TY - JOUR
T1 - Genome-wide study of response to platinum, taxane, and combination therapy in ovarian cancer
T2 - In vitro phenotypes, inherited variation, and disease recurrence
AU - Fridley, Brooke L.
AU - Ghosh, Taraswi M.
AU - Wang, Alice
AU - Raghavan, Rama
AU - Dai, Junqiang
AU - Goode, Ellen L.
AU - Lamba, Jatinder K.
N1 - Publisher Copyright:
© 2016 Fridley, Ghosh, Wang, Raghavan, Dai, Goode and Lamba.
PY - 2016/3/22
Y1 - 2016/3/22
N2 - 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.
AB - 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.
KW - Apoptosis
KW - Carboplatin
KW - Cell viability
KW - Genome-wide association
KW - Lymphoblastoid cell lines
KW - Ovarian cancer
KW - Paclitaxel
KW - Pharmacogenomics
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U2 - 10.3389/fgene.2016.00037
DO - 10.3389/fgene.2016.00037
M3 - Article
AN - SCOPUS:84964903098
SN - 1664-8021
VL - 7
JO - Frontiers in Genetics
JF - Frontiers in Genetics
IS - MAR
M1 - 37
ER -