
grant nos. K99 HL138272, R00 HL138272, 3R01AG066707-01S1 and R01AG066707
to F.C. This work was also supported in part by NIH grant nos. U01 HG007690, P50
GM107618, U54 HL119145, R01 HL155107 and R01 HL155096 to J.L., as well as by
AHA grant nos. D700382 and CV-19 to J.L. F.C.L. was supported by AHA CRADA
no. TC02274.0. C.E. is the Sondra J. and Stephen R. Hardis Endowed Chair in Cancer
Genomic Medicine at the Cleveland Clinic, and an ACS Clinical Research Professor.
M.V. and D.E.H. were supported by NIH grant nos. P50 HG004233 and U41 HG001715 from NHGRI. This work has been also supported in part by the VeloSano Pilot Program
(Cleveland Clinic Taussig Cancer Institute) to F.C.
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外文
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大类|1 区生物
小类|1 区遗传学
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小类|1 区遗传学
第一作者：
第一作者机构：[1]Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.[2]Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH, USA.[3]Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
共同第一作者：
通讯作者：
推荐引用方式(GB/T 7714)：
Feixiong Cheng,Junfei Zhao,Yang Wang,et al.Comprehensive characterization of protein-protein interactions perturbed by disease mutations.[J].Nature genetics.2021,53(3):342-353.doi:10.1038/s41588-020-00774-y.
APA：
Feixiong Cheng,Junfei Zhao,Yang Wang,Weiqiang Lu,Zehui Liu...&Joseph Loscalzo.(2021).Comprehensive characterization of protein-protein interactions perturbed by disease mutations..Nature genetics,53,(3)
MLA：
Feixiong Cheng,et al."Comprehensive characterization of protein-protein interactions perturbed by disease mutations.".Nature genetics 53..3(2021):342-353
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