妊娠滋养细胞疾病患者的二氢嘧啶脱氢酶基因多态性分析

Genetic Polymorphism Analysis of DPYD in the Patients with Gestational Trophoblastic Disease

目的探索妊娠滋养细胞疾病患者的二氢嘧啶脱氢酶基因（DPYD）多态性。方法采用多聚酶链反应（PCR）一直接测序方法检测DPYD中A74G，T85C（DPYD^＊9），IVS14＋IG→A（DPYD^＊2），C2303A和A2846T等5个位点的突变频率，并对DPD活性缺乏以及使用氟化嘧啶类药物出现严重不良反应的回访患者的DPYD基因中外显子4、外显子5、外显子6、外显子7、外显子8、外显子10、外显子11、外显子12、外显子13、外显子21和外显子23进行分析。结果130名妊娠滋养细胞疾病患者中，化疗组患者105名，使用含氟化嘧啶类药物治疗发生严重不良反应的回访患者25名。患者中存在DPYD^＊2，DPYD^＊9，A496G，A1627G和C2303A等位点变异，新发现A720C和A2670C2种同义突变。化疗组患者DPYD^＊9等位基因发生频率为6．93％，C2303A发生频率为0．49％；未发现DPYD^＊2、A74G和A2846T位点变异。DPYD^＊2，DPYD^＊9，A496G，A720C，A1627G，C2303A和A2670C在DPD活性缺乏及曾出现严重不良反应的回访患者中的发生频率分别为1．14％，7．95％，3．41％，37．50％，18．18％，1．14％和15．91％。结论在中国妊娠滋养细胞疾病患者中发现DPYD^＊2，DPYD^＊9，A496G，A1627G等位点变异，首次在中国人群中发现C2303A，A720C和A2670C变异。DPYD^＊2和C2303A变异可能与DPD活性缺乏相关。

OBJECTIVE To investigate the genetic polymorphism of dihydropyrimidine dehydrogenase gene （DPYD） in the patients with gestational trophohlastic disease. METHODS The polymerase chain reaction （PCR）-DNA sequencing technique was used to identify 5 mutation points of DPYD, including A74G, T85C （DPYD^＊9）, IVS14＋IG→A （DPYD^＊2）, C2303A and A2846T. Exon 4, 5, 6, 7, 8, 10, 11, 12, 1 3, 21, and 23 were also analyzed in the patients with DPD activity deficiency or suffering from severe toxicity after the administration of fluoropyrimidines. RESULTS Among 130 enrolled subjects, 105 of them were treated with fluoropyrimidines-containing regime, 25 were follow-up who had been suffered severe toxicity with fluoropyrimidinescontaining treatment. DPYD^＊2, DPYD^＊9, A496G, A1627G and C2303A mutations were found; while 2 novel silent mutations, A720C and A2670C, were detected. The allelic frequencies of DPYD^＊9 and C2303A were 6.93% and 0.49% in treatment group, respectively. The allelic frequencies of DPYD^＊2, DPYD^＊9, A496G, A720C, A1627G, C2303A and A2670C were 1.14%, 7.95%, 3.41%, 37.50%, 18.18%, 1.14% and 15.91% in the patients with DPD deficiency and follow-up group. CONCLUSION DPYD^＊2, DPYD^＊9, A496G, A720C, A1627G, C2303A and A2670C were found. DPYD＊2 and C2303A may be associated with DPD deficiency.