A predicted functional single-nucleotide polymorphism of bone morphogenetic protein-4 gene affects mRNA expression and shows a significant association with cutaneous melanoma in Southern Italian population

Abstract

An altered expression of bone morphogenetic protein 4 (BMP4) has been found in malignant melanoma cells. We performed an association study to investigate the effect of putative functional single nucleotide polymorphisms (SNPs) of BMP4 on development of cutaneous melanoma (CM). We selected the predicted functional SNPs 6007 C/T (rs17563) and -3445 T/G (rs4898820) by the combination of three computational tools (FASTSNP, F-SNP and SNP Function Portal) plus another tool (SNP@promoter) skilled in identifying SNPs in transcription regulatory regions. Both SNPs were genotyped in a case-control study of 215 individuals with CM and 342 controls. We also evaluated the BMP4 hypothetical mRNA secondary structure by GeneBee program, the BMP4 mRNA levels and protein concentrations according to the genotype of two selected SNPs in transformed B-cells of 80 controls and in plasma samples of 38 controls, respectively. The BMP4 T-allele was associated with CM (OR: 1.39, 95% CI: 1.09-1.78, P = 0.007). The T-allele was predicted to change mRNA structure and the BMP4 mRNA levels were significantly higher in T-allele carriers compared with C-allele carriers (P = 0.01), even the BMP4 protein plasma levels were higher among T-allele carries, but without reaching the statistical significance. No significant association was found between the SNP -3445 T/G alleles and either the risk of CM, or the mRNA levels of BMP4. This study evidences the relevance of using bioinformatics tools in searching for cancer-associated gene polymorphisms and suggests that the predicted functional SNP 6007 C/T affects BMP4 gene expression and the risk to development of CM.