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)].
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.
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.
In the present study, we show that melanoma risk alleles correlate with a MTAP allele-specific hyper-methylation and down-regulation of gene expression.
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).
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.
Loss of methylthioadenosine phosphorylase (MTAP) expression and a concomitant accumulation of 5'-methyl-thioadenosine (MTA) characterise several tumour entities including malignant melanoma.
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).
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.
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.
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.