中国人群CYP2D6基因多态性及其与激素受体阳性早期乳腺癌他莫昔芬代谢的关系

Variation of CYP2D6 genotype between Caucasian and Asian population and inconsistency of serum endoxifen concentration and phenotype of CYP2D6 in Chinese breast cancer patients

目的拟行前瞻Ⅱ期临床研究,探讨CYP2D6基因多态性在中国人群中的分布及其与激素受体阳性早期乳腺癌他莫昔芬代谢的关系。方法使用ABI 3500遗传分析仪通过Sanger测序行CYP2D6基因型测定。使用HPLC-MS/MS(API 2000)测定他莫昔芬和吲哚昔芬的血药浓度。CPIP数据库下载CYP2D6等位基因型数据进行统计学分析。结果 (1)中国乳腺癌患者最常见的等位基因型是CYP2D6*1,*2和*10;主要的双倍型是*1/*10(38.3%)和*10/*10(18.8%)。(2)在不同的CYP2D6活性预测标准下,代谢表型的分布存在差异,吲哚昔芬血药浓度以及吲哚昔芬/他莫昔芬血药浓度比值在正常代谢表型(EM)与中间表型(IM)之间结果不一致。(3)通过聚类分析三组之间吲哚昔芬血药浓度以及吲哚昔芬/他莫昔芬血药浓度比值差异有统计学意义。结论中国人CYP2D6基因型分布与西方人不同。以前被称为CYP2D6中间代谢型的患者间血清吲哚昔芬浓度有相当大的差异。在目前精准医学的时代,仅靠标准的CYP2D6基因型-表型分类系统不能对中国人群中不同吲哚昔芬浓度进行分层。

Objective To conduct a prospective phase II clinical study to explore the distribution ofCYP2 D6 gene polymorphism in Chinese population and its relationship with the metabolism of tamoxifen in early-stage hormonal receptor-positive breast cancer. Methods CYP2 D6 genotype was tested by Sanger sequencing usingthe ABI 3500 Genetic Analyzer. Plasma concentrations of tamoxifen and endoxifen were measured using the HPLC-MS/MS（API 2000）assay. We downloaded the data of CYP2 D6 allele from the CPIP database. Results In Chi-nese patients,the most common alleles were CYP2 D6＊1,＊2,and ＊10;the predominant diplotypes were ＊1/＊10（38.3%）and ＊10/＊10（18.8%）. The distribution of metabolic phenotype,plasma concentration of endoxifen,andendoxifen：tamoxifen plasma concentration ratio were inconsistent between the normal metabolic phenotype（EM）and the intermediate phenotype（IM）under different CYP2 D6 activity prediction criteria.The differences in theratios and endoxifen plasma concentrations were statistically significant between the three groups by cluster analysis.Conclusions The CYP2 D6 genotype distribution in Chinese population is different from that in the Western popu-lation. There is considerable variation of serum endoxifen concentration in Chinese breast cancer patients possess-ing the phenotype previously known as the intermediate active metabolizers of CYP2 D6. Therefore,in the currentera of precision medicine,the standard CYP2 D6 genotype-phenotype classification system cannot properly stratifythe Chinese population with different levels of endoxifen plasma concentration.