Abstract：
Known genetic variations in dihydropyrimidine dehydrogenase (gene name DPYD ) do not fully predict patients at risk for severe fluoropyrimidine-associated chemotherapy toxicity. Dihydropyrimidinase (gene name DPYS ), the second catabolic enzyme in fluoropyrimidine metabolism, has been noted as a potential determinant of variation in fluoropyrimidine metabolism and response. In this study, we genotyped for DPYS c.-1T>C (rs2959023), c.265-58T>C (rs2669429) and c.541C>T (rs36027551) in a Canadian cohort of 248 patients who were wild type for Clinical Pharmacogenetics Implementation Consortium recommended DPYD variants and had received a standard dose of fluoropyrimidine chemotherapy. None of our patients were found to carry the DPYS c.541C>T variant, while the minor allele frequencies were 63% and 54% for c.-1T>C and c.265-58T>C, respectively. There was no association between DPYS c.-1T>C wild type and heterozygote [odds ratio (OR) (95% confidence interval, CI) = 1.10 (0.51-2.40)] or homozygote variant carriers [OR (95% CI) = 1.22 (0.55-2.70)], or between DPYS c.265-58T>C wild-type patients and heterozygote [OR (95% CI) = 0.93 (0.48-1.80)] or homozygote variant carriers [OR (95% CI) = 0.76 (0.37-1.55)] in terms of fluoropyrimidine-associated toxicity. Therefore, in our cohort of mostly Caucasian Canadians, genetic variations in DPYS do not appear to be a significant contributor to severe fluoropyrimidine-associated toxicity.
摘要：
二氢嘧啶脱氢酶中已知的遗传变异（基因名称DPYD）不能完全预测有严重氟嘧啶相关化疗毒性风险的患者。二氢嘧啶酶（基因名称DPYS），氟嘧啶代谢中的第二种分解代谢酶，已被认为是氟嘧啶代谢和反应变化的潜在决定因素。在这项研究中,我们对DPYSc.-1T>C(rs2959023)进行基因分型，C.265-58T>C（rs2669429）和C.541C>T（rs36027551）在加拿大的248例患者队列中，这些患者是临床药物遗传学实施联盟的野生型，推荐了DPYD变体，并接受了标准剂量的氟嘧啶化疗。我们的患者都没有发现携带DPYSc.541C>T变体，c.-1T>C和c.265-58T>C的次要等位基因频率分别为63%和54%，分别。DPYSc.-1T>C野生型与杂合子[比值比（OR）（95％置信区间，CI）=1.10（0.51-2.40）]或纯合子变异携带者[OR（95％CI）=1.22（0.55-2.70）]，或DPYSc.265-58T>C野生型患者与杂合子[OR（95％CI）=0.93（0.48-1.80）]或纯合子变异携带者[OR（95％CI）=0.76（0.37-1.55）]之间氟嘧啶相关毒性。因此,在我们大多数白人加拿大人的队列中，DPYS中的遗传变异似乎不是导致氟嘧啶相关严重毒性的重要因素.
