Study On Genetic Variations Of Apoptosis Pathway Genes Associated With Chemoradiotherapy Sensitivity,Acute Adverse Events And Survival In Patients With Rectal Cancer

Colorectal cancer is the main malignant disease of the gastrointestinal tract.Its incidence is the third in cancer,and it ranks the second leading cause of cancer death worldwide.The treatment options for locally advanced rectal cancer include preoperative concurrent chemoradiotherapy combined with total mesorectal excision surgery and concurrent chemoradiotherapy after surgical resection.Patients vary in their response to the preoperative chemoradiotherapy or the postoperative chemoradiotherapy.A lot of them suffer from adverse events or tumor progression or even death.Inherited genetic factors may explain some of the variability of patients’response and prognosis.In this study,candidate gene strategy was used to investigate the associations between the genetic variations of apoptosis genes and the sensitivity,acute adverse events and survival prognosis of concurrent chemoradiotherapy in patients with rectal cancer.In this study,two groups of patients with rectal cancer were enrolled in succession,including 136 patients who underwent radical resection of rectal cancer after preoperative concurrent chemoradiotherapy and 362 patients who underwent concurrent chemoradiotherapy after surgical resection.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 56 tagSNPs in seventeen apoptosis genes,including APAF1,BAK,BAX,BCL2,BID,CASP3,CASP6,CASP7,CASP8,CASP9,CASP10,FAS,FASL,TNFR,TRAIL,TRAILR1 and TRAILR2.Logistic regression model was used to correct clinical factors,and 56 tagSNPs were associated with the sensitivity of preoperative concurrent chemoradiotherapy or the risk of acute adverse events of postoperative concurrent chemoradiotherapy in rectal cancer patients.FAS rs4934431,BID rs8190256 and BAX rs905238 significantly affected the sensitivity of chemoradiotherapy,odds ratios(ORs)values calculated by the additive model were 2.25(95%CI=1.28-3.95,P=0.005),0.36(95%CI=0.15-0.87,P=0.023),0.58(95%CI=0.34-0.99,P=0.048),respectively.The Cox proportional regression model calculated the association between 56 tagSNPs and the overall survival of patients undergoing preoperative concurrent chemoradiotherapy for rectal cancer.CASP3 rs116609630,CASP7 rs12415607 and FAS rs1800682 were associated to the overall survival of this group of patients,and hazard ratios(HRs)and 95%confidence intervals(CIs)were 2.31(95%CI=1.00-5.34,P=0.050),0.48(95%CI=0.24-0.96,P=0.037),2.59(95%CI=1.07-6.28,P=0.035),respectively.A combined analysis of CASP7 rs12415607 and FAS rs1800682 found that patients with 3 to 4 risk alleles had a significantly increased risk of death compared with 0 to 2 risk alleles(HR=2.84,95%CI=1.46-5.53,P=0.002).In patients with rectal cancer who were undergoing postoperative concurrent chemoradiotherapy,three SNPs were associated with the risk of grade≥2 myelosuppression by the additive model,including APAF1 rs 11296996(OR=0.69,95%CI=0.49-0.98,P=0.039),BAX rs4645904(OR=0.69,95%CI=0.50-0.97,P=0.030),FAS rs1468063(OR=1.51,95%CI=1.07-2.15,P=0.020).Five SNPs that significantly associated with risk of grade≥2 diarrhea,including APAF1 rs11296996(OR=1.42,95%CI=1.02-2.00,P=0.040)and 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)and rs12247479(OR=1.85,95%CI=1.12-3.08,P=0.017),TRAIL rs112822654(OR=0.68,95%CI=0.48-0.69,P=0.027).The Cox proportional regression model calculated the association between 56 tagSNPs and overall survival of patients with rectal cancer undergoing concurrent postoperative chemoradiotherapy,and found six SNPs that significantly associated with overall survival of the patients,including BAK rs74499662(HR=0.57,95%CI=0.36-0.91,P=0.019),BCL2 rs34811186(HR=1.91,95%CI=1.13-3.19,P=0.014),BID rs148719901(HR=0.52,95%CI 0.31-0.86,P=0.011),CASP9 rs1052576(HR=0.52,95%CI 0.32-0.83,P=0.006),rs12741552(HR=0.54,95%CI 0.34-0.88,P=0.013)and FASL rs763110(HR=0.61,95%CI 0.37-0.99,P=0.044).The combined analysis of the three SNPs including CASP9 rs1052576,PMS1 rs4920657 and hsa-miR-4274 rs202195689 showed that patients with 2 to 3 risk genotypes had a significantly increased risk of death compared with patients carrying 0 to 1 risk genotype(HR=2.07,95%CI=1.30-3.30,P=0.002).Our study found that the genetic variations of the apoptosis pathway genes FAS,BID,BAX are significantly associated with the sensitivity of preoperative chemoradiotherapy in patients with rectal cancer;the genetic variations of FAS,APAF1 and BAX are associated with the occurrence of severe bone marrow suppression in rectal cancer patients undergoing postoperative chemoradiotherapy.The genetic variations of APAF1,CASP7 and TRAIL are associated with the occurrence of severe diarrhea in patients undergoing concurrent radiotherapy and chemotherapy.The genetic variations of CASP3,CASP7 and FAS are significantly associated with the overall survival of patients with rectal cancer preoperative concurrent radiotherapy and chemotherapy.The genetic variations of BAK,BCL2,BID,CASP9 and FASL are significantly associated with the overall survival of rectal cancer patients who had postoperative chemoradiotherapy.These genetic variations may be potential genetic biomarkers for individualized treatment of rectal cancer.