Clinical Pharmacology and Pharmacogenetics Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
Medical Oncology Division and Breast Unit, Civil Hospital, Brindisi, Italy.
Pharmacogenomics J. 2019 Dec;19(6):556-563. doi: 10.1038/s41397-019-0077-1. Epub 2019 Feb 6.
Dihydropyrimidine dehydrogenase (DPYD) is a highly polymorphic gene and classic deficient variants (i.e., c.1236G>A/HapB3, c.1679T>G, c.1905+1G>A and c.2846A>T) are characterized by impaired enzyme activity and risk of severe adverse drug reactions (ADRs) in patients treated with fluoropyrimidines. The identification of poor metabolizers by pre-emptive DPYD screening may reduce the rate of ADRs but many patients with wild-type genotype for classic variants may still display ADRs. Therefore, the search for additional DPYD polymorphisms associated with ADRs may improve the safety of treatment with fluoropyrimidines. This study included 1254 patients treated with fluoropyrimidine-containing regimens and divided into cohort 1, which included 982 subjects suffering from gastrointestinal G≥2 and/or hematological G≥3 ADRs, and cohort 2 (control group), which comprised 272 subjects not requiring dose reduction, delay or discontinuation of treatment. Both groups were screened for DPYD variants c.496A>G, c.1236G>A/HapB3, c.1601G>A (DPYD4), c.1627A>G (DPYD5), c.1679T>G (DPYD13), c.1896T>C, c.1905 + 1G>A (DPYD2A), c.2194G>A (DPYD*6), and c.2846A>T to assess their association with toxicity. Genetic analysis in the two cohorts were done by Real-Time PCR of DNA extracted from 3 ml of whole blood. DPYD c.496A>G, c.1601G>A, c.1627A>G, c.1896T>C, and c.2194G>A variants were found in both cohort 1 and 2, while c.1905+1G>A and c.2846A>T were present only in cohort 1. DPYD c.1679T>G and c.1236G>A/HapB3 were not found. Univariate analysis allowed the selection of c.1905+1G>A, c.2194G>A and c.2846A>T alleles as significantly associated with gastrointestinal and hematological ADRs (p < 0.05), while the c.496A>G variant showed a positive trend of association with neutropenia (p = 0.06). In conclusion, c.2194G>A is associated with clinically-relevant ADRs in addition to the already known c.1905+1G>A and c.2846A>T variants and should be evaluated pre-emptively to reduce the risk of fluoropyrimidine-associated ADRs.
二氢嘧啶脱氢酶（DPYD）是一个高度多态性的基因，经典的缺陷型变异（即 c.1236G>A/HapB3、c.1679T>G、c.1905+1G>A 和 c.2846A>T）的特征是酶活性受损，接受氟嘧啶类药物治疗的患者发生严重药物不良反应（ADR）的风险增加。通过预先进行 DPYD 筛查来识别代谢不良者可能会降低 ADR 发生率，但许多具有经典变异型野生型基因型的患者仍可能发生 ADR。因此，寻找与 ADR 相关的其他 DPYD 多态性可能会提高氟嘧啶类药物治疗的安全性。本研究纳入了 1254 例接受氟嘧啶类药物治疗的患者，并将其分为队列 1（982 例胃肠道 G≥2 级和/或血液学 G≥3 级 ADR 患者）和队列 2（对照组，272 例无需减少剂量、延迟或停止治疗的患者）。两组均对 DPYD 变异型 c.496A>G、c.1236G>A/HapB3、c.1601G>A（DPYD4）、c.1627A>G（DPYD5）、c.1679T>G（DPYD13）、c.1896T>C、c.1905+1G>A（DPYD2A）、c.2194G>A（DPYD*6）和 c.2846A>T 进行筛查，以评估其与毒性的相关性。通过对 3ml 全血提取的 DNA 进行实时 PCR 分析，对两组进行基因分析。c.496A>G、c.1601G>A、c.1627A>G、c.1896T>C 和 c.2194G>A 变异在队列 1 和队列 2 中均有发现，而 c.1905+1G>A 和 c.2846A>T 仅在队列 1 中存在。未发现 DPYD c.1679T>G 和 c.1236G>A/HapB3。单因素分析选择 c.1905+1G>A、c.2194G>A 和 c.2846A>T 等位基因与胃肠道和血液学 ADR 显著相关（p<0.05），而 c.496A>G 变异与中性粒细胞减少呈阳性趋势（p=0.06）。总之，c.2194G>A 与已发现的 c.1905+1G>A 和 c.2846A>T 变异一样，与临床相关的 ADR 相关，应进行预先评估以降低氟嘧啶类药物相关 ADR 的风险。
