Predicting Synthetic Lethal Interactions using Heterogeneous Data Sources.

MOTIVATION A synthetic lethal (SL) interaction is a relationship between two functional entities where the loss of either one of the entities is viable but the loss of both entities is lethal to the cell. Such pairs can be used as drug targets in targeted anticancer therapies, and so, many methods have been developed to identify potential candidate SL pairs. However, these methods use only a subset of available data from multiple platforms, at genomic, epigenomic and transcriptomic levels; and hence are limited in their ability to learn from complex associations in heterogeneous data sources. RESULTS In this paper we develop techniques that can seamlessly integrate multiple heterogeneous data sources to predict SL interactions. Our approach obtains latent representations by collective matrix factorization based techniques, which in turn are used for prediction through matrix completion. Our experiments, on a variety of biological datasets, illustrate the efficacy and versatility of our approach, that outperforms state-of-the-art methods for predicting SL interactions and can be used with heterogeneous data sources with minimal feature engineering. AVAILABILITY Software available at https://github.com/lianyh.

[1]  Shan Zhao,et al.  Mining protein networks for synthetic genetic interactions , 2008, BMC Bioinformatics.

[2]  Ricard V. Solé,et al.  Human synthetic lethal inference as potential anti-cancer target gene detection , 2009, BMC Systems Biology.

[3]  Kevin R Brown,et al.  Essential gene profiles in breast, pancreatic, and ovarian cancer cells. , 2012, Cancer discovery.

[4]  Christian M. Metallo,et al.  Combinatorial CRISPR-Cas9 Metabolic Screens Reveal Critical Redox Control Points Dependent on the KEAP1-NRF2 Regulatory Axis. , 2018, Molecular cell.

[5]  Mark D. M. Leiserson,et al.  Precision Oncology: The Road Ahead. , 2017, Trends in molecular medicine.

[6]  Wolfgang Huber,et al.  Mapping genetic interactions in human cancer cells with RNAi and multiparametric phenotyping , 2013, Nature Methods.

[7]  Hui Liu,et al.  SynLethDB: synthetic lethality database toward discovery of selective and sensitive anticancer drug targets , 2015, Nucleic Acids Res..

[8]  Martin H. Schaefer,et al.  HIPPIE v2.0: enhancing meaningfulness and reliability of protein–protein interaction networks , 2016, Nucleic Acids Res..

[9]  Gary D Bader,et al.  International network of cancer genome projects , 2010, Nature.

[10]  Subarna Sinha,et al.  Systematic discovery of mutation-specific synthetic lethals by mining pan-cancer human primary tumor data , 2017, Nature Communications.

[11]  Eytan Ruppin,et al.  Predicting Cancer-Specific Vulnerability via Data-Driven Detection of Synthetic Lethality , 2014, Cell.

[12]  A. Tutt,et al.  Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial , 2010, The Lancet.

[13]  J. Martens,et al.  A novel independence test for somatic alterations in cancer shows that biology drives mutual exclusivity but chance explains most co-occurrence , 2016, bioRxiv.

[14]  Sue Povey,et al.  The HGNC Database in 2008: a resource for the human genome , 2007, Nucleic Acids Res..

[15]  Eyal Gottlieb,et al.  Inborn and acquired metabolic defects in cancer , 2011, Journal of Molecular Medicine.

[16]  M. Zelen,et al.  Rethinking centrality: Methods and examples☆ , 1989 .

[17]  Vaibhav Rajan,et al.  Deep collective matrix factorization for augmented multi-view learning , 2018, Machine Learning.

[18]  Davide Heller,et al.  STRING v10: protein–protein interaction networks, integrated over the tree of life , 2014, Nucleic Acids Res..

[19]  A. Tutt,et al.  Phase II trial of the oral PARP inhibitor olaparib in BRCA-deficient advanced breast cancer. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[20]  Samuel Schmidt,et al.  The political network in Mexico , 1996 .

