Genetic variants in the calcium signaling pathway genes are associated with cutaneous melanoma-specific survival

Abstract

Remodeling or deregulation of the calcium signaling pathway is a relevant hallmark of cancer including cutaneous melanoma (CM). In this study, using data from a published genome-wide association study (GWAS) from The University of Texas M.D. Anderson Cancer Center, we assessed the role of 41,377 common single-nucleotide polymorphisms (SNPs) of 167 calcium signaling pathway genes in CM survival. We used another GWAS from Harvard University as the validation dataset. In the single-locus analysis, 1830 SNPs were found to be significantly associated with CM-specific survival (CMSS; P ≤ 0.050 and false-positive report probability ≤ 0.2), of which 9 SNPs were validated in the Harvard study (P ≤ 0.050). Among these, three independent SNPs (i.e. PDE1A rs6750552 T>C, ITPR1 rs6785564 A>G and RYR3 rs2596191 C>A) had a predictive role in CMSS, with a meta-analysis-derived hazards ratio of 1.52 (95% confidence interval = 1.19-1.94, P = 7.21 × 10-4), 0.49 (0.33-0.73, 3.94 × 10-4) and 0.67 (0.53-0.86, 0.0017), respectively. Patients with an increasing number of protective genotypes had remarkably improved CMSS. Additional expression quantitative trait loci analysis showed that these genotypes were also significantly associated with mRNA expression levels of the genes. Taken together, these results may help us to identify prospective biomarkers in the calcium signaling pathway for CM prognosis.

Figure 1.

Study flowchart. AUC, area under the curve; FPRP, false-positive report probability; GWAS, genome-wide association study; HWE, Hardy–Weinberg equilibrium; MAF, minor allele frequency; MDACC, The University of Texas M.D. Anderson Cancer Center; ROC, receiver operating characteristic; SNP, single nucleotide polymorphism.

Figure 2.

The independent SNPs and CMSS. (a–f) Kaplan–Meier survival curves of the protective genotypes: the exact numbers of protective genotypes in the (a) MDACC study, (c) Harvard study and (e) combination of these two datasets; dichotomized groups of protective genotypes in the (b) MDACC study, (d) Harvard study and (f) combined dataset. (g and h) Receiver operating characteristic (ROC) curve and time-dependent area under the curve (AUC) estimation for prediction of melanoma-specific survival in the combined dataset. (g) Five-year melanoma-specific survival prediction by ROC curve; (h) time-dependent AUC estimation based on age, sex and the protective genotypes of the three genes.

Figure 3.

The eQTLs analysis from The Cancer Genome Atlas database. Correlation between PDE1A mRNA expression and rs2368253 genotypes in metastatic cutaneous melanoma tumor tissue in the (a) additive model, (b) dominant model, (c) recessive model. Correlation between ITPR1 mRNA expression and rs6785564 genotype in primary cutaneous melanoma tumor tissue in the (d) additive model, (e) dominant model and (f) recessive model. Correlation between RYR3 mRNA expression and rs2596191 genotype in metastatic cutaneous melanoma tumor tissue in the (g) additive model, (h) dominant model and (i) recessive model.