ABCG2/FLT3/VEGFR2基因多态性与舒尼替尼治疗国人晚期肾透明细胞癌致血小板减少的相关性研究

Genetic polymorphisms of ABCG2/FLT3/VEGFR2 associated with thrombocytopenia in Chinese patients with clear-cell metastatic renal cell carcinoma treated with sunitinib

目的探讨在舒尼替尼药效学和药代学途径上ABCG2、FLT3、VEGFR2基因多态性与舒尼替尼治疗后血小板减少之间的相关性。方法 82例接受舒尼替尼单药治疗的晚期肾透明细胞癌患者,治疗前进行ABCG2(rs2231137、rs2231142),FLT3(rs1933437)和VEGFR2(rs2305948)基因多态性检测,记录患者治疗后血小板减少程度,评价基因多态性与血小板减少之间的相关性。结果 rs2231137、rs2231142、rs1933437和rs2305948基因型分布符合Hardy-Weinberg遗传平衡定律。rs2231142的CC基因型和AA/AC基因型3、4级血小板减少分别为25.0%和47.6%,两组血小板减少程度有显著差异(χ2=4.518,P=0.034)。rs1933437的TT基因型和CC/CT基因型3、4级血小板减少分别为48.7%和25.6%,两组血小板减少程度有显著差异(χ2=4.719,P=0.030)。rs2231137或rs2305948不同基因型之间的血小板减少程度无显著差异(P>0.05)。结论中国晚期肾透明细胞癌人群应用舒尼替尼治疗后,rs2231142的CC基因型患者比AA/AC基因型患者发生血小板减少的可能性更小,而rs1933437的TT基因型患者比CC/CT基因型患者发生血小板减少可能性更大,测定基因型有利于选择合适的舒尼替尼治疗人群,为个体化治疗提供了依据。

Objective To identify genetic polymorphisms ABCG2/FLT3/VEGFR2 related to the pharmacokinetics and pharmacodynamics of sunitinib that are associated with thrombocytopenia in Chinese patients with metastatic clear-cell renal cell carcinoma（mcc-RCC） treated with sunitinib.Methods Eighty-two mcc-RCC patients treated with sunitinib were enrolled in this study.Genotype analyses were done before treatment and thrombocytopenia was recorded on the first three cycles of treatment.Genetic polymorphisms of ABCG2（rs2231137,rs2231142）,FLT3（rs1933437） and VEGFR2（rs2305948） were analyzed for a possible association with thrombocytopenia.Results Gene types of rs2231137,rs2231142,rs1933437 and rs2305948 were according to Hardy-Weinberg law.The rs2231142 CC genotype was associated with a lower risk for thrombocytopenia grade 3,4 when compared with the AA/AC genotypes（25.0% vs.47.6%,P=0.034）.The rs1933437 TT genotype was associated with a higher risk for thrombocytopenia grade 3,4 when compared with the CC/CT genotypes（48.7% vs.25.6%,P=0.030）.No significant differences were detected in thrombocytopenia grade 3,4 among rs2231137（34.9% vs.37.5% vs.42.9%,P=0.912） and rs2305948（31.7% vs.47.6% vs.100%,P=0.177） genotype subgroups.Conclusion This study showed that the risk for thrombocytopenia was increased in the presence of the A allele genotype in ABCG2 421C/A,and C allele genotype of FLT3 738T/C has a protective effect against sunitinib-induced thrombocytopenia.