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. 2009 Dec;135(12):1799-807.
doi: 10.1007/s00432-009-0628-y. Epub 2009 Jun 26.

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

Mario Capasso  1 , Fabrizio Ayala, Roberta Russo, Rosa Anna Avvisati, Roberta Asci, Achille Iolascon
Affiliations

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

Mario Capasso et al. J Cancer Res Clin Oncol. 2009 Dec.

Abstract

Purpose: 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).

Methods: 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.

Results: 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.

Conclusions: 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.

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Conflict of interest statement

The authors declare that they have no competing interest.

Figures

Fig. 1
Fig. 1
Ongoing overlapping structure of wild protein (red color) with mutant protein Val152Ala (blue color) (a–d). Final superimposed structure of wild protein with mutant protein (yellow color, panel e)
Fig. 2
Fig. 2
The predicted mRNA secondary structures (partial) of the two BMP4 coding region alleles. Only part of the structure containing the non-synonymous single nucleotide polymorphism (SNP) is shown, while the truncated part of mRNA structure (not shown) exhibits no difference between the two alleles. The free energy (kcal/mol) of the full-length mRNA is shown in parentheses. The difference between C and T alleles is indicated by arrows
Fig. 3
Fig. 3
Expression levels of BMP4 in transformed B-cell lines from healthy individuals. Panels a and b show the mRNA levels of BMP4 (2−ΔCt) in 80 healthy controls from Southern Italy stratified according to genotype at SNPs 6007 CT and −3445 TG, respectively. The tables on the bottom of the graph report the results of statistical analysis
Fig. 4
Fig. 4
Protein plasma levels of BMP4 in healthy individuals. The plasma levels of BMP4 in 38 healthy controls from Southern Italy stratified according to genotype at SNPs 6007 CT. The table on bottom of the graph reports the results of statistical analysis
See this image and copyright information in PMC

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