Association of Interferon Regulatory Factor-4 Polymorphism rs12203592 With Divergent Melanoma Pathways

Abstract

Background: Solar elastosis and neval remnants are histologic markers characteristic of divergent melanoma pathways linked to differences in age at onset, host phenotype, and sun exposure. However, the association between these pathway markers and newly identified low-penetrance melanoma susceptibility loci remains unknown.

Methods: In the Genes, Environment and Melanoma (GEM) Study, 2103 Caucasian participants had first primary melanomas that underwent centralized pathology review. For 47 single-nucleotide polymorphisms (SNPs) previously identified as low-penetrant melanoma risk variants, we used multinomial logistic regression to compare melanoma with solar elastosis and melanoma with neval remnants simultaneously to melanoma with neither of these markers, excluding melanomas with both markers. All statistical tests were two-sided.

Results: IRF4 rs12203592 was the only SNP to pass the false discovery threshold in baseline models adjusted for age, sex, and study center. rs12203592*T was associated positively with melanoma with solar elastosis (odds ratio [OR] = 1.47, 95% confidence interval [CI] = 1.18 to 1.82) and inversely with melanoma with neval remnants (OR = 0.65, 95% CI = 0.48 to 0.87) compared with melanoma with neither marker (P global = 3.78 x 10(-08)). Adjusting for phenotypic characteristics and total sun exposure hours did not materially affect rs12203592's associations. Distinct early- and late-onset age distributions were observed in patients with IRF4 rs12203592 [CC] and [TT] genotypes, respectively.

Conclusions: Our findings suggest a role of IRF4 rs12203592 in pathway-specific risk for melanoma development. We hypothesize that IRF4 rs12203592 could underlie in part the bimodal age distribution reported for melanoma and linked to the divergent pathways.

Figure 1.

Associations of single-nucleotide polymorphisms (SNPs) with histologic solar elastosis and neval remnants adjacent to first primary melanomas in the Genes, Environment and Melanoma Study (n = 1754). A) Association of SNPs with melanomas with adjacent solar elastosis but without neval remnants (SE+/NR-). B) Association of SNPs with melanomas with adjacent neval remnants but without solar elastosis (SE-/NR+). Per-allele odds ratios (ORs), color coded by chromosome, and 95% confidence intervals (CIs) were estimated using multinomial logistic regression models comparing melanomas with SE-/NR+ and SE+/NR- simultaneously to melanomas with neither marker (SE-/NR-). Excluded were melanomas with both markers (SE+/NR+). All models were adjusted for age (tertiles), sex, and study center (Supplementary Table 2, available online). All statistical tests were two-sided. Square markers and * denote IRF4 rs12205392—the only SNP to pass false discovery for its association with SE+/NR- and SE-/NR+ melanomas compared with melanomas with neither marker (P _global = 3.78 x 10^-08) (ORs and 95% CIs provided in the figure). CI = confidence interval; OR = odds ratio.

Figure 2.

Age distributions of patients with first primary melanomas scored for both solar elastosis (SE) and neval remnants (NR) in the Genes, Environment and Melanoma Study (n = 2103) shown for (A) all cases, (B) histologic markers of divergent melanoma pathways, and (C) IRF4 rs12203592 genotype. The y-axis shows the smoothed density estimate of the proportion of patients who were diagnosed with melanoma at a given age plotted in years on the x-axis. GEM = Genes, Environment and Melanoma; SE+/NR- = melanomas with solar elastosis but without neval remnants; SE-/NR+ = melanomas with neval remnants but without solar elastosis; SE-/NR- = melanomas without solar elastosis or neval remnants; SE+/NR+ = melanoma with solar elastosis and neval remnants.