Genetic variations in apoptosis genes are associated with acute adverse events in postoperative rectal cancer patients receiving concurrent chemoradiotherapy

Abstract

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.