Cumulative genetic risk predicts platinum/taxane-induced neurotoxicity.
Cumulative genetic risk predicts platinum/taxane-induced neurotoxicity.
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DOI：
10.1158/1078-0432.ccr-13-0774
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发表时间：
2013-10-15
期刊：
影响因子：
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通讯作者：
Scottish Gynaecological Clinical Trials Group
中科院分区：
文献类型：
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作者：
McWhinney-Glass S;Winham SJ;Hertz DL;Yen Revollo J;Paul J;He Y;Brown R;Motsinger-Reif AA;McLeod HL;Scottish Gynaecological Clinical Trials Group
铂和紫杉烷的组合是许多癌症的标准治疗方法，但由于神经毒性，其实用性往往受到限制。我们检查了注释候选基因的单核苷酸多态性 (SNP) 是否能够识别化疗引起的神经毒性的遗传风险。进行了一项候选基因关联研究，以验证 SCOTROC1 试验中接受铂/紫杉烷化疗的 404 名卵巢癌患者的 60 个候选基因内的 1261 个 SNP 的相关性。然后评估统计显着变异在来自 SCOTROC1 的单独 404 名患者复制队列中的复制情况。 SOX10、BCL2、OPRM1 和 TRPV1 中的四个 SNP 与化疗引起的神经毒性存在显着相关性，并得到了重复。四个 SNP 的人群归因风险范围为 5-35%，累积风险为 62%。根据乘法模型，每种风险基因型发生神经毒性的几率都会增加 1.64 倍。与具有 0 个风险变异的个体相比，具有 3 个风险变异的患者的估计优势比为 4.49 (2.36-8.54)。四个 SNP 和风险评分均与无进展生存期或总生存期无关。这项研究表明，四个基因中的单核苷酸多态性（SNP）与化疗引起的神经毒性的风险增加具有显着的累积相关性，与患者的生存率无关。
The combination of a platinum and taxane are standard of care for many cancers, but the utility is often limited due to debilitating neurotoxicity. We examined whether single nucleotide polymorphisms (SNPs) from annotated candidate genes will identify genetic risk for chemotherapy-induced neurotoxicity. A candidate-gene association study was conducted to validate the relevance of 1261 SNPs within 60 candidate genes in 404 ovarian cancer patients receiving platinum/taxane chemotherapy on the SCOTROC1 trial. Statistically significant variants were then assessed for replication in a separate 404 patient replication cohort from SCOTROC1. Significant associations with chemotherapy-induced neurotoxicity were identified and replicated for four SNPs in SOX10, BCL2, OPRM1, and TRPV1. The Population Attributable Risk for each of the four SNPs ranged from 5-35%, with a cumulative risk of 62%. According to the multiplicative model, the odds of developing neurotoxicity increase by a factor of 1.64 for every risk genotype. Patients possessing 3 risk variants have an estimated odds ratio of 4.49 (2.36-8.54) compared to individuals with 0 risk variants. Neither the four SNPs nor the risk score were associated with progression free survival or overall survival. This study demonstrates that SNPs in four genes have a significant cumulative association with increased risk for the development of chemotherapy-induced neurotoxicity, independent of patient survival.