TY - JOUR
T1 - Genome-wide association study of paclitaxel and carboplatin disposition in women with epithelial ovarian cancer
AU - Gao, Bo
AU - Lu, Yi
AU - Nieuweboer, Annemieke J. M.
AU - Xu, Hongmei
AU - Beesley, Jonathan
AU - Boere, Ingrid
AU - De Graan, Anne Joy M.
AU - De Bruijn, Peter
AU - Gurney, Howard
AU - Kennedy, Catherine J.
AU - Chiew, Yoke Eng
AU - Johnatty, Sharon E.
AU - Beale, Philip
AU - Harrison, Michelle
AU - Luccarini, Craig
AU - Conroy, Don
AU - Mathijssen, Ron H.J.
AU - Harnett, Paul R.
AU - Balleine, Rosemary L.
AU - Chenevix-Trench, Georgia
AU - MacGregor, Stuart
AU - De Fazio, Anna
N1 - Copyright the Author(s) 2018. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.
PY - 2018/12/1
Y1 - 2018/12/1
N2 - Identifying single nucleotide polymorphisms (SNPs) that influence chemotherapy disposition may help to personalize cancer treatment and limit toxicity. Genome-wide approaches are unbiased, compared with candidate gene studies, but usually require large cohorts. As most chemotherapy is given cyclically multiple blood sampling is required to adequately define drug disposition, limiting patient recruitment. We found that carboplatin and paclitaxel disposition are stable phenotypes in ovarian cancer patients and tested a genome-wide association study (GWAS) design to identify SNPs associated with chemotherapy disposition. We found highly significant SNPs in ABCC2, a known carboplatin transporter, associated with carboplatin clearance (asymptotic P = 5.2 × 106, empirical P = 1.4 × 10-5), indicating biological plausibility. We also identified novel SNPs associated with paclitaxel disposition, including rs17130142 with genome-wide significance (asymptotic P = 2.0 × 10-9, empirical P = 1.3 × 10-7). Although requiring further validation, our work demonstrated that GWAS of chemotherapeutic drug disposition can be effective, even in relatively small cohorts, and can be adopted in drug development and treatment programs.
AB - Identifying single nucleotide polymorphisms (SNPs) that influence chemotherapy disposition may help to personalize cancer treatment and limit toxicity. Genome-wide approaches are unbiased, compared with candidate gene studies, but usually require large cohorts. As most chemotherapy is given cyclically multiple blood sampling is required to adequately define drug disposition, limiting patient recruitment. We found that carboplatin and paclitaxel disposition are stable phenotypes in ovarian cancer patients and tested a genome-wide association study (GWAS) design to identify SNPs associated with chemotherapy disposition. We found highly significant SNPs in ABCC2, a known carboplatin transporter, associated with carboplatin clearance (asymptotic P = 5.2 × 106, empirical P = 1.4 × 10-5), indicating biological plausibility. We also identified novel SNPs associated with paclitaxel disposition, including rs17130142 with genome-wide significance (asymptotic P = 2.0 × 10-9, empirical P = 1.3 × 10-7). Although requiring further validation, our work demonstrated that GWAS of chemotherapeutic drug disposition can be effective, even in relatively small cohorts, and can be adopted in drug development and treatment programs.
UR - http://www.scopus.com/inward/record.url?scp=85041059301&partnerID=8YFLogxK
U2 - 10.1038/s41598-018-19590-w
DO - 10.1038/s41598-018-19590-w
M3 - Article
C2 - 29367611
AN - SCOPUS:85041059301
SN - 2045-2322
VL - 8
SP - 1
EP - 10
JO - Scientific Reports
JF - Scientific Reports
IS - 1
M1 - 1508
ER -