Jennifer Hintzsche1, Jihye Kim2, Vinod Yadav3, Carol Amato1, Steven E Robinson1, Eric Seelenfreund1, Yiqun Shellman4, Joshua Wisell5, Allison Applegate1, Martin McCarter6, Neil Box4, John Tentler2, Subhajyoti De7, William A Robinson8, Aik Choon Tan9. 1. Division of Medical Oncology, Department of Medicine, School of Medicine. 2. Division of Medical Oncology, Department of Medicine, School of Medicine University of Colorado Cancer Center All: University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA. 3. Division of Biomedical Informatics and Personalized Medicine, Department of Medicine, School of Medicine. 4. Department of Dermatology, School of Medicine University of Colorado Cancer Center All: University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA. 5. Department of Pathology, School of Medicine University of Colorado Cancer Center All: University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA. 6. Department of Surgery, School of Medicine University of Colorado Cancer Center All: University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA. 7. Division of Biomedical Informatics and Personalized Medicine, Department of Medicine, School of Medicine Department of Biostatistics and Informatics, Colorado School of Public Health University of Colorado Cancer Center All: University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA. 8. Division of Medical Oncology, Department of Medicine, School of Medicine University of Colorado Cancer Center All: University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA aikchoon.tan@ucdenver.edu William.Robinson@ucdenver.edu. 9. Division of Medical Oncology, Department of Medicine, School of Medicine Department of Biostatistics and Informatics, Colorado School of Public Health University of Colorado Cancer Center All: University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA aikchoon.tan@ucdenver.edu William.Robinson@ucdenver.edu.
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.IMPACT is publicly available at http://tanlab.ucdenver.edu/IMPACT.
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 melanomapatienttumor 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 melanomapatient samples, we identified NRASp.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 patienttumor samples to discover effective drug targets for personalized medicine.IMPACT is publicly available at http://tanlab.ucdenver.edu/IMPACT.
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