Genome-wide association study of paclitaxel and carboplatin disposition in women with epithelial ovarian cancer

Bo Gao, Yi Lu, Annemieke J. M. Nieuweboer, Hongmei Xu, Jonathan Beesley, Ingrid Boere, Anne Joy M. De Graan, Peter De Bruijn, Howard Gurney, Catherine J. Kennedy, Yoke Eng Chiew, Sharon E. Johnatty, Philip Beale, Michelle Harrison, Craig Luccarini, Don Conroy, Ron H.J. Mathijssen, Paul R. Harnett, Rosemary L. Balleine, Georgia Chenevix-Trench & 2 others Stuart MacGregor, Anna De Fazio

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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.

LanguageEnglish
Article number1508
Pages1-10
Number of pages10
JournalScientific Reports
Volume8
Issue number1
DOIs
Publication statusPublished - 1 Dec 2018
Externally publishedYes

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Genome-Wide Association Study
Carboplatin
Paclitaxel
Single Nucleotide Polymorphism
Drug Therapy
Pharmaceutical Preparations
Genome
Ovarian Neoplasms
Patient Selection
Phenotype
Ovarian epithelial cancer
Therapeutics
Genes
Neoplasms

Bibliographical note

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.

Cite this

Gao, B., Lu, Y., Nieuweboer, A. J. M., Xu, H., Beesley, J., Boere, I., ... De Fazio, A. (2018). Genome-wide association study of paclitaxel and carboplatin disposition in women with epithelial ovarian cancer. Scientific Reports, 8(1), 1-10. [1508]. https://doi.org/10.1038/s41598-018-19590-w
Gao, Bo ; Lu, Yi ; Nieuweboer, Annemieke J. M. ; Xu, Hongmei ; Beesley, Jonathan ; Boere, Ingrid ; De Graan, Anne Joy M. ; De Bruijn, Peter ; Gurney, Howard ; Kennedy, Catherine J. ; Chiew, Yoke Eng ; Johnatty, Sharon E. ; Beale, Philip ; Harrison, Michelle ; Luccarini, Craig ; Conroy, Don ; Mathijssen, Ron H.J. ; Harnett, Paul R. ; Balleine, Rosemary L. ; Chenevix-Trench, Georgia ; MacGregor, Stuart ; De Fazio, Anna. / Genome-wide association study of paclitaxel and carboplatin disposition in women with epithelial ovarian cancer. In: Scientific Reports. 2018 ; Vol. 8, No. 1. pp. 1-10.
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Gao, B, Lu, Y, Nieuweboer, AJM, Xu, H, Beesley, J, Boere, I, De Graan, AJM, De Bruijn, P, Gurney, H, Kennedy, CJ, Chiew, YE, Johnatty, SE, Beale, P, Harrison, M, Luccarini, C, Conroy, D, Mathijssen, RHJ, Harnett, PR, Balleine, RL, Chenevix-Trench, G, MacGregor, S & De Fazio, A 2018, 'Genome-wide association study of paclitaxel and carboplatin disposition in women with epithelial ovarian cancer', Scientific Reports, vol. 8, no. 1, 1508, pp. 1-10. https://doi.org/10.1038/s41598-018-19590-w

Genome-wide association study of paclitaxel and carboplatin disposition in women with epithelial ovarian cancer. / Gao, Bo; Lu, Yi; Nieuweboer, Annemieke J. M.; Xu, Hongmei; Beesley, Jonathan; Boere, Ingrid; De Graan, Anne Joy M.; De Bruijn, Peter; Gurney, Howard; Kennedy, Catherine J.; Chiew, Yoke Eng; Johnatty, Sharon E.; Beale, Philip; Harrison, Michelle; Luccarini, Craig; Conroy, Don; Mathijssen, Ron H.J.; Harnett, Paul R.; Balleine, Rosemary L.; Chenevix-Trench, Georgia; MacGregor, Stuart; De Fazio, Anna.

In: Scientific Reports, Vol. 8, No. 1, 1508, 01.12.2018, p. 1-10.

Research output: Contribution to journalArticleResearchpeer-review

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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

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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.

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