title: Genome-Wide Study of Response to Platinum, Taxane, and Combination Therapy in Ovarian Cancer: In vitro Phenotypes, Inherited Variation, and Disease Recurrence.
abstract: BACKGROUND
  The standard treatment for epithelial ovarian cancer (EOC) patients with advanced disease is carboplatin-paclitaxel combination therapy following initial debulking surgery, yet there is wide inter-patient variation in clinical response. We sought to identify pharmacogenomic markers related to carboplatin-paclitaxel therapy.
  
  
  METHODS
  The lymphoblastoid cell lines, derived from 74 invasive EOC patients seen at the Mayo Clinic, were treated with increasing concentrations of carboplatin and/or paclitaxel and assessed for in vitro drug response using MTT viability and caspase3/7 apoptosis assays. Drug response phenotypes IC50 (effective dose at which 50% of cells are viable) and EC50 (dose resulting in 50% induction of caspase 3/7 activity) were estimated for each patient to paclitaxel and carboplatin (alone and in combination). For each of the six drug response phenotypes, a genome-wide association study was conducted.
  
  
  RESULTS
  Statistical analysis found paclitaxel in vitro drug response phenotypes to be moderately associated with time to EOC recurrence (p = 0.008 IC50; p = 0.058 EC50). Although no pharmacogenomic associations were significant at p < 5 × 10(-8), seven genomic loci were associated with drug response at p < 10(-6), including at 4q21.21 for carboplatin, 4p16.1 and 5q23.2 for paclitaxel, and 3q24, 10q, 1q44, and 13q21 for combination therapy. Nearby genes of interest include FRAS1, MGC32805, SNCAIP, SLC9A9, TIAL1, ZNF731P, and PCDH20.
  
  
  CONCLUSIONS
  These results suggest the existence of genetic loci associated with response to platinum-taxane therapies. Further research is needed to understand the mechanism by which these loci may impact EOC clinical response to this commonly used regimen.
authors.affiliation: Department of Biostatistics, University of Kansas Medical Center Kansas City, KS, USA.
authors.forename: Brooke L
authors.initials: BL
authors.lastname: Fridley
authors.affiliation: Department of Experimental and Clinical Pharmacology, University of Minnesota Minneapolis, MN, USA.
authors.forename: Taraswi M
authors.initials: TM
authors.lastname: Ghosh
authors.affiliation: Department of Biostatistics, University of Kansas Medical Center Kansas City, KS, USA.
authors.forename: Alice
authors.initials: A
authors.lastname: Wang
authors.affiliation: Department of Biostatistics, University of Kansas Medical Center Kansas City, KS, USA.
authors.forename: Rama
authors.initials: R
authors.lastname: Raghavan
authors.affiliation: Department of Biostatistics, University of Kansas Medical Center Kansas City, KS, USA.
authors.forename: Junqiang
authors.initials: J
authors.lastname: Dai
authors.affiliation: Department of Health Sciences Research, Mayo Clinic Rochester, MN, USA.
authors.forename: Ellen L
authors.initials: EL
authors.lastname: Goode
authors.affiliation: Department of Pharmacotherapy and Translational Research, University of Florida Gainesville, FL, USA.
authors.forename: Jatinder K
authors.initials: JK
authors.lastname: Lamba
keywords: apoptosis; carboplatin; cell viability; genome-wide association; lymphoblastoid cell lines; ovarian cancer; paclitaxel; pharmacogenomics