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Association of Interferon Regulatory Factor-4 Polymorphism rs12203592 With Divergent Melanoma Pathways
David C Gibbs1, Irene Orlow1, Jennifer I Bramson1
1Department of Dermatology, University of North Carolina, Chapel Hill, NC (DCG, NET); Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC (NET, DWO); Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, NY (IO, AS, ELP, KJB, CBB); Department of Surgery, University of North Carolina, Chapel Hill, NC (JIB, DWO); Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL (PAK); Department of Internal Medicine, University of New Mexico Cancer Center, University of New Mexico, Albuquerque, NM (LL, MB); Sydney School of Public Health, University of Sydney, Sydney, New South Wales, Australia (AEC, AK, BKA); Department of Epidemiology, University of California, Irvine, CA (HAC); USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA (SBG); Department of Population Studies and Surveillance, Cancer Care Ontario, Toronto, Ontario, Canada (LDM); Cancer Control Research, British Columbia Cancer Agency, Vancouver, British Columbia, Canada (RPG); Piedmont Cancer Registry, Centre for Epidemiology and Prevention in Oncology in Piedmont, Turin, Italy (RZ, SR); The George Institute for Global Health, Oxford Martin School of Public Health, University of Oxford, Oxford, UK (TD); Department of Pathology, Women's College Hospital, Toronto, Ontario, Canada (LF).
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.
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