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.

Unique CLR expression patterns on circulating and tumor-infiltrating DC subsets correlated with clinical outcome in melanoma patients

“…We demonstrated that perturbations of CLR expression profiles could be triggered directly by melanoma cells but also indirectly through melanoma-derived supernatants, suggesting that melanoma tumor cells displayed and released glycans that may interact with DCs through CLR molecules. Indeed, it has been shown that melanoma tumor cells exhibited a high ganglioside diversity ( 74 ), displayed alterations in the glycosylation pattern of glycoproteins and glycolipids ( 57 , 58 ), and perturbations of enzymes involved in glycosylation/deglycosylation processes ( 56 ). The impact of tumor-associated glycans on DCs in the context of melanoma remained unexplored.…”

“…Disruption of the Dectin 1galectin 9 axis reprogrammed efficient T-cell mediated antitumor immunity. Melanoma tumor cells exhibit many CLR ligands and display aberrant glycosylation patterns (56)(57)(58), yet the impact of such tumor glyco-code on the CLR machinery of DCs remains unexplored.…”

Integrated Multi-Omics Data Analysis Reveals Associations Between Glycosylation and Stemness in Hepatocellular Carcinoma

“…LCSCs with a specific phenotype are believed to promote HCC relapse, metastasis, and chemoresistance. Recent studies have shown that aberrant glycosylation of signaling pathways and LCSC markers directly impacts key processes that maintain cell survival, self-renewal, and extravasation properties (31)(32)(33). This study focused on the importance of glycosylation in promoting the stemness of HCC by assessing alterations in somatic mutations, immune cell infiltration, and clinical characteristics.…”

Robust Glycogene-Based Prognostic Signature for Proficient Mismatch Repair Colorectal Adenocarcinoma

“…Previous studies have shown that ALG8 could be a variate of prognostic model for gastric adenocarcinoma (51) and frequently amplified hotspot on 11q14.1 (ALG8) associated with significantly worse prognosis for breast cancer (52). The ALG6 single-nucleotide polymorphism (SNP) is a potential prognostic biomarker for cutaneous melanoma and is likely through modulating gene expression (53). Hsu et al (54) demonstrate that EMT enriched programmed death-ligand 1 (PD-L1) in cancer stem-like cells by the EMT/b-catenin/STT3/PD-L1 signaling axis, in which EMT transcriptionally induced N-glycosyltransferase STT3 (including isoforms STT3A and STT3B) through b-catenin, and subsequent STT3-dependent PD-L1 N-glycosylation stabilized and upregulated PD-L1.…”