@article{20e2c4e270de4a40ad72a30f744ab8d0,
title = "Comprehensive characterization of protein–protein interactions perturbed by disease mutations",
abstract = "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.",
author = "Feixiong Cheng and Junfei Zhao and Yang Wang and Weiqiang Lu and Zehui Liu and Yadi Zhou and Martin, {William R.} and Ruisheng Wang and Jin Huang and Tong Hao and Hong Yue and Jing Ma and Yuan Hou and Castrillon, {Jessica A.} and Jiansong Fang and Lathia, {Justin D.} and Keri, {Ruth A.} and Lightstone, {Felice C.} and Antman, {Elliott Marshall} and Raul Rabadan and Hill, {David E.} and Charis Eng and Marc Vidal and Joseph Loscalzo",
note = "Funding Information: We thank S. Tribuna for expert technical assistance. A portion of this work was performed under the auspices of the US Department of Energy by Lawrence Livermore National Laboratory under contract no. DE-AC52-07NA27344 (release no. LLNL-JRNL-797982). 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. Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2021",
month = mar,
doi = "10.1038/s41588-020-00774-y",
language = "English (US)",
volume = "53",
pages = "342--353",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Publishing Group",
number = "3",
}