Yin L L, Yang J, Feng Y R, Huang Y, Feng T, Chen J N, Chen H X, Lin D X, Li Y X, Jin J, Tan W
State Key Laboratory of Molecular Oncology, Department of Etiology & Carcinogenesis, Beijing Key Laboratory for Carcinogenesis and Cancer Prevention, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
Zhonghua Zhong Liu Za Zhi. 2020 May 23;42(5):376-382. doi: 10.3760/cma.j.cn112152-112152-20190801-00488.
To investigate the associations between the genetic variations of apoptosis genes and the adverse events of postoperative concurrent chemoradiotherapy in patients with rectal cancer. 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. 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 (=1.51, 95% 1.07-2.15, =0.020), APAF1 rs11296996 (=0.69, 95% 0.49-0.98, =0.039) and BAX rs4645904 (=0.69, 95% 0.50-0.97, =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 (=1.42, 95% 1.02-2.00, =0.040), rs74619561 (=2.16, 95% 1.27-3.68, =0.005), CASP7 rs12263370 (=1.67, 95% 1.05-2.66, =0.029), rs12247479 (=1.85, 95% 1.12-3.08, =0.017) and TRAIL rs112822654 (=0.68, 95% 0.48-0.96, =0.027). The remaining SNPs were not related to the adverse events of chemoradiotherapy (all >0.05). Grade≥2 myelosuppression occurred less frequently in male than in female (=0.046); Surgical treatment and tumor location had great impact on the occurrence of grade≥2 diarrhea (all <0.001) and dermatitis (all <0.05). 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.
为了研究凋亡基因的遗传变异与直肠癌患者术后同步放化疗不良事件之间的关联。我们纳入了362例接受同步放化疗的Ⅱ至Ⅲ期直肠癌患者。在入组时治疗前采集患者2ml全血样本。采用Sequenom MassARRAY技术检测8个凋亡基因中29个单倍型标签单核苷酸多态性（htSNP）的基因型，这8个基因包括Fas细胞表面死亡受体（FAS）、Fas配体（FASL）、凋亡肽酶激活因子1（APAF1）、BCL2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）和半胱天冬酶7（CASP7）。通过非条件逻辑回归模型测量基因型与放化疗不良事件之间的关联。362例患者接受了全直肠系膜切除术，随后在5周内分25次给予总剂量50Gy的放疗，同时每日给予卡培他滨（1600mg/m²，持续2周，每21天周期休息1周）。106例患者（29.3%）发生≥2级骨髓抑制。与≥2级骨髓抑制风险相关的3个单核苷酸多态性包括FAS rs1468063（比值比=1.51，95%置信区间1.07 - 2.15，P=0.020）、APAF1 rs11296996（比值比=0.69，95%置信区间0.49 - 0.98，P=0.039）和BAX rs4645904（比值比=0.69，95%置信区间0.50 - 0.97，P=0.030）。161例患者（44.5%）发生≥2级腹泻。与≥2级腹泻风险显著相关的5个单核苷酸多态性包括APAF1 rs11296996（比值比=1.42，95%置信区间1.02 - 2.00，P=0.040）、rs74619561（比值比=2.16，95%置信区间1.27 - 3.68，P=0.005）、CASP7 rs12263370（比值比=1.67，95%置信区间1.05 - 2.66，P=0.029）、rs12247479（比值比=1.85，95%置信区间1.12 - 3.08，P=0.017）和TRAIL rs112822654（比值比=0.68，95%置信区间0.48 - 0.96，P=0.027）。其余单核苷酸多态性与放化疗不良事件无关（均P>0.05）。≥2级骨髓抑制在男性中的发生率低于女性（P=0.046）；手术治疗和肿瘤位置对≥2级腹泻（均P<0.001）和皮炎（均P<0.05）的发生有很大影响。FAS、APAF1、BAX、TRAIL和CASP7的基因变异与直肠癌患者同步放化疗的不良事件相关，这可能是直肠癌个体化治疗的潜在遗传生物标志物。
