CaDrA: A computational framework for performing candidate driver analyses using binary genomic features

Identifying complementary genetic drivers of a given phenotypic outcome is a challenging task that is important to gaining new biological insight and discovering targets for disease therapy. Existing methods aimed at achieving this task lack analytical flexibility. We developed Candidate Driver Analysis or CaDrA, a framework to identify functionally-relevant subsets of binary genomic features that, together, are associated with a specific outcome of interest. We evaluate CaDrA’s sensitivity and specificity for typically-sized multi-omic datasets, and demonstrate CaDrA’s ability to identify both known and novel drivers of oncogenic activity in cancer cell lines and primary tumors.

[1]  Stefano Monti,et al.  ASSIGN: context-specific genomic profiling of multiple heterogeneous biological pathways , 2015, Bioinform..

[2]  C. Der,et al.  Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer , 2007, Oncogene.

[3]  Stefano Piccolo,et al.  YAP/TAZ at the Roots of Cancer. , 2016, Cancer cell.

[4]  Kam Y. J. Zhang,et al.  Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity , 2008, Proceedings of the National Academy of Sciences.

[5]  A. Frigessi,et al.  Principles and methods of integrative genomic analyses in cancer , 2014, Nature Reviews Cancer.

[6]  E. Kohn,et al.  The MAPK pathway across different malignancies: A new perspective , 2014, Cancer.

[7]  J. F. Burrows,et al.  Identification of RBCK1 as a novel regulator of FKBPL: implications for tumor growth and response to tamoxifen , 2014, Oncogene.

[8]  Douglas B. Johnson,et al.  Treatment of NRAS-Mutant Melanoma , 2015, Current Treatment Options in Oncology.

[9]  Ronald Simon,et al.  Loss of reelin expression in breast cancer is epigenetically controlled and associated with poor prognosis. , 2010, The American journal of pathology.

[10]  Xaralabos Varelas,et al.  The Hippo pathway effectors TAZ and YAP in development, homeostasis and disease , 2014, Development.

[11]  Justin Guinney,et al.  Systematic Assessment of Analytical Methods for Drug Sensitivity Prediction from Cancer Cell Line Data , 2013, Pacific Symposium on Biocomputing.

[12]  F. Cecconi,et al.  Physiological and pathological roles of Apaf1 and the apoptosome , 2003, Journal of cellular and molecular medicine.

[13]  Philippe P Roux,et al.  Activation and Function of the MAPKs and Their Substrates, the MAPK-Activated Protein Kinases , 2011, Microbiology and Molecular Reviews.

[14]  Douglas A. Chapnick,et al.  Partners in crime: the TGFβ and MAPK pathways in cancer progression , 2011, Cell & Bioscience.

[15]  Jeffrey T. Chang,et al.  Oncogenic pathway signatures in human cancers as a guide to targeted therapies , 2006, Nature.

[16]  F. Lozupone,et al.  Mutually exclusive NRASQ61R and BRAFV600E mutations at the single-cell level in the same human melanoma , 2006, Oncogene.

[17]  Michal Sheffer,et al.  Pathway-based personalized analysis of cancer , 2013, Proceedings of the National Academy of Sciences.

[18]  Eli Upfal,et al.  De Novo Discovery of Mutated Driver Pathways in Cancer , 2011, RECOMB.

[19]  M. Yaffe,et al.  TAZ: a novel transcriptional co‐activator regulated by interactions with 14‐3‐3 and PDZ domain proteins , 2000, The EMBO journal.

[20]  S. Bicciato,et al.  Aerobic glycolysis tunes YAP/TAZ transcriptional activity , 2015, The EMBO journal.

[21]  Xaralabos Varelas,et al.  The Transcriptional Regulators TAZ and YAP Direct Transforming Growth Factor β-induced Tumorigenic Phenotypes in Breast Cancer Cells*♦ , 2014, The Journal of Biological Chemistry.

[22]  L. Staudt,et al.  Diffuse large B-cell lymphoma subgroups have distinct genetic profiles that influence tumor biology and improve gene-expression-based survival prediction. , 2005, Blood.

[23]  A. Hauschild,et al.  Improved survival with vemurafenib in melanoma with BRAF V600E mutation. , 2011, The New England journal of medicine.

