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Invariant Differential Expression Analysis Reveals Mechanism of Cancer Resistance to Cell Cycle Inhibitors

Amit Chatterjee, Sonalisa Pandey, Ravikanth Danda, View ORCID ProfileR Ranjith Kumar, View ORCID ProfileS Maheswari, View ORCID ProfileVikas Khetan, View ORCID ProfilePukhraj Rishi, S Ramaprabhu, View ORCID ProfileSailaja V Elchuri, View ORCID ProfileDebashis Sahoo
doi: https://doi.org/10.1101/2021.02.17.431607
Amit Chatterjee
1Department of Nano-Biotechnology, Vision Research Foundation, Sankara Nethralaya, Chennai, Tamil Nadu, India
2School of chemical and Biotechnology, SASTRA University Tanjore, Tamil Nadu,India
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Sonalisa Pandey
6Department of Pediatrics, Department of Computer Science and Engineering, University of California San Diego, 9500 Gilman Drive, MC 0703, La Jolla, CA
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Ravikanth Danda
1Department of Nano-Biotechnology, Vision Research Foundation, Sankara Nethralaya, Chennai, Tamil Nadu, India
2School of chemical and Biotechnology, SASTRA University Tanjore, Tamil Nadu,India
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R Ranjith Kumar
1Department of Nano-Biotechnology, Vision Research Foundation, Sankara Nethralaya, Chennai, Tamil Nadu, India
5Centre for Nanotechnology and Advanced Biomaterials, Anna University, Chennai, Tamil Nadu, India
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S Maheswari
7Department of Physics IIT Madras, Chennai, india
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Vikas Khetan
4Shri Bhagwan Mahavir Vitreoretinal Services and Ocular Oncology Services, Medical Research Foundation, Sankara Nethralaya, Chennai, Tamil Nadu, India
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Pukhraj Rishi
4Shri Bhagwan Mahavir Vitreoretinal Services and Ocular Oncology Services, Medical Research Foundation, Sankara Nethralaya, Chennai, Tamil Nadu, India
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S Ramaprabhu
7Department of Physics IIT Madras, Chennai, india
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Sailaja V Elchuri
1Department of Nano-Biotechnology, Vision Research Foundation, Sankara Nethralaya, Chennai, Tamil Nadu, India
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  • For correspondence: dsahoo@ucsd.edu sailaja.elchuri@gmail.com
Debashis Sahoo
6Department of Pediatrics, Department of Computer Science and Engineering, University of California San Diego, 9500 Gilman Drive, MC 0703, La Jolla, CA
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  • For correspondence: dsahoo@ucsd.edu sailaja.elchuri@gmail.com
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Abstract

Retinoblastoma (RB) is a good model to study drug resistance to cell-cycle inhibitors because it is driven by mutations in the core components of cell-cycle, i.e, Rb gene. However, there is limited gene expression dataset in RB which has major reproducibility issues. We have developed invariant differential expression analysis (iDEA) that improves the state of the art in differential expression analysis (DEA). iDEA uses strong Boolean implication relationships in a large diverse human dataset GSE119087 (n = 25,955) to filter the noisy differentially expressed genes (DEGs). iDEA was applied to RB datasets and a gene signature was computed that led to prediction and mechanism of drug sensitivity. The prediction was confirmed using drugs-sensitive/resistant RB cell-lines and mouse xenograft models using CDC25 inhibitor NSC663284. iDEA improved reproducibility of differential expression across diverse retina/RB cohorts and RB cell-lines with different drug sensitivity (Y79/Weri vs NCC). Pathway analysis revealed WNT/β-catenin involved in distinguishing drug sensitivity to CDC25 inhibitor NSC663284. NSC663284 inhibited tumour cell proliferation in mouse xenograft model containing Y79 cells indicating novel therapeutic option in RB. Invariant differentially expressed genes (iDEGs) are robustly associated with outcome in diverse cancer datasets and supports for a fundamental mechanism of drug resistance.

  • Abbreviations

    Idea
    invariant differential expression analysis
    iDEGs
    invariant differentially expressed genes
    RB
    retinoblastoma tumors
    Rb
    Retinoblastoma protein
    RT
    retina
    ROC
    Receiver operating characteristic
    AUC
    Area under the curve
    GEO
    Gene Expression Omnibus
    BIRs
    Boolean implication relationships
    BIN
    Boolean implication network
    NCBI
    National Center for Biotechnology Information
    EMBL-EBI
    European Molecular Biology Laboratory European Bioinformatics Institutes
    RMA
    Robust Multichip Average
    TPM
    Transcripts Per Millions
  • Copyright 
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    Posted February 17, 2021.
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    Invariant Differential Expression Analysis Reveals Mechanism of Cancer Resistance to Cell Cycle Inhibitors
    Amit Chatterjee, Sonalisa Pandey, Ravikanth Danda, R Ranjith Kumar, S Maheswari, Vikas Khetan, Pukhraj Rishi, S Ramaprabhu, Sailaja V Elchuri, Debashis Sahoo
    bioRxiv 2021.02.17.431607; doi: https://doi.org/10.1101/2021.02.17.431607
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    Invariant Differential Expression Analysis Reveals Mechanism of Cancer Resistance to Cell Cycle Inhibitors
    Amit Chatterjee, Sonalisa Pandey, Ravikanth Danda, R Ranjith Kumar, S Maheswari, Vikas Khetan, Pukhraj Rishi, S Ramaprabhu, Sailaja V Elchuri, Debashis Sahoo
    bioRxiv 2021.02.17.431607; doi: https://doi.org/10.1101/2021.02.17.431607

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