The Polymorphic ICOS/CD28-ICOSL Pathway Is Related To The Response And Adverse Events Of Capecitabine-Based Therapy In Advanced Colon Cancer

Objective:Polymorphisms within the 3'-UTR of genes may modulate the posttranscriptional regulation of gene expression and explain individual sensitivity to chemotherapy.To investigate the correlation between single nucleotide polymorphisms(SNPs)in the miRNA binding-sites(called miRSNPs)and the efficacy of capecitabine-based chemotherapy in colon cancer.Method:Firstly,the SNPs in the 3'-UTR of B7/CD28 genes and their allele frequencies were obtained from the published databases of NCBI dbSNP BUILED129 and ENSEMBL v58.Secondly,the possible miRNA binding-sites in the 3'-UTR of the B7/CD28 family genes were predicted by using the online softwares miRanda and TargetScan v5.1.Thirdly,the genomic DNAs were extracted from the whole blood obtained from 274 patients with advanced colon cancer.Then,the genotype distribution of 16 miRSNPs was detected by MALDI-TOF-MS method.Finally,the association between genotypes and the efficacy and occurrence of adverse events of capecitabine-based chemotherapy were statistically analyzed.Results:(1)Statistical analysis indicated that ICOS rs4404254,rs1559931 and rs4675379 were significantly related to the response of chemotherapy.The response rate of rs4404254 T/C heterozygous patients was apparently less than those with the T/T genotype(30.43%vs 48.77%;P=0.011)or carrying homozygous genotypes TT and CC(30.43%vs 49.27%;P = 0.008).The patients with either rs1559931 G/A(31.34%vs 48.29%;P=0.016)or carrying A allele(33.33%vs 48.29%;P= 0.036)had worse response to the chemotherapy than the G/G homozygous patients.The patients with either rs4675379 G/C(28.13%vs 49.04%;P=0.004)or carrying C allele(30.30%vs 40.04%;P= 0.010)had worse response to the chemotherapy than the G/G homozygous patients.(2)Moreover,three miRSNPs ICOSL rsl5927,ICOSL rs3804033 and CD28 rs3181113 were significantly associated with the occurrence of side effects of chemotherapy.The patients with ICOSL rs15927 G/G genotype(78.26%),ICOSL rs3804033 G/G genotype(76.00%),or CD28 rs3181113 T/T genotype(82.05%)were much more prone to experiencing adverse events.Conclusion:Our findings demonstrate that polymorphisms in the 3'-UTR of B7/CD28 family genes may influence the efficacy of capecitabine-based chemotherapy in advanced colon cancer patients.