Novel Genetic Variants of ALG6 and GALNTL4 of the Glycosylation Pathway Predict Cutaneous Melanoma-Specific Survival

Abstract

Because aberrant glycosylation is known to play a role in the progression of melanoma, we hypothesize that genetic variants of glycosylation pathway genes are associated with the survival of cutaneous melanoma (CM) patients. To test this hypothesis, we used a Cox proportional hazards regression model in a single-locus analysis to evaluate associations between 34,096 genetic variants of 227 glycosylation pathway genes and CM disease-specific survival (CMSS) using genotyping data from two previously published genome-wide association studies. The discovery dataset included 858 CM patients with 95 deaths from The University of Texas MD Anderson Cancer Center, and the replication dataset included 409 CM patients with 48 deaths from Harvard University nurse/physician cohorts. In the multivariable Cox regression analysis, we found that two novel single-nucleotide polymorphisms (SNPs) (ALG6 rs10889417 G>A and GALNTL4 rs12270446 G>C) predicted CMSS, with an adjusted hazards ratios of 0.60 (95% confidence interval = 0.44-0.83 and p = 0.002) and 0.66 (0.52-0.84 and 0.004), respectively. Subsequent expression quantitative trait loci (eQTL) analysis revealed that ALG6 rs10889417 was associated with mRNA expression levels in the cultured skin fibroblasts and whole blood cells and that GALNTL4 rs12270446 was associated with mRNA expression levels in the skin tissues (all p < 0.05). Our findings suggest that, once validated by other large patient cohorts, these two novel SNPs in the glycosylation pathway genes may be useful prognostic biomarkers for CMSS, likely through modulating their gene expression.

Keywords: cutaneous melanoma; expression quantitative trait loci; glycosylation; single-nucleotide polymorphism; survival analysis.

Figure 1

A flow chart of the study design for the selected Single-nucleotide polymorphisms (SNPs) in the glycosylation pathway-related genes.

Figure 2

Association of two independent SNPs in glycosylation-related pathway genes with CMSS and their genotypes. Assuming the dominant model was used in the (a) MDACC, (b) NHS/HPFS, and (c) MDACC and NHS/HPFS combined dataset, the Kaplan–Meier survival curve of CMSS with ALG6 rs10889417 stratification. Assuming the dominant model was used in (d) MDACC, (e) NHS/HPFS, and (f) the MDACC and NHS/HPFS combined dataset, the Kaplan–Meier survival curve of CMSS with GALNTL4 rs12270446 stratification. The combined risk genotypes on CMSS (Kaplan–Meier survival curves): the dichotomized 0 NPG (Number of Protective Genotype) group and 1-2 NPG group in (g) MDACC, (h) NHS/HPFS, and (i) the MDACC and NHS/HPFS combined dataset. (j) The correlation between ALG6 rs10889417 genotypes with its mRNA expression levels in both cultured skin fibroblasts and whole blood cells from the GTEx (Genotype-Tissue Expression) database. (k) The correlations of GALNTL4 rs12270446 genotypes with its mRNA expression levels in skin tissues from the GTEx database.