title: A germline variant in the interferon regulatory factor 4 gene as a novel skin cancer risk locus.
abstract: Genome-wide association studies on pigmentary phenotypes provide a pool of candidate genetic markers for skin cancer risk. The SNPs identified from a genome-wide association study of natural hair color were assessed for associations with the risk of three types of skin cancer simultaneously in a nested case-control study within the Nurses' Health Study [218 melanoma, 285 squamous cell carcinoma (SCC), and 300 basal cell carcinoma (BCC) cases, and 870 common controls]. Along with two known pigmentation loci, MC1R and OCA2, the IRF4 rs12203592 T allele was associated with an increased risk of each type of skin cancer (P value, 6.6 × 10(-4) for melanoma, 7.0 × 10(-7) for SCC, and 0.04 for BCC). This association was further replicated in additional samples (190 melanoma, 252 SCC, and 634 common controls). The P value in the replication set was 0.03 for melanoma and 4.2 × 10(-3) for SCC. The risk of BCC was replicated in an independent set of 213 cases and 718 controls (P value, 0.02). The combined results showed that the association with SCC reached the genome-wide significance level [odds ratio (OR) for additive model = 1.61, 95%CI, 1.36-1.91, P = 3.2 × 10(-8)]. The OR was 1.49 for melanoma (95%CI, 1.23-1.80; P = 4.5 × 10(-5)), and 1.32 for BCC (95%CI, 1.11-1.57; P = 1.6 × 10(-3)). Given that the T allele was shown previously to be associated with increased expression of IRF4 locus, further studies are warranted to elucidate the role of the IRF4 gene in human pigmentation and skin cancer development.
authors.affiliation: Clinical Research Program, Department of Dermatology, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts, USA. jiali.han@channing.harvard.edu
authors.forename: Jiali
authors.initials: J
authors.lastname: Han
authors.forename: Abrar A
authors.initials: AA
authors.lastname: Qureshi
authors.forename: Hongmei
authors.initials: H
authors.lastname: Nan
authors.forename: Jiangwen
authors.initials: J
authors.lastname: Zhang
authors.forename: Yiqing
authors.initials: Y
authors.lastname: Song
authors.forename: Qun
authors.initials: Q
authors.lastname: Guo
authors.forename: David J
authors.initials: DJ
authors.lastname: Hunter
mesh_terms: D002280:Basal Cell Carcinoma / Q000235:genetics*; D002294:Carcinoma, Squamous Cell / Q000235:genetics*; D016022:Case-Control Studies; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics*; D008545:Melanoma / Q000235:genetics*; D026901:Membrane Transport Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D044102:Receptor, Melanocortin, Type 1 / Q000235:genetics; D012307:Risk Factors; D012878:Skin Neoplasms / Q000235:genetics*; D012880:Skin Pigmentation / Q000235:genetics; D000099218:Interferon Regulatory Factor-4
chemical_list: D050835:Interferon Regulatory Factors; D026901:Membrane Transport Proteins; D044102:Receptor, Melanocortin, Type 1; D000099218:Interferon Regulatory Factor-4; C489600:OCA2 protein, human