UGT1A1~*28/6基因多态性与广西壮族晚期结直肠癌伊立替康化疗的相关性研究

Association of UGT1A1~*28/6 Gene Polymorphism with Efficacy and Toxicity of Irinotecan-based Chemotherapy in Zhuang Patients with Advanced Colorectal Cancer in Guangxi

[目的]探讨尿苷二膦酸葡萄糖醛酸转移酶1A1 (uridine diphosphate-glucuronosy1transferase1A1,UGT1A1)基因多态性在壮族晚期结直肠癌(metastatic colorectal cancer,mCRC)患者以伊立替康(Irinotecan,CPT-11)为基础方案化疗的毒副反应及疗效关系。[方法]收集120例广西壮族m CRC患者外周血标本,采用聚合酶链式反应(polymerasechaainreaction,PCR)法扩增目的基因片段,检测UGT1A1^*28/6基因型,评估以CPT-11为基础方案化疗的毒副反应及近期疗效。[结果]120例转移性结直肠癌中,UGT1A1^*28野生型(TA6/6)81例,杂合型(TA6/7)37例,纯合型(TA7/7)2例;UGT1A1^*6野生型(G/G)93例,杂合型(G/A)24例,纯合型(A/A)3例。UGT1A1^*6基因突变(杂合型+纯合型)可增加3~4级中性粒细胞和3~4级迟发性腹泻风险的发生率(χ^2=6.172,P=0.017;χ^2=19.079,P<0.001),UGT1A1^*28基因突变(杂合型+纯合型)可增加3~4级迟发性腹泻发生的风险(χ^2=8.274,P=0.004)。联合UGTl Al^*28和UGTlAl^*6基因,野生型患者3~4级中性粒细胞减少和迟发性腹泻的发生率明显低于单点突变型和双点突变型(χ^2=6.860,P=0.032;χ^2=10.277,P=0.006)。同时较之野生型,单点突变型和双点突变型患者化疗后中性粒细胞计数显著减少(P=0.008;P=0.001)。野生型与突变型患者的总缓解率(over response rate,ORR)和疾病控制率(disease control rate,DCR)差异均无统计学意义(P=0.739;P=0.789)。两种基因联合,野生型、单点突变型和双点突变型患者的ORR和DCR差异亦均无统计学意义(P=0.968,P=0.865)。[结论] UGT1A1^*28基因和UGT1A1^*6基因双点突变型可增加壮族结直肠癌患者CPT-11严重骨髓抑制和重度延迟性腹泻发生的预测价值与效能,但UGT1A1^*28/6基因多态性与近期疗效无关。

[Objective]To investigate the association between the polymorphism of uridine diphosphateglucuronosy1 transferase 1 A1(UGT1 A1) gene and the toxicity,efficacy of irinotecan(CPT-11)-based chemotherapy in patients with metastatic colorectal cancer(mCRC) of Zhuang nationality in Guangxi.[Methods]The peripheral blood samples of 120 Zhuangpatients with metastatic colorectal cancer in Guangxi were collected. The target gene fragments were amplified by polymerase chain reaction(PCR)and UGT1 A1^*28/6 genotype was detected.The association of gene polymorphism with the toxicity and short-term efficacy of CPT-11-based chemotherapy was analyzed. [Results]Among 120 cases of metastatic colorectal cancer,81 cases were UGT1 A1^*28 wild type(TA6/6),37 cases were heterozygousmutant type(TA6/7),2 cases were homozygousmutant type(TA7/7).And 93 cases were UGT1 A1^*6 wild type(G/G),24 cases were heterozygous mutant type(G/A),and 3 cases were homozygous mutant type(A/A).UGT1 A1^*6 mutation(heterozygous + homozygous) increased the risk of grade 3-4 neutropenia and delayed diarrhea(χ^2=6.172,P=0.017;χ^2=19.079,P<0.001).While UGT1 A1^*28 mutation(heterozygous +homozygous) increased the risk of grade 3-4 delayed diarrhea(χ^2=8.274,P=0.004). Combination of UGTlAl^*28 and UGTlAl^*6 genes,the probability of occurrence of grade 3-4 neutropenia and delayed diarrhea in wild-type patients was significantly lower than that in single-point and double-point mutants(χ^2=6.860,P=0.032;χ^2=10.277,P=0.006).At the same time,compared with the wild type patients,the neutrophil count of single point mutation and double point mutation patients decreased significantly after chemotherapy(P=0.003,P=0.000).There was no significant difference in overall response rate(ORR) and disease control rate(DCR) between wild type and mutant type patients(P=0.739;P=0.789).Combination of two genes,there was no significant difference in ORR and DCR between wild type,single point mutation and double point mutation(P=0.968,P=0.865).[Conclusion] Dual point mutations of UGT1 A1^*28 and UGT1 A1^*6 genes can increase the predictive value of severe myelosuppression and severe delayed diarrhea of CPT-11 in patients with colorectal cancer of Zhuang. However,UGT1 A1^*28/6 gene polymorphism is not related to short-term efficacy.