氟嘧啶 (FL) [5-氟尿嘧啶、卡培他滨] 用于治疗多种实体瘤。二氢嘧啶脱氢酶（DPD）是 FL 解毒的限速酶，其缺乏可能导致 FL 给药后严重、危及生命或致命的毒性。科学联盟建议在 FL 治疗前使用二氢嘧啶脱氢酶基因 (DPYD) 中四种有害变异（DPYD*2A、DPYD*13、c.2846A > T、c.1129-5923C > G）的药物遗传学小组进行测试（例如 CPIC、DPWG）和药品监管机构（例如 EMA）。然而，该小组确定< 20% 的患者面临严重 FL 相关毒性的风险。最近累积的证据强调了罕见（次要等位基因频率 < 1%）和新型 DPYD 基因变异的潜在临床价值，可用于识别另外一部分 DPD 缺陷患者，其严重 FL 相关毒性风险增加。在这篇综述中，我们的目的是全面描述关于新型和罕见的 DPYD 变体作为 FL 治疗患者毒性标志物的潜在临床预测作用的现有证据，并讨论根据此类药物的临床应用调整 FL 治疗的挑战和机遇。标记。尽管我们必须克服临床实施的现有障碍，但现有数据支持，与目前的靶向方法相比，对 DPYD 序列（包括罕见和新的遗传变异）的全面评估可能会显着增强对高危患者的先发制人识别.© 作者。

Fluoropyrimidines (FLs) [5-Fluorouracil, Capecitabine] are used in the treatment of several solid tumors. Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme for FL detoxification, and its deficiency could lead to severe, life-threatening or fatal toxicity after FL administration. Testing with a pharmacogenetic panel of four deleterious variants in the dihydropyrimidine dehydrogenase gene (DPYD) (DPYD*2A, DPYD*13, c.2846A > T, c.1129-5923C > G) prior to FL treatment, is recommended by scientific consortia (e.g., CPIC, DPWG) and drug regulatory agencies (e.g., EMA). However, this panel identifies < 20% of patients at risk of severe FL-related toxicity. Cumulative recent evidence highlights the potential clinical value of rare (minor allele frequency < 1%) and novel DPYD genetic variants for identifying an additional fraction of DPD-deficient patients at increased risk of severe FL-related toxicity. In this review, we aimed to comprehensively describe the available evidence regarding the potential clinical predictive role of novel and rare DPYD variants as toxicity markers in FL-treated patients, and to discuss the challenges and opportunities in tailoring FL treatment based upon clinical application of such markers. Although we must overcome existing barriers to the clinical implementation, the available data support that comprehensive assessment of the DPYD sequence, including rare and novel genetic variants, may significantly enhance the pre-emptive identification of at-risk patients, compared to the current targeted approach.© The author(s).