[24]  Yi Yuan,et al.  Reelin Is Involved in Transforming Growth Factor-β1-Induced Cell Migration in Esophageal Carcinoma Cells , 2012, PloS one.

[25]  Adam A. Margolin,et al.  The Cancer Cell Line Encyclopedia enables predictive modeling of anticancer drug sensitivity , 2012, Nature.

[26]  T. Golub,et al.  The molecular signature of mediastinal large B-cell lymphoma differs from that of other diffuse large B-cell lymphomas and shares features with classical Hodgkin lymphoma. , 2003, Blood.

[27]  J. O’Leary,et al.  BRAFV600E: Implications for Carcinogenesis and Molecular Therapy , 2011, Molecular Cancer Therapeutics.

[28]  Stefano Monti,et al.  Integrative analysis reveals an outcome-associated and targetable pattern of p53 and cell cycle deregulation in diffuse large B cell lymphoma. , 2012, Cancer cell.

[29]  M. Sudol,et al.  Yes-associated protein (YAP65) is a proline-rich phosphoprotein that binds to the SH3 domain of the Yes proto-oncogene product. , 1994, Oncogene.

[30]  Stefano Monti,et al.  A YAP/TAZ-Regulated Molecular Signature Is Associated with Oral Squamous Cell Carcinoma , 2015, Molecular Cancer Research.

[31]  David M. Thomas,et al.  The Hippo pathway and human cancer , 2013, Nature Reviews Cancer.

[32]  E. Choi,et al.  Pathological roles of MAPK signaling pathways in human diseases. , 2010, Biochimica et biophysica acta.

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

[34]  Antonio Rosato,et al.  Genome-wide association between YAP/TAZ/TEAD and AP-1 at enhancers drives oncogenic growth , 2015, Nature Cell Biology.

[35]  G. Getz,et al.  GISTIC2.0 facilitates sensitive and confident localization of the targets of focal somatic copy-number alteration in human cancers , 2011, Genome Biology.

[36]  Roded Sharan,et al.  Simultaneous Identification of Multiple Driver Pathways in Cancer , 2013, PLoS Comput. Biol..

[37]  Yan Zhou,et al.  Anti-Müllerian Hormone Signaling Regulates Epithelial Plasticity and Chemoresistance in Lung Cancer. , 2016, Cell reports.

[38]  Jun S. Liu,et al.  The Genotype-Tissue Expression (GTEx) pilot analysis: Multitissue gene regulation in humans , 2015, Science.

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

[40]  C. Sander,et al.  Mutual exclusivity analysis identifies oncogenic network modules. , 2012, Genome research.

[41]  C. Heldin,et al.  Non-Smad TGF-β signals , 2005, Journal of Cell Science.

[42]  Wei Huang,et al.  Frequent epigenetic inactivation of the receptor tyrosine kinase EphA5 by promoter methylation in human breast cancer. , 2010, Human pathology.

[43]  Joshua M. Stuart,et al.  Subtype and pathway specific responses to anticancer compounds in breast cancer , 2011, Proceedings of the National Academy of Sciences.

[44]  Laura M. Heiser,et al.  Modeling precision treatment of breast cancer , 2013, Genome Biology.

[45]  W. Grady,et al.  TGF-beta receptor levels regulate the specificity of signaling pathway activation and biological effects of TGF-beta. , 2009, Biochimica et biophysica acta.

[46]  C. Heldin,et al.  Non-Smad TGF-beta signals. , 2005, Journal of cell science.

[47]  S. Dupont,et al.  The biology of YAP/TAZ: hippo signaling and beyond. , 2014, Physiological reviews.

[48]  Kun-Liang Guan,et al.  The emerging roles of YAP and TAZ in cancer , 2015, Nature Reviews Cancer.

[49]  Ying E. Zhang,et al.  Smad-dependent and Smad-independent pathways in TGF-β family signalling , 2003, Nature.

[50]  Vivienne Marsh,et al.  Biological Characterization of ARRY-142886 (AZD6244), a Potent, Highly Selective Mitogen-Activated Protein Kinase Kinase 1/2 Inhibitor , 2007, Clinical Cancer Research.

[51]  W. Gerald,et al.  Apaf-1 expression in malignant melanoma , 2006, Cell Death and Differentiation.