[21]  Martijn A. Huynen,et al.  Genome evolution predicts genetic interactions in protein complexes and reveals cancer drug targets , 2013, Nature Communications.

[22]  Nagarajan Natarajan,et al.  Inductive matrix completion for predicting gene–disease associations , 2014, Bioinform..

[23]  P. Bonacich Factoring and weighting approaches to status scores and clique identification , 1972 .

[24]  M. Friedman A Comparison of Alternative Tests of Significance for the Problem of $m$ Rankings , 1940 .

[25]  Thomas Helleday,et al.  Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase , 2005, Nature.

[26]  Trey Ideker,et al.  A Network of Conserved Synthetic Lethal Interactions for Exploration of Precision Cancer Therapy. , 2016, Molecular cell.

[27]  Bonnie Berger,et al.  Compact Integration of Multi-Network Topology for Functional Analysis of Genes. , 2016, Cell systems.

[28]  L. Freeman,et al.  Centrality in valued graphs: A measure of betweenness based on network flow , 1991 .

[29]  Leonard M. Freeman,et al.  A set of measures of centrality based upon betweenness , 1977 .

[30]  Xiangrong Chen,et al.  Predicting synthetic lethal interactions using conserved patterns in protein interaction networks , 2019, PLoS Comput. Biol..

[31]  Fan Zhang,et al.  In Silico Prediction of Synthetic Lethality by Meta-Analysis of Genetic Interactions, Functions, and Pathways in Yeast and Human Cancer , 2014, Cancer informatics.

[32]  Joshua M. Stuart,et al.  The Cancer Genome Atlas Pan-Cancer analysis project , 2013, Nature Genetics.

[33]  Steven J. M. Jones,et al.  Comprehensive molecular portraits of human breast tumors , 2012, Nature.

[34]  Fei Ji,et al.  PhyloGene server for identification and visualization of co-evolving proteins using normalized phylogenetic profiles , 2015, Nucleic Acids Res..

[35]  Gabriela Alexe,et al.  Characterizing genomic alterations in cancer by complementary functional associations , 2016, Nature Biotechnology.

[36]  Niko Beerenwinkel,et al.  TiMEx: a waiting time model for mutually exclusive cancer alterations , 2015, Bioinform..

[37]  Gaurav Pandey,et al.  Prediction of Genetic Interactions Using Machine Learning and Network Properties , 2015, Front. Bioeng. Biotechnol..

[38]  Benjamin E. Gross,et al.  Integrative Analysis of Complex Cancer Genomics and Clinical Profiles Using the cBioPortal , 2013, Science Signaling.

[39]  Vipin Kumar,et al.  An Integrative Multi-Network and Multi-Classifier Approach to Predict Genetic Interactions , 2010, PLoS Comput. Biol..

[40]  Eytan Ruppin,et al.  Harnessing synthetic lethality to predict the response to cancer treatment , 2018, Nature Communications.

[41]  D. Hanahan,et al.  Hallmarks of Cancer: The Next Generation , 2011, Cell.

[42]  Aaron N. Chang,et al.  Combinatorial CRISPR-Cas9 screens for de novo mapping of genetic interactions , 2017, Nature Methods.

[43]  Hans-Werner Mewes,et al.  CORUM: the comprehensive resource of mammalian protein complexes , 2007, Nucleic Acids Res..

[44]  Martijn A. Huynen,et al.  Predicting Human Genetic Interactions from Cancer Genome Evolution , 2015, PloS one.

[45]  Roland Arnold,et al.  A negative genetic interaction map in isogenic cancer cell lines reveals cancer cell vulnerabilities , 2013, Molecular systems biology.

[46]  Pablo Tamayo,et al.  Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[47]  P. Hieter,et al.  Synthetic lethality and cancer , 2017, Nature Reviews Genetics.

[48]  B. Taylor,et al.  Implementing Genome-Driven Oncology , 2017, Cell.

[49]  Gary D Bader,et al.  The Genetic Landscape of a Cell , 2010, Science.