Association of genetic variants of TMEM135 and PEX5 in the peroxisome pathway with cutaneous melanoma-specific survival

Abstract

Background: Peroxisomes are ubiquitous and dynamic organelles that are involved in the metabolism of reactive oxygen species (ROS) and lipids. However, whether genetic variants in the peroxisome pathway genes are associated with survival in patients with melanoma has not been established. Therefore, our aim was to identify additional genetic variants in the peroxisome pathway that may provide new prognostic biomarkers for cutaneous melanoma (CM).

Methods: We assessed the associations between 8,397 common single-nucleotide polymorphisms (SNPs) in 88 peroxisome pathway genes and CM disease-specific survival (CMSS) in a two-stage analysis. For the discovery, we extracted the data from a published genome-wide association study from The University of Texas MD Anderson Cancer Center (MDACC). We then replicated the results in another dataset from the Nurse Health Study (NHS)/Health Professionals Follow-up Study (HPFS).

Results: Overall, 95 (11.1%) patients in the MDACC dataset and 48 (11.7%) patients in the NHS/HPFS dataset died of CM. We found 27 significant SNPs in the peroxisome pathway genes to be associated with CMSS in both datasets after multiple comparison correction using the Bayesian false-discovery probability method. In stepwise Cox proportional hazards regression analysis, with adjustment for other covariates and previously published SNPs in the MDACC dataset, we identified 2 independent SNPs (TMEM135 rs567403 C>G and PEX5 rs7969508 A>G) that predicted CMSS (P=0.003 and 0.031, respectively, in an additive genetic model). The expression quantitative trait loci analysis further revealed that the TMEM135 rs567403 GG and PEX5 rs7969508 GG genotypes were associated with increased and decreased levels of mRNA expression of their genes, respectively.

Conclusions: Once our findings are replicated by other investigators, these genetic variants may serve as novel biomarkers for the prediction of survival in patients with CM.

Keywords: Cutaneous melanoma (CM); expression quantitative trait loci; melanoma-specific survival; peroxisome; single-nucleotide polymorphism (SNP).

Figure 1

Study workflow for SNPs in the peroxisome pathway. AUC, area under the receiver operating characteristic curve; BFDP, Bayesian false-discovery probability; CMSS, cutaneous melanoma-specific survival; GWAS, genome wide association study; HWE, Hardy-Weinberg equilibrium; HPFS, Health Professionals Follow-up Study; MAF, minor allele frequency; MDACC, The University of Texas MD Anderson Cancer Center; NHS, the Nurse Health Study; PEX5, peroxisomal biogenesis factor 5; ROC, receiver operating characteristic; SNP, single nucleotide polymorphism; TMEM135, transmembrane protein 135.

Figure 2

Kaplan-Meier survival curves of cutaneous melanoma-specific survival (CMSS): TMEM35 rs567403 in dominant model in MDACC dataset (A), NHS/HPFS dataset (B), and the MDACC and NHS/HPFS combined dataset, (C) and PEX5 rs7969508 in dominant model in the MDACC dataset (D), NHS/HPFS dataset (E), and the MDACC and NHS/HPFS combined dataset (F). Kaplan-Meier survival curves of the combined risk genotypes in CMSS: 0-1 risk genotypes group and 2 risk genotype group in MDACC (G), NHS/HPFS (H), and MDACC and NHS/HPFS combined datasets (I). 1Univariate analysis; 2Multivariate analysis. SNP, single nucleotide polymorphism; CM, cutaneous melanoma; PEX5, peroxisomal biogenesis factor 5; TMEM135, transmembrane protein 135; MDACC, The University of Texas MD Anderson Cancer Center; NHS, the Nurse Health Study; HPFS, the Health Professionals Follow-up Study.

Figure 3

The expression quantitative trait loci (eQTL) analysis for genotypes of PEX5 rs7969508 and TMEM135 rs567403. (A) Correlation between TMEM135 mRNA expression levels and rs567403 in 373 Europeans from the 1000 Genomes Project in an additive model. Correlation between PEX5 mRNA expression and rs7969508 genotypes in 373 Europeans from the 1000 Genomes Project in additive (B), dominant (C), and recessive (D) models. Correlation between PEX5 mRNA expression and rs7969508 in unexposed skin (E), sun-exposed skin (lower leg) (F), and whole blood cells (G) in GTEx. GTEx, Genotype-Tissue Expression Project; PEX5, peroxisomal biogenesis factor 5; TMEM135, transmembrane protein 135.