The single-nucleotide polymorphism T>C rs4353229 in CASP7 gene and mir-224 as new biomarkers of oxaliplatin-induced neurotoxicity in advanced colorectal cancer.

Abstract

513 Background: Oxaliplatin represents a central component of colorectal (CCR) cancer treatment. It is known that the ways in which oxaliplatin is neurotoxic include not only DNA damage, but also the modulation of specific molecules, such as caspases 3 and 7, involved in regulating the cellular equilibrium between apoptotic death and the cell cycle. MiRNAs are non-coding RNAs that can block mRNA traslation. Recent evidences indicate that variations in miRNA binding sites may contribute to the susceptibility to CCR. However, the effect of these SNPs on miRNA-target interaction remains to be determined. The SNP T>C rs4353229 in CASP7 gene is binding site of miR-224. We hypothesize that miR-224 and the SNP T>C rs4353229 could be new predictive biomarkers of oxaliplatin-induced neurotoxicity in advanced colorectal cancer. Methods: We examined the SNP T>C rs4353229 in CASP7 gene in 62 patients with advanced CCR. All patients had received first line of chemotherapy based in fluoropirimidines plus oxaliplatin. The Oxaliplatin-Specific Neurotoxicity Scale was utilized to assess oxaliplatin-related symptoms. Time to progresion (TTP) and objetive response rate (ORR) were calculated. Genomic DNA was extracted from peripheral blood and genotyped by allelic discrimination. We explored the possible correlation of rs4353229 with neurotoxicity, DCR and TTP using and Chi-cuadrado test and Kaplan-Meier model (log rank) respectively. Results: SNP distribution was 3,2% (ancestral homozygous CC), 46,7% (variant homocygous TT) and 43,7% (heterocygous CT). Median TTP was 10 months (IC95%: 7,4-12,5); regarding CASP7 polymorphism, there were not differences (p=0,41; log rank). ORR was 64,5% and there are not differences between CC, CT and TT patients (p=0,50). Fifteen patients experienced neurotoxicity grade III/IV (24,19%) and it was correlated significantly with ancestral homoygous CC patients (p=0,003). Conclusions: The SNP T>C rs4353229 in CASP7 gene and miR-224 may be new candidates predictor of oxaliplatin-induced neurotoxicity. Further characterization of CASP7 SNPs and miR-224 may open new avenues for the study of cancer and therapeutic interventions.