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Genetic variants in the vitamin D pathway genes VDBP and RXRA modulate cutaneous melanoma disease-specific survival.

ABSTRACT: Single nucleotide polymorphisms (SNPs) in the vitamin D pathway genes have been implicated in cutaneous melanoma (CM) risk, but their role in CM disease-specific survival (DSS) remains obscure. We comprehensively analyzed the prognostic roles of 2669 common SNPs in the vitamin D pathway genes using data from a published genome-wide association study (GWAS) at The University of Texas M.D. Anderson Cancer Center (MDACC) and then validated the SNPs of interest in another GWAS from the Nurses' Health Study and Health Professionals Follow-up Study. Among the 2669 SNPs, 203 were significantly associated with DSS in MDACC dataset (P < 0.05 and false-positive report probability < 0.2), of which 18 were the tag SNPs. In the replication, two of these 18 SNPs showed nominal significance: the VDBP rs12512631 T > C was associated with a better DSS [combined hazards ratio (HR) = 0.66]; and the same for RXRA rs7850212 C > A (combined HR = 0.38), which were further confirmed by the Fine and Gray competing-risks regression model. Further bioinformatics analyses indicated that these loci may modulate corresponding gene methylation status.

SUBMITTER: Yin J

PROVIDER: S-EPMC5275751 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Genetic variants in the vitamin D pathway genes VDBP and RXRA modulate cutaneous melanoma disease-specific survival.

Yin Jieyun J Liu Hongliang H Yi Xiaohua X Wu Wenting W Amos Christopher I CI Fang Shenying S Lee Jeffrey E JE Han Jiali J Wei Qingyi Q

Pigment cell & melanoma research 20160129 2

Single nucleotide polymorphisms (SNPs) in the vitamin D pathway genes have been implicated in cutaneous melanoma (CM) risk, but their role in CM disease-specific survival (DSS) remains obscure. We comprehensively analyzed the prognostic roles of 2669 common SNPs in the vitamin D pathway genes using data from a published genome-wide association study (GWAS) at The University of Texas M.D. Anderson Cancer Center (MDACC) and then validated the SNPs of interest in another GWAS from the Nurses' Healt ...[more]

PMID: 26575331

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Project description:BackgroundFolate 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 (GWASs) 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.ObjectivesTo examine associations between SNPs in folate metabolic pathway genes and CMSS.MethodsWe comprehensively evaluated 2645 (422 genotyped and 2223 imputed) common SNPs in folate metabolic pathway genes from a published GWAS of 858 patients from The University of Texas MD 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 (11·7%) patients died of cutaneous melanoma, respectively.ResultsWe 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 the biological 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.ConclusionsTwo 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. What is already known about this topic? Existing data show that survival rates vary among patients with melanoma with similar clinical characteristics; therefore, it is necessary to identify additional complementary biomarkers for melanoma-specific prognosis. A hypothesis-driven approach, by pooling the effects of single-nucleotide polymorphisms (SNPs) in a specific biological pathway as genetic risk scores, may provide a prognostic utility, and genetic variants of genes in folate metabolism have been reported to be associated with cancer risk. What does this study add? Two genetic variants in the folate metabolic pathway genes, MTHFD1 rs1950902 and ALPL rs10917006, are significantly associated with cutaneous melanoma-specific survival (CMSS). What is the translational message? The identification of genetic variants will make a risk-prediction model possible for CMSS. The SNPs in the folate metabolic pathway genes, once validated in larger studies, may be useful in the personalized management and treatment of patients with cutaneous melanoma.

Dataset Information

Genetic variants in the vitamin D pathway genes VDBP and RXRA modulate cutaneous melanoma disease-specific survival.

Publications

Genetic variants in the vitamin D pathway genes VDBP and RXRA modulate cutaneous melanoma disease-specific survival.

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