AUTHOR=Fridley Brooke L. , Ghosh Taraswi M. , Wang Alice , Raghavan Rama , Dai Junqiang , Goode Ellen L. , Lamba Jatinder K. 

TITLE=Genome-Wide Study of Response to Platinum, Taxane, and Combination Therapy in Ovarian Cancer: In vitro Phenotypes, Inherited Variation, and Disease Recurrence

JOURNAL=Frontiers in Genetics

VOLUME=7

YEAR=2016

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2016.00037

DOI=10.3389/fgene.2016.00037

ISSN=1664-8021

ABSTRACT=<p><bold>Background:</bold> 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.</p><p><bold>Methods:</bold> 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 <italic>in vitro</italic> 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.</p><p><bold>Results:</bold> Statistical analysis found paclitaxel <italic>in vitro</italic> drug response phenotypes to be moderately associated with time to EOC recurrence (<italic>p</italic> = 0.008 IC50; <italic>p</italic> = 0.058 EC50). Although no pharmacogenomic associations were significant at <italic>p</italic> &lt; 5 × 10<sup>−8</sup>, seven genomic loci were associated with drug response at <italic>p</italic> &lt; 10<sup>−6</sup>, 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 <italic>FRAS1, MGC32805, SNCAIP, SLC9A9, TIAL1, ZNF731P</italic>, and <italic>PCDH20</italic>.</p><p><bold>Conclusions:</bold> 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.</p>