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Individualized Genetic Network Analysis Reveals New Therapeutic Vulnerabilities in Cancer

56 Pages Posted: 3 Oct 2018

See all articles by Chuang Liu

Chuang Liu

Hangzhou Normal University - Alibaba Research Center for Complexity Sciences

Junfei Zhao

Columbia University - Department of Systems Biology; Columbia University - Department of Biomedical Informatics

Yao Dai

Hangzhou Normal University - Alibaba Research Center for Complexity Sciences

Jennifer Hockings

Cleveland Clinic - Genomic Medicine Institute

Ruth Nussinov

National Institutes of Health (NIH) - National Cancer Institute at Frederick ; Tel Aviv University - Department of Human Molecular Genetics and Biochemistry

Charis Eng

Cleveland Clinic, Lerner Research Institute, Genomic Medicine Institute; Cleveland Clinic, Lerner College of Medicine, Department of Molecular Medicine; Case Western Reserve University, School of Medicine, Case Comprehensive Cancer Center; Case Western Reserve University, School of Medicine, Department of Genetics and Genome Sciences; Cleveland Clinic - Taussig Cancer Institute

Feixiong Cheng

Cleveland Clinic, Lerner Research Institute, Genomic Medicine Institute; Cleveland Clinic, Lerner College of Medicine, Department of Molecular Medicine; Case Western Reserve University, School of Medicine, Case Comprehensive Cancer Center

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Abstract

Background: Tumor-specific genomic alterations derived from multi-center cancer genome projects allow systematic identification of genetic interactions that promote tumor vulnerabilities, offering novel strategies for development of targeted therapies for individual tumors.

Methods: In this study, we develop an Individualized Network-based Co-Mutation (INCM) methodology by inspecting over 2.5 million nonsynonymous somatic mutations and RNA-Seq profiles derived from 6,789 tumor exomes across 14 cancer types from The Cancer Genome Atlas (TCGA).

Findings: Our INCM analysis reveals a higher genetic interaction burden on the significantly mutated genes in cancer populations, experimentally validated cancer genes, chromosome regulatory factors, and DNA repair genes, as compared to human essential genes identified by CRISPR-Cas9 screenings of cancer cell lines. We find that genes identified in the cancer type-specific genetic subnetworks by INCM are significantly enriched in established cancer pathways, and the INCM-predicted putative genetic interactions (e.g., BCL2L1-HRAS and BACH2-KRAS) are correlated with patient survival. By analyzing drug pharmacogenomics profiles across over 1,000 cancer cell lines from the Genomics of Drug Sensitivity in Cancer (GDSC) database, we show that the network-predicted putative genetic interactions (e.g., BRCA2-TP53 and KRAS-TP53) are significantly correlated with sensitivity/resistance of multiple therapeutic agents in cancer cell lines. Finally, drug-target network analysis reveals multiple potentially druggable genetic interactions (e.g., CETN2-CDK4 and PIK3CA-PTEN) by targeting tumor vulnerabilities. In summary, this study offers a powerful network-based methodology for comprehensive identification of candidate therapeutic pathways that target tumor vulnerabilities and prioritization of potential pharmacogenomics biomarkers for development of personalized cancer medicine.

Funding: This work was supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health under Award Number K99HL138272 and R00HL138272 to F.C. This work has been also funded in whole or in part with Federal funds from the Frederick National Laboratory for Cancer Research, National Institutes of Health, under contract HHSN261200800001E. This research was supported (in part) by the Intramural Research Program of NIH, Frederick National Lab, Center for Cancer Research.

Declaration of Interest: The authors declare no competing financial interest.

Keywords: tumor vulnerability; genetic interaction; pharmacogenomics; somatic mutations; network analysis; personalized cancer medicine

Suggested Citation

Liu, Chuang and Zhao, Junfei and Dai, Yao and Hockings, Jennifer and Nussinov, Ruth and Eng, Charis and Cheng, Feixiong, Individualized Genetic Network Analysis Reveals New Therapeutic Vulnerabilities in Cancer (August 17, 2018). Available at SSRN: https://ssrn.com/abstract=3235623

Chuang Liu

Hangzhou Normal University - Alibaba Research Center for Complexity Sciences

Hangzhou, 311121
China

Junfei Zhao

Columbia University - Department of Systems Biology

College of Physicians and Surgeons
630 West 168th Street, 3rd Floor, Suite 3-470
New York, NY 10032
United States

Columbia University - Department of Biomedical Informatics

New York, NY 10032
United States

Yao Dai

Hangzhou Normal University - Alibaba Research Center for Complexity Sciences

Hangzhou, 311121
China

Jennifer Hockings

Cleveland Clinic - Genomic Medicine Institute

Cleveland, OH 44106
United States

Ruth Nussinov

National Institutes of Health (NIH) - National Cancer Institute at Frederick

Frederick, MD 21702-1201
United States

Tel Aviv University - Department of Human Molecular Genetics and Biochemistry

Tel Aviv, 69978
Israel

Charis Eng

Cleveland Clinic, Lerner Research Institute, Genomic Medicine Institute

Cleveland, OH 44106
United States

Cleveland Clinic, Lerner College of Medicine, Department of Molecular Medicine

9500 Euclid Avenue
Cleveland, OH 44195
United States

Case Western Reserve University, School of Medicine, Case Comprehensive Cancer Center

Cleveland, OH 44195
United States

Case Western Reserve University, School of Medicine, Department of Genetics and Genome Sciences

2511 Overlook Road
Cleveland Heights, OH
United States

Cleveland Clinic - Taussig Cancer Institute

9500 Euclid Avenue
Cleveland, OH 44195
United States

Feixiong Cheng (Contact Author)

Cleveland Clinic, Lerner Research Institute, Genomic Medicine Institute ( email )

Cleveland, OH 44106
United States

Cleveland Clinic, Lerner College of Medicine, Department of Molecular Medicine ( email )

9500 Euclid Avenue
Cleveland, OH 44195
United States

Case Western Reserve University, School of Medicine, Case Comprehensive Cancer Center ( email )

2511 Overlook Road
Cleveland Heights, OH 44195
United States

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