Genetic variants in ELOVL2 and HSD17B12 predict melanoma-specific survival

Abstract

Fatty acids play a key role in cellular bioenergetics, membrane biosynthesis and intracellular signaling processes and thus may be involved in cancer development and progression. In the present study, we comprehensively assessed associations of 14,522 common single-nucleotide polymorphisms (SNPs) in 149 genes of the fatty-acid synthesis pathway with cutaneous melanoma disease-specific survival (CMSS). The dataset of 858 cutaneous melanoma (CM) patients from a published genome-wide association study (GWAS) by The University of Texas M.D. Anderson Cancer Center was used as the discovery dataset, and the identified significant SNPs were validated by a dataset of 409 CM patients from another GWAS from the Nurses' Health and Health Professionals Follow-up Studies. We found 40 noteworthy SNPs to be associated with CMSS in both discovery and validation datasets after multiple comparison correction by the false positive report probability method, because more than 85% of the SNPs were imputed. By performing functional prediction, linkage disequilibrium analysis, and stepwise Cox regression selection, we identified two independent SNPs of ELOVL2 rs3734398 T>C and HSD17B12 rs11037684 A>G that predicted CMSS, with an allelic hazards ratio of 0.66 (95% confidence interval = 0.51-0.84 and p = 8.34 × 10^-4 ) and 2.29 (1.55-3.39 and p = 3.61 × 10^-5 ), respectively. Finally, the ELOVL2 rs3734398 variant CC genotype was found to be associated with a significantly increased mRNA expression level. These SNPs may be potential markers for CM prognosis, if validated by additional larger and mechanistic studies.

Keywords: cutaneous melanoma; fatty acid synthesis; genome-wide association study; melanoma-specific survival; single-nucleotide polymorphism.

Figure 1.. Study workflow for SNPs in the fatty acid synthesis pathway genes.

Abbreviations: AUC, area under curve; CMSS, cutaneous melanoma-specific survival; ELOVL2, elongation of very long-chain fatty acids 2; FPRP, false positive report probability; GWAS, genome wide association study; HSD17B12, hydroxysteroid dehydrogenase type 12; HWE, Hardy Weinberg equilibrium; MAF, minor allele frequency; MDACC, The University of Texas MD Anderson Cancer Center; NHS/HPFS, the Nurses’ Health Study and Health Professionals Follow-up Study; ROC, receiver operating characteristic; SNP, single nucleotide polymorphism.

Figure 2.. Two independent SNPs predict cutaneous melanoma survival and eQTL analysis for ELOVL2 rs3734398.

Kaplan-Meier survival curves of CMSS stratified by ELOVL2 rs3734398 (a) and HSD17B12 rs11037684 (b), assuming a dominant model in the combined dataset of both MDACC and NHS/HPFS. (c) Kaplan-Meier survival curves of the combined risk genotypes on CMSS: dichotomized 0 risk genotype group and 1–2 risk genotypes group in the combined dataset of both MDACC and NHS/HPFS; n stands for the number of specific genotype or group of number of risk genotypes, and event means the number of patients died of cutaneous melanoma. The table below the Kaplan-Meier curves illustrates the numbers at risk for each time points. (d) The eQTL analysis for ELOVL2 rs3734398 in blood cells in the 1,000 Genomes Project in an additive model. (e) The eQTL analysis from the Genotype-Tissue Expression project for ELOVL2 rs3734398 in an additive genetic model. Abbreviations: CM, cutaneous melanoma; CMSS, cutaneous melanoma-specific survival; ELOVL2, elongation of very long-chain fatty acids 2; eQTL, expression quantitative trait loci; HSD17B12, hydroxysteroid dehydrogenase type 12; MDACC, The University of Texas MD Anderson Cancer Center; NHS/HPFS, the Nurses’ Health Study and Health Professionals Follow-up Study; SNP, single-nucleotide polymorphism.