The MTAPmelanoma risk SNP genotype, associated with darker pigmentation, (rs4636294*A/A) was less common in amelanotic/hypomelanotic melanoma patients [OR (CI 95%) 0.8 (0.3-2.1) vs. 2.0 (1.3-3.1)].
Our results suggest that the relationship between MTAP and melanoma is subtype-specific, and that the association between IRF4 and melanoma is more evident for cases with a younger age at onset.
In the supplementary meta-analyses, a locus at 9p21.3 (CDKN2A/MTAP) reached genome-wide statistical significance with CM and had strong epidemiological credibility.
Individuals having melanoma in a visibly UV-damaged site were more likely to carry MC1R rs75570604 (odds ratio [OR] 2.5), 9q31.2 rs10816595 (OR 2.5), and MTAPrs869329 (OR 1.4); these same alleles were more common in MPM patients diagnosed ≤40 years.
We recently discovered a lack of methylthioadenosine phosphorylase (MTAP) expression in melanoma, which resulted in an accumulation of the metabolite 5'-methylthioadenosine (MTA) in melanoma cells and in the extracellular environment.
In the present study, we show that melanoma risk alleles correlate with a MTAP allele-specific hyper-methylation and down-regulation of gene expression.
Loss of methylthioadenosine phosphorylase (MTAP) expression and a concomitant accumulation of 5'-methyl-thioadenosine (MTA) characterise several tumour entities including malignant melanoma.
This exploratory study is the first to show a significant association between the rs869330 variant (in the MTAP gene) and outcome in a large CM population.
Two of the MTAPase-deficient cell preparations (from a liver carcinoma and from a melanoma) are primary cultures thus directly representing the original cancer genotypes.
In a multivariable model that included only the most statistically significant findings from univariable modeling and adjusted for pigmentary phenotype, back nevi, and baseline features, we found TERT/CLPTM1L rs401681 (P = 0.004), TYRP1 rs2733832 (P = 0.006), MTAPrs1335510 (P = 0.0005), TYR rs10830253 (P = 0.003), and MX2 rs45430 (P = 0.008) to be significantly associated with multiple primary melanoma, while NCOA6 rs4911442 approached significance (P = 0.06).
One SNP in MTAP (methylthioadenosine phosphorylase) (rs7023329) that was previously associated with melanoma and nevi in multiple genome-wide association studies was associated with CRC, CA and OS by ASSET (P=0.007).
In summary, we demonstrate significant inverse correlation between MTAP protein expression and progression of melanocytic tumors as the amount of MTAP protein staining decreases from benign melanocytic nevi to metastatic melanomas.