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 mar...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2016-03-01
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| Series: | Frontiers in Genetics |
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| Online Access: | http://journal.frontiersin.org/Journal/10.3389/fgene.2016.00037/full |
| _version_ | 1828761847890706432 |
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| author | Brooke L Fridley Taraswi Mitra Ghosh Alice eWang Rama eRaghavan Junqiang eDai Ellen L Goode Jatinder K Lamba |
| author_facet | Brooke L Fridley Taraswi Mitra Ghosh Alice eWang Rama eRaghavan Junqiang eDai Ellen L Goode Jatinder K Lamba |
| author_sort | Brooke L Fridley |
| collection | DOAJ |
| description | 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 <5x10-8, 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. |
| first_indexed | 2024-12-11T01:35:13Z |
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| id | doaj.art-59de20e5e3654457919c52bd87b560ea |
| institution | Directory Open Access Journal |
| issn | 1664-8021 |
| language | English |
| last_indexed | 2024-12-11T01:35:13Z |
| publishDate | 2016-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Genetics |
| spelling | doaj.art-59de20e5e3654457919c52bd87b560ea2022-12-22T01:25:14ZengFrontiers Media S.A.Frontiers in Genetics1664-80212016-03-01710.3389/fgene.2016.00037184951Genome-wide study of response to platinum, taxane, and combination therapy in ovarian cancer: in vitro phenotypes, inherited variation, and disease recurrenceBrooke L Fridley0Taraswi Mitra Ghosh1Alice eWang2Rama eRaghavan3Junqiang eDai4Ellen L Goode5Jatinder K Lamba6University of Kansas Medical CenterUniversity of MinnesotaUniversity of Kansas Medical CenterUniversity of Kansas Medical CenterUniversity of Kansas Medical CenterMayo ClinicUniversity of FloridaAbstract: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 <5x10-8, 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.http://journal.frontiersin.org/Journal/10.3389/fgene.2016.00037/fullApoptosisCarboplatinPaclitaxelpharmacogenomicsovarian cancergenome-wide association |
| spellingShingle | Brooke L Fridley Taraswi Mitra Ghosh Alice eWang Rama eRaghavan Junqiang eDai Ellen L Goode Jatinder K Lamba Genome-wide study of response to platinum, taxane, and combination therapy in ovarian cancer: in vitro phenotypes, inherited variation, and disease recurrence Frontiers in Genetics Apoptosis Carboplatin Paclitaxel pharmacogenomics ovarian cancer genome-wide association |
| title | Genome-wide study of response to platinum, taxane, and combination therapy in ovarian cancer: in vitro phenotypes, inherited variation, and disease recurrence |
| title_full | Genome-wide study of response to platinum, taxane, and combination therapy in ovarian cancer: in vitro phenotypes, inherited variation, and disease recurrence |
| title_fullStr | Genome-wide study of response to platinum, taxane, and combination therapy in ovarian cancer: in vitro phenotypes, inherited variation, and disease recurrence |
| title_full_unstemmed | Genome-wide study of response to platinum, taxane, and combination therapy in ovarian cancer: in vitro phenotypes, inherited variation, and disease recurrence |
| title_short | Genome-wide study of response to platinum, taxane, and combination therapy in ovarian cancer: in vitro phenotypes, inherited variation, and disease recurrence |
| title_sort | genome wide study of response to platinum taxane and combination therapy in ovarian cancer in vitro phenotypes inherited variation and disease recurrence |
| topic | Apoptosis Carboplatin Paclitaxel pharmacogenomics ovarian cancer genome-wide association |
| url | http://journal.frontiersin.org/Journal/10.3389/fgene.2016.00037/full |
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