Department of Gynaecological Oncology, Westmead Hospital, Sydney, Australia.
The Westmead Institute for Medical Research, Sydney Medical School, The University of Sydney, Sydney, Australia.
Sci Rep. 2018 Jan 24;8(1):1508. doi: 10.1038/s41598-018-19590-w.
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 × 10, empirical P = 1.4 × 10), indicating biological plausibility. We also identified novel SNPs associated with paclitaxel disposition, including rs17130142 with genome-wide significance (asymptotic P = 2.0 × 10, empirical P = 1.3 × 10). 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.
鉴定影响化疗药物处置的单核苷酸多态性(SNPs)可能有助于实现癌症治疗的个体化,同时限制药物毒性。与候选基因研究相比,全基因组方法更具客观性,但通常需要较大的队列。由于大多数化疗是周期性进行的,因此需要多次采血以充分定义药物处置,这限制了患者的招募。我们发现卵巢癌患者的卡铂和紫杉醇处置是稳定的表型,并测试了全基因组关联研究(GWAS)设计,以鉴定与化疗处置相关的 SNPs。我们在已知的卡铂转运蛋白 ABCC2 中发现了与卡铂清除率显著相关的高度显著 SNPs(渐近 P=5.2×10,经验 P=1.4×10,表明具有生物学合理性。我们还鉴定了与紫杉醇处置相关的新型 SNPs,包括具有全基因组意义的 rs17130142(渐近 P=2.0×10,经验 P=1.3×10)。尽管需要进一步验证,但我们的工作表明,即使在相对较小的队列中,化疗药物处置的 GWAS 也可以有效进行,并且可以在药物开发和治疗计划中采用。