Folate metabolism plays an important role in DNA methylation and nucleic acid synthesis and thus may function as a regulatory factor in cancer development. Genome-wide association studies (GWAS) have identified some single-nucleotide polymorphisms (SNPs) associated with cutaneous melanoma-specific survival (CMSS), but no SNPs were found in genes involved in the folate metabolic pathway.

To examine associations between SNPs in folate metabolic pathway genes and CMSS.

We comprehensively evaluated 2,645 (422 genotyped and 2,223 imputed) common SNPs in folate metabolic pathway genes from a published GWAS of 858 patients from The University of Texas M.D. Anderson Cancer Center and performed the validation in another GWAS of 409 patients from the Nurses' Health Study and Health Professionals Follow-up Study, in which 95/858 (11.1%) and 48/409 (11.5%) patients died of cutaneous melanoma, respectively.

We identified two independent SNPs (MTHFD1 rs1950902 G>A and ALPL rs10917006 C>T) to be associated with CMSS in both datasets, and their meta-analysis yielded an allelic hazards ratio of 1.75 (95% confidence interval=1.32-2.32, P=9.96×10^-5 ) and 2.05 (1.39-3.01, P=2.84×10^-4 ), respectively. The genotype-phenotype correlation analyses provided additional support for biologic plausibility of these two variants' roles in tumour progression, suggesting that variation in SNP-related mRNA expression levels is likely to be the mechanism underlying the observed associations with CMSS.

Two possibly functional genetic variants, MTHFD1 rs1950902 and ALPL rs10917006, were likely to be independently or jointly associated with CMSS, which may add to personalized treatment in the future, once further validated.