汉族结直肠癌患者胞苷脱氨酶基因单核苷酸多态性与卡培他滨治疗不良反应的关系

Relationship between single nucleotide polymorphisms of cytidine deaminase gene and capecitabine related adverse reaction in Han patients with colorectal cancer

目的检测汉族人群结直肠癌患者胞苷脱氨酶(cytidine deaminase,CDA)基因rs3215400、rs532545位点单核苷酸多态性(single nucleotide polymorphism,SNP),评估其与卡培他滨治疗不良反应的关系。方法汉族结直肠癌患者62例,均接受卡培他滨单药或联合奥沙利铂方案化疗至少2个周期,依据美国国家癌症研究所常见不良反应事件评价标准评估卡培他滨治疗不良反应,包括手足综合征(hand foot syndrome,HFS)、腹泻、中性粒细胞减少症。化疗2个周期时,采集患者静脉血提取基因组DNA,采用高通量测序技术检测CDA基因rs532545、rs3215400位点SNP并计算突变率,比较rs532545、rs3215400位点不同基因型不良反应差异,在显性模型、隐性模型中分析CDA基因rs532545、rs3215400位点不同基因型发生不良反应的风险。结果 62例结直肠癌患者,CDA基因rs532545位点基因型野生型(G/G)50例,杂合突变型(A/G)12例,突变率为19.4%;CDA基因rs3215400位点基因型野生型(-/-)18例,杂合突变型(-/C)30例,纯合突变型(C/C)14例,突变率为71.0%;化疗2个周期时,CDA基因rs532545位点野生型(G/G)0~1级HFS发生率(36.0%)高于杂合突变型(A/G)(0)(P<0.05),2~4级HFS发生率(64.0%)低于杂合突变型(A/G)(100.0%)(P<0.05),腹泻、中性粒细胞减少症发生率与杂合突变型(A/G)比较差异均无统计学意义(P>0.05);化疗2个周期时,CDA基因rs3215400位点野生型(-/-)0~1级HFS发生率(5.6%)低于杂合突变型(-/C)(53.3%),2~4级HFS发生率(94.4%)高于杂合突变型(-/C)(46.7%)(P<0.05);野生型(-/-)0~1级及2~4级HFS发生率与纯合突变型(C/C)(7.1%、92.9%)比较差异无统计学意义(P>0.05);野生型(-/-)、杂合突变型(-/C)及纯合突变型(C/C)腹泻、中性粒细胞减少症发生率比较差异均无统计学意义(P>0.05);在显性模型中,CDA基因rs532545位点杂合突变型(A/G)2~4级HFS发生风险明显高于野生型(G/G)(OR=1.563,95%CI:1.269~1.924,P=0.013),腹泻、中性粒细胞减少症发生风险与野生型(G/G)比较差异均无统计学意义(P>0.05);rs3215400位点野生型(-/-)2~4级HFS发生风险明显高于杂合突变型(-/C)和纯合突变型(C/C)(OR=10.704,95%CI:1.303~87.943,P=0.022),腹泻、中性粒细胞减少症发生风险与杂合突变型(-/C)和纯合突变型(C/C)比较差异无统计学意义(P>0.05);隐性模型中,rs3215400位点纯合突变型(C/C)2~4级中性粒细胞减少症发生风险明显低于野生型(-/-)和杂合突变型(-/C)(OR=0.278,95%CI:0.080~0.967,P=0.038),HFS、腹泻发生风险与野生型(-/-)和杂合突变型(-/C)比较差异无统计学意义(P>0.05)。结论汉族人群中结直肠癌患者CDA基因rs3215400位点突变较rs532545多见,其位点SNP可能与卡培他滨治疗后HFS、中性粒细胞减少症发生有关。

Objective To detect the single nucleotide polymorphisms（SNPs）of cytidine deaminase（CDA）gene rs3215400 and rs532545 in Han patients with colorectal cancer and to evaluate its relationship with capecitabine related adverse reaction.Methods Sixty-two Han patients with colorectal cancer received capecitabine alone or combined with oxaliplatin chemotherapy for at least 2 cycles.The adverse reaction of capecitabine treatment was evaluated according to the Common Terminology Criteria for Adverse Events by the National Cancer Institute,including hand foot syndrome（HFS）,diarrhea,and neutropenia.During 2 cycles of chemotherapy,genomic DNA was extracted from patientsvenous blood.High-throughput sequencing was used to detect the SNPs of rs532545 and rs3215400 in the CDA gene and calculate the mutation rate.The difference of toxicities between rs532545 and rs3215400 locus of different genotypes was compared,and the risk for adverse reaction was analyzed between the genotypes of the CDA gene rs532545 and rs3215400 in the dominant model and the recessive model.Results In 62 patients with colorectal cancer,there were CDA gene rs532545 locus genotype wild type（G/G）in 50 cases and heterozygous mutation type（A/G）in 12 cases,with the mutation rate of 19.4%,and there were CDA gene rs3215400 locus genotype wild type（-/-）in 18 cases,heterozygous mutant（-/C）in 30 cases and homozygous mutant（C/C）in 14 cases,with the mutation rate of 71.0%.In CDA gene rs532545 locus,the 0-1 HFS incidence of wild type（G/G）（36.0%）was significantly higher than that in heterozygous mutant type（A/G）（0）（P〈0.05）,and the 2-4 HFS incidence of wild type（G/G）（64.0%）was significantly lower than that of heterozygous mutant type（A/G）（100.0%）（P〈0.05）,and there was no significant difference in the incidence of diarrhea and neutropenia of wild type（G/G）in comparison with that of heterozygous mutant type（A/G）（P〈0.05）.In CDA gene rs3215400 locus,the 0-1 HFS incidence of wild type（-/-）（5.6%）was significantly lower than that in heterozygous mutant type（-/C）（53.3%）,the 2-4 HFS incidence of wild type（-/-）（94.4%）was significantly higher than that in heterozygous mutant type（-/C）（46.7%）（P〈0.05）,and there was no significant difference in the incidence of 0-1 and 2-4 HFS of wild type（-/-）in comparison with that of homozygous mutant type（C/C）（7.1%,92.9%）（P〈0.05）.There were no significant differences in the incidences of diarrhea and neutropenia among these three gene types（P〈0.05）.In dominant model,the risk of 2-4 HFS of rs532545 heterozygous mutant type（A/G）was significantly higher than that of wild type（G/G）（OR=1.563,95%CI：1.269-1.924,P=0.013）,and there were no significant differences in the incidences of diarrhea and neutropenia between heterozygous mutant type（A/G）and wild type（G/G）（P〈0.05）.The risk of 2-4 HFS of rs3215400 wild type（-/-）was significantly higher than that of heterozygous mutant type（-/C）and homozygous mutant type（C/C）（OR=10.704,95%CI：1.303-87.943,P=0.022）,and there were no significant differences in the incidences of diarrhea and neutropenia among these three gene types（P〈0.05）.In recessive model,the risk of 2-4 neutropenia of rs3215400 homozygous mutant type（C/C）was significantly lower than that of wild type（-/-）and heterozygous mutant type（-/C）（OR=0.278,95%CI：0.080-0.967,P=0.038）,and there were no significant differences in the incidences of HFS and diarrhea among these three gene types（P〈0.05）.Conclusion The CDA rs3215400 mutant type genotype is more common than rs532545 in Han patients,and these two loci may be associated with HFS and neutropenia after the treatment with capecitabine.