更新DPYD HapB3 哈普洛型结构和对药物基因组测试的影响.
Amy J Turner1, Cyrine E Haidar2, Wenjian Yang2
1RPRD Diagnostics LLC, Milwaukee, Wisconsin, USA.
Clinical and translational science
|December 22, 2023
概括
准确的DPYD基因变异测试对于预测二皮里米丁脱酶 (DPD) 活性至关重要. 依靠c.1236G>A变异作为功能c.1129-5923C>G变异的代理,可能导致患者DPD代谢器状态不正确和癌症治疗不理想.
科学领域:
- 药物基因组学 药物基因组学
- 分子生物学分子生物学
- 在瘤学瘤学.
背景情况:
- DPYD基因编码了二皮里米丁脱酶 (DPD),这对于代谢5-甲和capecitabine等皮里米丁药物至关重要.
- DPYD的遗传变异显著影响DPD酶活性,影响患者对基于胺的疗法的反应和毒性.
- 准确的DPD代谢器状态预测对于个性化癌症治疗策略至关重要.
研究的目的:
- 为了研究DPYD基因中的两个单核酸多态体 (SNP) 之间的链接不平衡 (LD):c.1129-5923C>G (功能) 和c.1236G>A (以前使用的代理).
- 为了确定c.1236G>A变异是否是临床DPYD基因型定型中的功能c.1129-5923C>G变异的可靠替代品.
- 评估仅依靠c.1236G>A变体来预测DPD活动的临床影响.
主要方法:
- 对DPYD变异的临床基因定型数据的回顾性分析.
- 包括来自儿童怜悯数据库和我们所有人的研究计划 (版本7) 的患者数据.
- 对SNP链接和与DPD酶活性相关性的比较分析.
主要成果:
- 已识别的个体具有c.1236G>A变体而没有功能c.1129-5923C>G变体,表明不完全的链接不平衡 (LD).
- 在多个队伍中证实了不完整的SNP链接,挑战了完美的LD的假设.
- 证明仅测试c.1236G>A可以导致DPD代谢器状态的错误阳性预测.
结论:
- 之前假设DPYD SNPs c.1236G>A 和 c.1129-5923C>G 之间的完美联系在患者群体中并不一致观察到.
- 依靠c.1236G>A变体作为功能变体的代理,可能导致不准确的DPD活动预测和潜在有害的低于最佳剂量.
- 为了预测DPD活性,DPYD基因型必须包括功能变异c.1129-5923C>G,而不仅仅是c.1236G>A代理,以确保准确的患者分层和优化胺治疗.
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