title: IMPACT: a whole-exome sequencing analysis pipeline for integrating molecular profiles with actionable therapeutics in clinical samples.
abstract: 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.
authors.affiliation: Division of Medical Oncology, Department of Medicine, School of Medicine.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hintzsche
authors.affiliation: 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.
authors.forename: Jihye
authors.initials: J
authors.lastname: Kim
authors.affiliation: Division of Biomedical Informatics and Personalized Medicine, Department of Medicine, School of Medicine.
authors.forename: Vinod
authors.initials: V
authors.lastname: Yadav
authors.affiliation: Division of Medical Oncology, Department of Medicine, School of Medicine.
authors.forename: Carol
authors.initials: C
authors.lastname: Amato
authors.affiliation: Division of Medical Oncology, Department of Medicine, School of Medicine.
authors.forename: Steven E
authors.initials: SE
authors.lastname: Robinson
authors.affiliation: Division of Medical Oncology, Department of Medicine, School of Medicine.
authors.forename: Eric
authors.initials: E
authors.lastname: Seelenfreund
authors.affiliation: Department of Dermatology, School of Medicine University of Colorado Cancer Center All: University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Yiqun
authors.initials: Y
authors.lastname: Shellman
authors.affiliation: Department of Pathology, School of Medicine University of Colorado Cancer Center All: University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Wisell
authors.affiliation: Division of Medical Oncology, Department of Medicine, School of Medicine.
authors.forename: Allison
authors.initials: A
authors.lastname: Applegate
authors.affiliation: Department of Surgery, School of Medicine University of Colorado Cancer Center All: University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: McCarter
authors.affiliation: Department of Dermatology, School of Medicine University of Colorado Cancer Center All: University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Neil
authors.initials: N
authors.lastname: Box
authors.affiliation: 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.
authors.forename: John
authors.initials: J
authors.lastname: Tentler
authors.affiliation: 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.
authors.forename: Subhajyoti
authors.initials: S
authors.lastname: De
authors.affiliation: 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.
authors.forename: William A
authors.initials: WA
authors.lastname: Robinson
authors.affiliation: 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.
authors.forename: Aik Choon
authors.initials: AC
authors.lastname: Tan
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics*; D000077192:Adenocarcinoma of Lung; D019295:Computational Biology; D056915:DNA Copy Number Variations; D004252:DNA Mutational Analysis; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D059472:Exome; D018773:Genes, erbB-1; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D008545:Melanoma / Q000235:genetics*; D009154:Mutation; D057285:Precision Medicine
keywords: bioinformatics; cancer; personalized medicine; therapeutics; whole exome sequencing