Abstract 888: Reduced folate carrier gene polymorphism (RFC 80G>A): Associations with clinical outcome in NMYC amplified neuroblastoma patients

Abstract

Abstract Background Folate plays an important role in cell function, division and differentiation. Gene polymorphisms in the folate pathway have been shown to influence folate uptake and metabolism. The aims of our study were to examine how specific gene variants in the folate pathway influence the clinical outcome of childhood neuroblastoma and to measure the correlation between specific genotypes and levels of gene expression. Methods Common single nucleotide polymorphisms (SNPs) in the folate pathway were examined in DNA from 174 children diagnosed with neuroblastoma between 1985 and 2000. Cox proportion hazard analysis was used to investigate the association between the presence or absence of specific gene polymorphisms and the risk of relapse or death in the 5 year follow up period, while adjusting for known prognostic cofactors. Relative quantification of reduced folate carrier (RFC) mRNA expression was performed in a subset of 43 neuroblastoma tissues by real-time quantitative PCR. Results No significant difference in EFS was observed between individuals with different folate genotypes (P>0.05). However, in multivariate analysis children homozygous for the RFC 80A gene variant were significantly less likely to relapse or die compared to those with RFC 80G allele after adjusting for prognostic factors such as NMYC status, stage and age at diagnosis (HR=0.46; 95% CI=0.24-0.90, P=0.024). Moreover, in those patients with NMYC amplification, the cumulative 5 year EFS was 0% in those homozygous for RFC 80GG; 9% in those heterozygous for RFC 80GA; and 50% in those homozygous for RFC 80AA (Log-rank test, P=0.005). However, no apparent association was observed for any of the additional gene polymorphisms examined (P>0.05) even after adjusting for NMYC status, age, or tumour stage at diagnosis. Quantitative mRNA analysis in a subset of 43 patients showed that expression of RFC was three times higher in those with RFC 80GG genotype compared to those with other genotypes, although this was not statistically significant (P=0.587). Conclusions Our results show that the RFC 80A variant allele confers superior survival in patients with NMYC amplification. These findings suggest that the RFC G80A polymorphism may play an important role in modifying folate transport in rapidly dividing neuroblastoma cells regulated by NMYC proto-oncogene. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 888.