Objective: To investigate the associations between the genetic variations of apoptosis genes and the adverse events of postoperative concurrent chemoradiotherapy in patients with rectal cancer. Methods: We enrolled 362 patients with stage Ⅱ to Ⅲ rectal cancer who received concurrent chemoradiotherapy. Whole blood sample (2 ml) was collected from patient at the time of enrollment before therapy. Sequenom MassARRAY was used to detect the genotypes of 29 haplotype-tagging single nucleotide polymorphisms (htSNPs) in eight apoptosis genes, including Fas cell surface death receptor(FAS), Fas ligand(FASL), apoptotic peptidase activating factor 1(APAF1), BCL2 associated X(BAX), TNF-related apoptosis-inducing ligand(TRAIL), TNF-related apoptosis-inducing ligand receptor 1(TRAILR1), TNF-related apoptosis-inducing ligand receptor 2(TRAILR2) and caspase-7(CASP7). The associations between genotypes and adverse events of chemoradiotherapy were measured by unconditional logistic regression model. Results: Three hundred and sixty two patients were treated with total mesorectal excision surgery followed by a total radiation dose of 50 Gy applied in 25 fractions over a period of 5 weeks concurrently with daily administration of capecitabine (1 600 mg/m(2) per day, continuously for 2 weeks and taking a week off every 21-day cycle). One hundred and six patients (29.3%) had grade≥2 myelosuppression. Three SNPs associated with the risk of grade ≥2 myelosuppression included FAS rs1468063 (OR=1.51, 95% CI: 1.07-2.15, P=0.020), APAF1 rs11296996 (OR=0.69, 95% CI: 0.49-0.98, P=0.039) and BAX rs4645904 (OR=0.69, 95% CI: 0.50-0.97, P=0.030). One hundred and sixty one patients (44.5%) developed grade≥2 diarrhea. Five SNPs that significantly associated with risk of grade≥2 diarrhea included APAF1 rs11296996 (OR=1.42, 95% CI: 1.02-2.00, P=0.040), rs74619561 (OR=2.16, 95% CI: 1.27-3.68, P=0.005), CASP7 rs12263370 (OR=1.67, 95% CI: 1.05-2.66, P=0.029), rs12247479 (OR=1.85, 95% CI: 1.12-3.08, P=0.017) and TRAIL rs112822654 (OR=0.68, 95% CI: 0.48-0.96, P=0.027). The remaining SNPs were not related to the adverse events of chemoradiotherapy (all P>0.05). Grade≥2 myelosuppression occurred less frequently in male than in female (P=0.046); Surgical treatment and tumor location had great impact on the occurrence of grade≥2 diarrhea (all P<0.001) and dermatitis (all P<0.05). Conclusions: The genetic variations of FAS, APAF1, BAX, TRAIL and CASP7 are related to the adverse events of concurrent chemoradiotherapy in patients with rectal cancer, which may be potential genetic biomarkers for individualized treatment of rectal cancer.
目的： 探讨凋亡通路相关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： 选择362例接受术后同步放化疗的Ⅱ～Ⅲ期直肠癌患者，同步放化疗前抽取静脉血，采用Sequenom MassARRAY检测凋亡通路中的Fas细胞表面死亡受体(FAS)、Fas配体(FASL)、凋亡蛋白活性因子1(APAF1)、Bcl-2相关X蛋白(BAX)、肿瘤坏死因子相关凋亡诱导配体(TRAIL)、肿瘤坏死因子相关凋亡诱导配体受体1(TRAILR1)、肿瘤坏死因子相关凋亡诱导配体受体2(TRAILR2)和半胱氨酸天冬氨酸蛋白酶7(CASP7)基因共29个标签单核苷酸多态位点(htSNP)的基因型，分析基因型与放化疗不良反应之间的关系。基因型与放化疗不良反应的关联分析采用非条件Logistic回归模型。 结果： 362例患者接受全直肠系膜切除手术后，行照射总剂量为50 Gy、化疗方案为卡培他滨单药的同步放化疗。106例(29.3%)发生≥2级骨髓抑制，FAS rs1468063 (OR＝1.51，95% CI为1.07～2.15，P＝0.020)、APAF1 rs11296996(OR＝0.69，95% CI为0.49～0.98，P＝0.039)、BAX rs4645904(OR＝0.69，95% CI为0.50～0.97，P＝0.030)与该不良反应发生有关。161例(44.5%)患者发生≥2级的腹泻，APAF1 rs11296996(OR＝1.42，95% CI为1.02～2.00，P＝0.040)和rs74619561(OR＝2.16，95% CI为1.27～3.68，P＝0.005)、CASP7 rs12263370(OR＝1.67，95% CI为1.05～2.66，P＝0.029)和rs12247479(OR＝1.85，95% CI为1.12～3.08，P＝0.017)、TRAIL rs112822654 (OR＝0.68，95% CI为0.48～0.96，P＝0.027)与该不良反应发生有关。其余位点与直肠癌放化疗不良反应的发生无关(均P>0.05)。直肠癌患者的性别与中重度骨髓抑制的发生有关(P＝0.046)；手术方式、病灶距齿状线距离与中重度腹泻的发生有关(均P<0.001)，也与中重度放射性皮炎的发生有关(均P<0.05)。 结论： 凋亡通路相关基因FAS、APAF1、BAX、TRAIL和CASP7遗传变异与直肠癌患者接受术后同步放化疗不良反应的发生有关，可能作为直肠癌个体化治疗的潜在遗传生物标志物。.
Keywords: Adverse reaction; Apoptosis; Chemoradiotherapy; Polymorphism, single nucleotide; Rectal neoplasms.