ABCC1 G2012T single nucleotide polymorphism is associated with patient outcome in primary neuroblastoma and altered stability of the ABCC1 gene transcript

Abstract

Multidrug resistance is a major cause of treatment failure in neuroblastoma. Multidrug resistance protein 1 has been previously implicated in the development of drug resistance, particularly with regard to influencing clinical outcomes in neuroblastoma. Numerous single nucleotide polymorphisms (SNPs) in the gene encoding multidrug resistance protein 1, namely ATP-binding cassette sub-family C member 1 (ABCC1), have been identified, however, less is known about their potential association with patient outcome. Our aim was to determine the prognostic implications of ABCC1 polymorphisms in neuroblastoma. We assessed the frequency of four nonsynonymous ABCC1 SNPs, namely G128C, G1299T, G2168A, and G2012T in both neuroblastoma samples and normal cord blood cells. Polymorphism rates and associations with clinicopathologic characteristics were assessed. The initial three examined polymorphisms were found to be present at very low levels in the Australian population. Of 195 neuroblastoma samples and 158 cord blood samples, none carried the G2012T homozygous variant allele, whereas 13% were heterozygous. The presence of the variant allele was associated with an improved outcome in patients with aggressive neuroblastoma, particularly in older children (P<0.05) and those with nonmetastatic disease (P<0.005). Tumor cell lines that were heterozygous for this SNP, expressed the variant ABCC1 gene transcript at significantly lower levels than the wild-type ABCC1 transcript, and this was associated with the reduced mRNA stability of the variant transcript. Collectively, our findings indicated a potential prognostic role of the G2012T ABCC1 polymorphism in clinically relevant subsets of patients with neuroblastoma, and provided further evidence for the ABCC1 gene being a major determinant in neuroblastoma biology.