IMPACT: A whole-exome sequencing analysis pipeline for integrating molecular profiles with actionable therapeutics in clinical samples

Jennifer Hintzsche, Jihye Kim, Vinod Yadav, Carol Amato, Steven E. Robinson, Eric Seelenfreund, Yiqun Shellman, Joshua Wisell, Allison Applegate, Martin McCarter, Neil Box, John Tentler, Subhajyoti De, William A. Robinson, Aik Choon Tan

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Objective: 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. Methods and materials: 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. Results: 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. Conclusion: 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.

Original languageEnglish
Pages (from-to)721-730
Number of pages10
JournalJournal of the American Medical Informatics Association
Volume23
Issue number4
DOIs
Publication statusPublished - 2016

Keywords

  • Bioinformatics
  • Cancer
  • Personalized medicine
  • Therapeutics
  • Whole exome sequencing

ASJC Scopus subject areas

  • Health Informatics

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    Hintzsche, J., Kim, J., Yadav, V., Amato, C., Robinson, S. E., Seelenfreund, E., Shellman, Y., Wisell, J., Applegate, A., McCarter, M., Box, N., Tentler, J., De, S., Robinson, W. A., & Tan, A. C. (2016). IMPACT: A whole-exome sequencing analysis pipeline for integrating molecular profiles with actionable therapeutics in clinical samples. Journal of the American Medical Informatics Association, 23(4), 721-730. https://doi.org/10.1093/jamia/ocw022