Variability in genes involved in drug pharmacokinetics or drug response can be responsible for suboptimal treatment efficacy or predispose to adverse drug reactions. In addition to common genetic variations, large-scale sequencing studies have uncovered multiple rare genetic variants predicted to cause functional alterations in genes encoding proteins implicated in drug metabolism, transport and response. To understand the functional importance of rare genetic variants in DPYD, a pharmacogene whose alterations can cause severe toxicity in patients exposed to fluoropyrimidine-based regimens, massively parallel sequencing of the exonic regions and flanking splice junctions of the DPYD gene was performed in a series of nearly 3000 patients categorized according to pre-emptive DPD enzyme activity using the dihydrouracil/uracil ([UH₂]/[U]) plasma ratio as a surrogate marker of DPD activity. Our results underscore the importance of integrating next-generation sequencing-based pharmacogenomic interpretation into clinical decision making to minimize fluoropyrimidine-based chemotherapy toxicity without altering treatment efficacy.

药物药代动力学或药物反应相关基因的变异可能导致治疗效果不佳或容易出现药物不良反应。除了常见的遗传变异之外，大规模测序研究还发现了多种罕见的遗传变异，这些变异预计会导致编码与药物代谢、运输和反应有关的蛋白质的基因发生功能改变。为了了解DPYD中罕见遗传变异的功能重要性，DPYD 是一种药物基因，其改变可能对接受基于氟嘧啶的治疗方案的患者造成严重毒性，对DPYD基因的外显子区域和侧翼剪接点进行了大规模并行测序。使用二氢尿嘧啶/尿嘧啶 ([UH ₂ ]/[U]) 血浆比率作为 DPD 活性的替代标志物，根据先发性 DPD 酶活性对近 3000 名患者进行分类。我们的结果强调了将基于下一代测序的药物基因组学解释整合到临床决策中的重要性，以最大限度地减少基于氟嘧啶的化疗毒性而不改变治疗效果。