焦亡通路基因的遗传变异与直肠癌患者术后同步放化疗不良反应相关

Associations of genetic variations in pyroptosis related genes with acute adverse events in postoperative rectal cancer patients receiving concurrent chemoradiotherapy

目的探讨焦亡通路关键基因的遗传变异与直肠癌患者术后同步放化疗不良反应的关系。方法抽取2005年1月至2015年6月中国医学科学院肿瘤医院347例Ⅱ~Ⅲ期直肠癌患者术后同步放化疗治疗前的外周血,提取DNA,采用Sequenom MassARRAY方法检测焦亡通路中的黑色素瘤缺乏因子2(AIM2)、半胱天冬酶1(CASP1)、CASP4、CASP5、CASP11、消皮素D(GSDMD)、消皮素E(GSDME)和含Nod样受体家族pyrin域蛋白3(NLRP3)共8个关键基因的43个标签单核苷酸多态(htSNP)的基因分型,采用非条件logistic回归模型分析htSNP基因型与直肠癌患者术后同步放化疗不良反应发生的关系。结果347例患者术后接受持续5周的术后同步放化疗,发生中重度骨髓抑制101例(29.1%),发生中重度腹泻156例(45.0%),发生中重度放射性皮炎66例(19.0%)。手术方式、病灶距齿状线距离与直肠癌患者术后同步放化疗发生中重度腹泻和放射性皮炎有关(均P<0.01)。CASP4基因的rs11226565(OR=0.41,95%CI:0.21~0.79)、rs579408(OR=1.54,95%CI:1.03~2.29)和rs543923(OR=0.63,95%CI:0.41~0.98)3个遗传变异位点与中重度骨髓抑制发生有关;CASP11 rs10880868(OR=0.55,95%CI:0.33~0.91)和GSDME rs2954558(OR=1.52,95%CI:1.01~2.31)与中重度腹泻发生有关;GSDME rs2237314(OR=0.36,95%CI:0.16~0.83)、GSDME rs12540919(OR=0.52,95%CI:0.27~0.99)和NLRP3 rs3806268(OR=1.51,95%CI:1.03~2.22)与中重度放射性皮炎的发生有关。其余35个htSNP位点与直肠癌患者术后同步放化疗不良反应发生无关(均P>0.05)。结论焦亡通路相关基因CASP4、CASP11、GSDME和NLRP3的遗传变异与Ⅱ~Ⅲ期直肠癌患者术后同步放化疗的不良反应发生有关,可能是直肠癌个体化治疗的潜在遗传标志物。

Objective This study aims to investigate the associations between genetic variations of pyroptosis pathway related key genes and adverse events(AEs)of postoperative chemoradiotherapy(CRT)in patients with rectal cancer.Methods DNA was extracted from the peripheral blood which was collected from 347 patients before CRT.Sequenom MassARRAY was used to detect the genotypes of 43 haplotype-tagging single nucleotide polymorphisms(htSNPs)in eight pyroptosis genes,including absent in melanoma 2(AIM2),caspase-1(CASP1),caspase-4(CASP4),caspase-5(CASP5),caspase-11(CASP11),gasdermin D(GSDMD),gasdermin E(GSDME)and NLR family pyrin domain containing 3(NLRP3).The associations between 43 htSNPs and AEs were evaluated by the odd ratios(ORs)and 95%confidence intervals(CIs)by unconditional logistic regression models,adjusted for sex,age,clinical stage,tumor grade,Karnofsky performance status(KPS),surgical procedure,and tumor location.Results Among the 347 patients with rectal cancer underwent concurrent CRT with capecitabine after surgery,a total of 101(29.1%)occurred grade≥2 leukopenia.rs11226565(OR=0.41,95%CI:0.21-0.79,P=0.008),rs579408(OR=1.54,95%CI:1.03-2.29,P=0.034)and rs543923(OR=0.63,95%CI:0.41-0.98,P=0.040)were significantly associated with the occurrence of grade≥2 leukopenia.One hundred and fifty-six(45.0%)had grade≥2 diarrhea,two SNPs were significantly associated with the occurrence of grade≥diarrhea,including CASP11 rs10880868(OR=0.55,95%CI:0.33-0.91,P=0.020)and GSDME rs2954558(OR=1.52,95%CI:1.01-2.31,P=0.050).In addition,sixty-six cases(19.0%)developed grade≥2 dermatitis,three SNPs that significantly associated with the risk of grade≥2 dermatitis included GSDME rs2237314(OR=0.36,95%CI:0.16-0.83,P=0.017),GSDME rs12540919(OR=0.52,95%CI:0.27-0.99,P=0.045)and NLRP3 rs3806268(OR=1.51,95%CI:1.03-2.22,P=0.037).There was no significant difference in the association between other genetic variations and AEs of rectal cancer patients(all P>0.05).Surgical procedure and tumor location had great impacts on the occurrence of grade≥2 diarrhea and dermatitis(all P<0.01).Conclusion The genetic variants of CASP4,CASP11,GSDME and NLRP3 are associated with the occurrence of AEs in patients with rectal cancer who received postoperative CRT,suggesting they may be potential genetic markers in predicting the grade of AEs to achieve individualized treatment of rectal cancer.