MDM2 SNP309 and p53 Arg72Pro in cutaneous melanoma: association between SNP309 GG genotype and tumor Breslow thickness

Abstract

A functional single nucleotide polymorphism (SNP) 309 T/G within mouse double minute 2 (MDM2) gene has been linked to onset and outcome of disease in tumors. Two published studies have shown discordant results regarding the effect of this SNP on age at diagnosis of cutaneous melanoma (CM) in Caucasian female populations. Here, we examined the age at diagnosis and clinical associations of CM with SNP309 and the related polymorphism, p53 Arg72Pro, in an Italian population (249 CM patients and 291 cancer-free controls) composed of women and men. MDM2 intronic region of 294 bp was directly sequenced, whereas Arg72Pro SNP was analyzed by polymerase chain reaction-restriction fragment length polymorphism. No associations were found among the SNP309, Arg72Pro, risk of CM, age at diagnosis and presence of metastasis in total subjects and when stratified according to the gender. The SNP309 was significantly associated with tumor Breslow thickness. The P-value in the minor allele recessive mode was 0.02, and the odds ratio (OR) adjusted for gender and age was 3.11 (95% confidential interval (CI)¼1.21-8.00). The SNP309 is not associated with the risk and age of onset of CM, and the presence of metastasis in an Italian population but the SNP309 GG may be a risk genotype for increasing in tumor Breslow thickness.

Investigation of the Effect of MDM2 SNP309 and TP53 Arg72Pro Polymorphisms on the Age of Onset of Cutaneous Melanoma

“…Collectively, the studies by Nan et al (2009), Capasso et al (2010, and ours agree in that the MDM2 SNP309 G does not appear to be a risk factor for developing melanoma at a young age. A very recent report unveils a second MDM2 promoter SNP in position 285 (SNP285G4C), which forms a distinct haplotype with SNP309 (SNP285C/SNP309G) (Knappskog et al, 2011).…”

“…However, when we stratified the groups into gender and decades of age at diagnosis, we found an increased frequency of the GG genotype among women diagnosed at an older age, which does not support the hypothesis of an active estrogen signaling via the SNP309 GG genotype. Another study conducted in 249 cases and 291 controls found that women having the SNP309 GG genotype were diagnosed at an older age, although the association did not reach statistical significance (Capasso et al, 2010). The same authors found a positive association between the GG genotype and tumor thickness (Capasso et al, 2010).…”

“…Another study conducted in 249 cases and 291 controls found that women having the SNP309 GG genotype were diagnosed at an older age, although the association did not reach statistical significance (Capasso et al, 2010). The same authors found a positive association between the GG genotype and tumor thickness (Capasso et al, 2010). Nan et al (2009) conducted a nested case-control study of the Nurses' Health Study among 219 cases and found no associations between SNP309 and risk or age of onset.…”

“…Some studies, but not all, reported that the MDM2 SNP309 might modify the risk, age of onset, or prognosis in a variety of cancers (Alhopuro et al, 2005;Bond et al, 2006b;Schmidt et al, 2007;Wilkening et al, 2007;Krekac et al, 2008;Fang et al, 2010;Yu et al, 2011). In melanoma, there are only a few investigations on MDM2 SNP309 to date, and the reported effect for this SNP is not consistent between studies: one study found an association between SNP309 and risk for melanoma, as well as age at diagnosis, and other studies found no effect on either risk, age at diagnosis, or progression (Firoz et al, 2009;Gluck et al, 2009;Nan et al, 2009;Capasso et al, 2010).…”

Familial Melanoma in Italy: A Review

“…Additionally, it was shown that a SNP in the MDM2 gene, the SNP309 (T>G variation) was linked to the tumour onset and outcome. However, discordant results were reported on the effect of this SNP on age at diagnosis of cutaneous melanoma in Caucasian female population and no associations were found among SNP309, melanoma risk, age at diagnosis and presence of metastasis in the Italian population, although SNP309 was significantly associated with tumour Breslow thickness (Capasso et al, 2010). It was proposed that the Vitamin D Receptor (VDR) gene might play a role in melanoma development as well, since its interaction with the calcitriol ligand results in antiproliferative and pro-differentiation signals on melanocytes.…”