Pharmacogenomic Prediction of Anthracycline-Induced Cardiotoxicity in Children
Pharmacogenomic Prediction of Anthracycline-Induced Cardiotoxicity in Children
复制标题
DOI：
10.1200/jco.2010.34.3467
复制
发表时间：
2012-05-01
影响因子：
45.3
通讯作者：
Hayden, Michael R.
中科院分区：
文献类型：
--
作者：
Visscher, Henk;Ross, Colin J. D.;Hayden, Michael R.
目的蒽环类药物引起的心脏毒性（ACT）是一种严重的药物不良反应，限制了蒽环类药物的使用，并导致大量的发病率和死亡率。我们的目的是确定儿童癌症治疗患者中与ACT相关的遗传变异。研究人员对来自不列颠哥伦比亚省的156名接受蒽环类药物治疗的儿童的220个关键药物生物转化基因的2,977个单核苷酸多态性（SNP）进行了研究，并在来自加拿大各地的188名儿童的第二队列中进行了复制，并在来自荷兰阿姆斯特丹的96名患者的第三队列中进一步复制了顶部SNP。结果我们发现SLC28A3基因内的同义编码变体rs7853758 （L461L）与ACT具有高度显著的相关性（优势比为0.35；所有队列合并P = 1.8 x 10(-5)）。其他基因（包括SLC28A1和几种三磷酸腺苷结合盒转运体（ABCB1、ABCB4和ABCC1））的风险和保护性变异存在其他关联（P < 0.01）。我们进一步探索将多个变异与临床危险因素结合成单一预测模型，并将患者分为三个危险组。在高风险组中，75%的患者被准确预测为ACT， 36%的患者仅在第一年就发展为ACT，而在低风险组中，96%的患者被准确预测为不会发展为ACT。结论SLC28A3及其他与ACT相关的基因存在多种遗传变异。结合临床风险因素，基因风险分析可以用来识别高风险患者，然后为他们提供更安全的治疗方案。
PurposeAnthracycline-induced cardiotoxicity (ACT) is a serious adverse drug reaction limiting anthracycline use and causing substantial morbidity and mortality. Our aim was to identify genetic variants associated with ACT in patients treated for childhood cancer.Patients and MethodsWe carried out a study of 2,977 single-nucleotide polymorphisms (SNPs) in 220 key drug biotransformation genes in a discovery cohort of 156 anthracycline-treated children from British Columbia, with replication in a second cohort of 188 children from across Canada and further replication of the top SNP in a third cohort of 96 patients from Amsterdam, the Netherlands.ResultsWe identified a highly significant association of a synonymous coding variant rs7853758 (L461L) within the SLC28A3 gene with ACT (odds ratio, 0.35; P = 1.8 x 10(-5) for all cohorts combined). Additional associations (P < .01) with risk and protective variants in other genes including SLC28A1 and several adenosine triphosphate-binding cassette transporters (ABCB1, ABCB4, and ABCC1) were present. We further explored combining multiple variants into a single-prediction model together with clinical risk factors and classification of patients into three risk groups. In the high-risk group, 75% of patients were accurately predicted to develop ACT, with 36% developing this within the first year alone, whereas in the low-risk group, 96% of patients were accurately predicted not to develop ACT.ConclusionWe have identified multiple genetic variants in SLC28A3 and other genes associated with ACT. Combined with clinical risk factors, genetic risk profiling might be used to identify high-risk patients who can then be provided with safer treatment options.