细胞色素P450 2A6基因rs8192725多态性对胃癌术后患者化疗效果的影响

The effect of cytochrome P450 2A6 gene rs8192725 polymorphism on clinical outcomes of chemotherapy in postoperative gastric cancer patients

目的探讨CYP2A6基因多态性对胃癌患者术后辅助替吉奥为基础的化疗方案疗效的影响。方法本研究纳入188例D2根治术后接受替吉奥为基础辅助化疗的胃癌患者,取患者的外周血提取DNA进行CYP2A6基因分型,提取66例患者的外周血单核细胞(peripheral blood mononuclear cell,PBMC)RNA进行CYP2A6基因mRNA表达的测定。结果纳入研究的CYP2A6的多态性位点均是经过NCBI数据库查阅在中国人群中突变频率>10%的3个位点(rs8192725、rs8192720和rs28399433位点),其中仅发现了rs8192725位点的临床意义。rs8192725位点在研究人群的基因分布频率为:CC型131例(69.7%),CT型51例(27.1%),TT型6例(3.2%),最小等位基因频率为0.17。CT/TT和CC基因型患者的3年无疾病生存率分别为61.5%和72.5%,差异有统计学意义(χ2=8.233,P=0.004);CT/TT和CC基因型患者的3年总生存率分别为73.7%和79.4%,差异有统计学意义(χ2=4.863,P=0.021)。构建多变量的COX模型校正之后发现,该位点CT/TT基因型对患者无疾病生存率的影响差异有统计学意义(OR=1.81,P=0.012)。rs8192725位点的CT/TT基因型66例患者相对于野生型的CC型患者的PBMC中CYP2A6的mRNA表达低(2.6±0.4比4.0±0.4,P<0.001)。结论CYP2A6基因rs8192725位点可能通过影响CYP2A6的mRNA表达而影响了胃癌术后患者接受以替吉奥为基础的辅助化疗的疗效。

Objective To investigate the associations between CYP2A6 polymorphisms and treatment outcomes of adjuvant S-1 in postoperative gastric cancer patients. Methods 188 patients after D2 radical resection received S-1 based adjuvant chemotherapy.PBMC cell specimen were collected for the genotyping of genetic variation and CYP2A6 gene mRNA expression.Univariate analysis of genotypes and prognosis was carried out by Kaplan-Meier survival analysis,and multivariate analysis were adjusted by COX regression analysis. Results The polymorphisms included in this study were collected in the NCBI database with the minor allele frequency >10% in Chinese population (rs8192725,rs8192720 and rs28399433),with rs8192725 only of clinical significance.The prevalence of rs8192725 in CYP2A6 were CC genotype 131 cases (69.7%),CT genotype 51 cases (27.1%),TT genotype 6 cases (3.2%),minor allele frequency of rs8192725 was 0.17.The 3 year disease-free survival (DFS) rate in patients with CT/TT genotype and CC genotype were 61.5% and 72.5%,respectively (χ2=8.233,P=0.004).The 3 year overall survival rate of the two genotypes were 73.7% and 79.4% (χ2=4.863,P=0.021).CT/TT genotypes were an independent factor for DFS (OR=1.81,P=0.012).The expression of CYP2A6 in PBMC of the patients with CT/TT genotypes were significantly lower than those of the CC genotype patients (P<0.001). Conclusions After D2 gastric cancer patients treated by S-1,the polymorphism rs8192725 of CYP2A6 may effect the clinical outcomes of adjuvant chemotherapy S-1 treatment through influencing the mRNA expression of CYP2A6.