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Am J Hum Genet. 2017 Jan 5;100(1):5-20. doi: 10.1016/j.ajhg.2016.09.020. Epub 2016 Dec 8.

Proteome-Scale Investigation of Protein Allosteric Regulation Perturbed by Somatic Mutations in 7,000 Cancer Genomes.

Author information

1
Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao-Tong University School of Medicine, Shanghai 200025, China.
2
State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, Sichuan, China; Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, TN 37203, USA.
3
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.
4
Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, TN 37203, USA.
5
Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA. Electronic address: zhongming.zhao@uth.tmc.edu.
6
Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao-Tong University School of Medicine, Shanghai 200025, China. Electronic address: jian.zhang@sjtu.edu.cn.

Abstract

The allosteric regulation triggering the protein's functional activity via conformational changes is an intrinsic function of protein under many physiological and pathological conditions, including cancer. Identification of the biological effects of specific somatic variants on allosteric proteins and the phenotypes that they alter during tumor initiation and progression is a central challenge for cancer genomes in the post-genomic era. Here, we mapped more than 47,000 somatic missense mutations observed in approximately 7,000 tumor-normal matched samples across 33 cancer types into protein allosteric sites to prioritize the mutated allosteric proteins and we tested our prediction in cancer cell lines. We found that the deleterious mutations identified in cancer genomes were more significantly enriched at protein allosteric sites than tolerated mutations, suggesting a critical role for protein allosteric variants in cancer. Next, we developed a statistical approach, namely AlloDriver, and further identified 15 potential mutated allosteric proteins during pan-cancer and individual cancer-type analyses. More importantly, we experimentally confirmed that p.Pro360Ala on PDE10A played a potential oncogenic role in mediating tumorigenesis in non-small cell lung cancer (NSCLC). In summary, these findings shed light on the role of allosteric regulation during tumorigenesis and provide a useful tool for the timely development of targeted cancer therapies.

PMID:
27939638
PMCID:
PMC5223033
DOI:
10.1016/j.ajhg.2016.09.020
[Indexed for MEDLINE]
Free PMC Article

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