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Abstract：
Variations in the activity, up to absolute deficiency, of the enzyme dihydropyrimidine dehydrogenase (DPD), result in the occurrence of adverse reactions to chemotherapy, and have been included among the pharmacogenetic factors underlying inter-individual variability in response to fluoropyrimidines. The study of single-nucleotide polymorphisms of the DPYD gene, which encodes the DPD enzyme, is one of the main parameters capable of predicting reduced enzymatic activity and the consequent influence on fluoropyrimidine treatment, in terms of reduction of both adverse reactions and therapeutic efficacy in disease control. In this paper, we describe a patient with metastatic breast cancer showing signs of increased toxicity following capecitabine therapy. The DPD enzyme activity analysis revealed a partial deficiency. The study of the most frequent polymorphisms of the DPYD gene suggested a wild-type genotype but indicated a novel variant c.1903A>G (p.Asn635Asp), not previously described, proximal to the splice donor site of exon 14. After excluding the potential pathogenic feature of the newly-identified variant, we performed cDNA sequencing of the entire DPYD coding sequence. This analysis identified the variants c.85T>C and c.496A>G, which were previously described as pivotal components of the haplotype associated with decreased enzyme activity and suggested that both variant alleles are related to DPD deficiency. The clinical case findings described in this study emphasize the importance of performing complete genetic analysis of the DPYD gene in order to identify rare and low frequency variants potentially responsible for toxic reactions to fluoropyrimidine treatment.
摘要：
活动的变化，直到绝对缺乏，二氢嘧啶脱氢酶（DPD），导致化疗不良反应的发生，并且已被包括在对氟嘧啶的反应的个体间差异的潜在药物遗传因素中。DPYD基因单核苷酸多态性的研究,编码DPD酶，是能够预测酶活性降低及其对氟嘧啶处理的影响的主要参数之一，在减少疾病控制中的不良反应和治疗效果方面。在本文中,我们描述了一名患有转移性乳腺癌的患者，在卡培他滨治疗后出现毒性增加的迹象。DPD酶活性分析显示部分缺乏。对DPYD基因最常见的多态性的研究表明是野生型基因型，但表明存在新的变体c.1903A>G（p。Asn635Asp），之前没有描述过，外显子14的剪接供体部位的近端。在排除新鉴定的变异体的潜在致病特征后，我们对整个DPYD编码序列进行了cDNA测序.此分析确定了变体c.85T>C和c.496A>G，先前被描述为与酶活性降低相关的单倍型的关键成分，并表明两个变体等位基因都与DPD缺乏症有关。本研究中描述的临床病例发现强调了对DPYD基因进行完整遗传分析的重要性，以鉴定可能导致氟嘧啶治疗毒性反应的稀有和低频率变异。
