Introduction

Currently, there is a disconnect between finding a patient's relevant molecular profile and predicting actionable therapeutics. Here we develop and implement the Integrating Molecular Profiles with Actionable Therapeutics (IMPACT) analysis pipeline, linking variants detected from whole-exome sequencing (WES) to actionable therapeutics.The IMPACT pipeline contains 4 analytical modules: detecting somatic variants, calling copy number alterations, predicting drugs against deleterious variants, and analyzing tumor heterogeneity. We tested the IMPACT pipeline on whole-exome sequencing data in The Cancer Genome Atlas (TCGA) lung adenocarcinoma samples with known EGFR mutations. We also used IMPACT to analyze melanoma patient tumor samples before treatment, after BRAF-inhibitor treatment, and after BRAF- and MEK-inhibitor treatment.IMPACT Food and Drug Administration (FDA) correctly identified known EGFR mutations in the TCGA lung adenocarcinoma samples. IMPACT linked these EGFR mutations to the appropriate FDA-approved EGFR inhibitors. For the melanoma patient samples, we identified NRAS p.Q61K as an acquired resistance mutation to BRAF-inhibitor treatment. We also identified CDKN2A deletion as a novel acquired resistance mutation to BRAFi/MEKi inhibition. The IMPACT analysis pipeline predicts these somatic variants to actionable therapeutics. We observed the clonal dynamic in the tumor samples after various treatments. We showed that IMPACT not only helped in successful prioritization of clinically relevant variants but also linked these variations to possible targeted therapies.IMPACT provides a new bioinformatics strategy to delineate candidate somatic variants and actionable therapies. This approach can be applied to other patient tumor samples to discover effective drug targets for personalized medicine.IMPACT is publicly available at http://tanlab.ucdenver.edu/IMPACT.

Publications

  1. IMPACT: a whole-exome sequencing analysis pipeline for integrating molecular profiles with actionable therapeutics in clinical samples.
    Cite this
    Hintzsche J, Kim J, Yadav V, Amato C, Robinson SE, Seelenfreund E, Shellman Y, Wisell J, Applegate A, McCarter M, Box N, Tentler J, De S, Robinson WA, Tan AC, 2016-07-01 - Journal of the American Medical Informatics Association

Credits

  1. Jennifer Hintzsche
    Developer

    Division of Medical Oncology, Department of Medicine, United States of America

  2. Jihye Kim
    Developer

    Division of Medical Oncology, Department of Medicine, United States of America

  3. Vinod Yadav
    Developer

    Division of Biomedical Informatics and Personalized Medicine, Department of Medicine, United States of America

  4. Carol Amato
    Developer

    Division of Medical Oncology, Department of Medicine, United States of America

  5. Steven E Robinson
    Developer

    Division of Medical Oncology, Department of Medicine, United States of America

  6. Eric Seelenfreund
    Developer

    Division of Medical Oncology, Department of Medicine, United States of America

  7. Yiqun Shellman
    Developer

    Department of Dermatology, School of Medicine University of Colorado Cancer Center All: University of Colorado Anschutz Medical Campus, United States of America

  8. Joshua Wisell
    Developer

    Department of Pathology, School of Medicine University of Colorado Cancer Center All: University of Colorado Anschutz Medical Campus, United States of America

  9. Allison Applegate
    Developer

    Division of Medical Oncology, Department of Medicine, United States of America

  10. Martin McCarter
    Developer

    Department of Surgery, School of Medicine University of Colorado Cancer Center All: University of Colorado Anschutz Medical Campus, United States of America

  11. Neil Box
    Developer

    Department of Dermatology, School of Medicine University of Colorado Cancer Center All: University of Colorado Anschutz Medical Campus, United States of America

  12. John Tentler
    Developer

    Division of Medical Oncology, Department of Medicine, United States of America

  13. Subhajyoti De
    Developer

    Division of Biomedical Informatics and Personalized Medicine, Department of Medicine, United States of America

  14. William A Robinson
    Developer

    Division of Medical Oncology, Department of Medicine, United States of America

  15. Aik Choon Tan
    Investigator

    Division of Medical Oncology, Department of Medicine, United States of America

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Summary
AccessionBT004687
Tool TypeApplication
Category
PlatformsLinux/Unix
TechnologiesPerl
User InterfaceTerminal Command Line
Download Count0
Country/RegionUnited States of America
Submitted ByAik Choon Tan