A Germline Variant in the Interferon Regulatory Factor 4 Gene as a Novel Skin Cancer Risk Locus

Clinical Research Program, Department of Dermatology, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts, USA.
Cancer Research (Impact Factor: 9.28). 02/2011; 71(5):1533-9. DOI: 10.1158/0008-5472.CAN-10-1818
Source: PubMed

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.

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    ABSTRACT: Actinic keratosis (AK) is a pre-malignant skin disease, highly prevalent in elderly Europeans. This study investigates genetic susceptibility to AK with a genome-wide association study (GWAS). A full body skin examination was performed in 3194 elderly individuals from the Rotterdam Study (RS) of exclusive north-western European origin (aged 51-99 years, 45% male). Physicians graded the number of AK into 4 severity levels: none (76%), 1-3 (14%), 4-9 (6%), and ≥10 (5%), and skin color was quantified using a spectrophotometer on sun-unexposed skin. A GWAS for AK severity was conducted, where promising signals at IRF4 and MC1R (P<4.2×10(-7)) were successfully replicated in an additional cohort of 623 RS individuals (IRF4, rs12203592, Pcombined=6.5×10(-13) and MC1R, rs139810560, Pcombined=4.1×10(-9)). Further, in an analysis of 10 additional well-known human pigmentation genes, TYR also showed significant association with AK (rs1393350, P=5.3×10(-4)) after correction for multiple testing. Interestingly, the strength and significance of above mentioned associations retained largely the same level after skin color adjustment. Overall, our data strongly suggest that IRF4, MC1R, and TYR genes likely have pleiotropic effects, a combination of pigmentation and oncogenic functions, resulting in an increased risk of AK. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email:
    Human Molecular Genetics 02/2015; 24(11). DOI:10.1093/hmg/ddv076 · 6.68 Impact Factor
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    ABSTRACT: Background Melanocytic naevi are an important risk factor for melanoma. Naevi with distinct dermoscopic patterns can differ in size, distribution, and host pigmentation characteristics.Objectives We examined MC1R and 85 other candidate loci in a cohort of children to test the hypothesis that the development and dermoscopic type of naevi is modulated by genetic variantsMethods Buccal DNAs were obtained from a cohort of 353 fifth graders. Polymorphisms were chosen based on known or anticipated role in naevi and melanoma. Associations between Single Nucleotide Polymorphisms (SNPs) and baseline naevus count were determined by multivariate regression adjusting for sex, race/ethnicity, and sun sensitivity. Dermoscopic images were available for 853 naevi from 290 children. Associations between SNPs and dermoscopic patterns were determined by polytomous regression.ResultsFour SNPs were significantly associated with increasing (IRF4) or decreasing (PARP1, CDK6, and PLA2G6) naevus count in multivariate shrinkage analyses with all SNPs included in the model: IRF4 rs12203952, showed the strongest association with log naevus count (RR=1.56, p<0.0001). Using homogeneous naevi as reference IRF4 rs12203952 and four other SNPs in TERT, CDKN1B, MTAP and PARP1 were associated with either globular or reticular dermoscopic patterns (p<0.05).Conclusions Our results provide evidence that subsets of naevi defined by dermoscopic patterns differ in their associations with germline genotypes and support the hypothesis that dermoscopically-defined subsets of naevi are biologically distinct. These results require confirmation in larger cohorts. If confirmed, these findings will improve the current knowledge of naevogenesis and assist in the identification of individuals with high risk phenotypes.This article is protected by copyright. All rights reserved.
    British Journal of Dermatology 10/2014; 172(4). DOI:10.1111/bjd.13467 · 4.10 Impact Factor
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    ABSTRACT: In an ongoing screen for DNA sequence variants that confer risk of cutaneous basal cell carcinoma (BCC), we conduct a genome-wide association study (GWAS) of 24,988,228 SNPs and small indels detected through whole-genome sequencing of 2,636 Icelanders and imputed into 4,572 BCC patients and 266,358 controls. Here we show the discovery of four new BCC susceptibility loci: 2p24 MYCN (rs57244888[C], OR=0.76, P=4.7 × 10(-12)), 2q33 CASP8-ALS2CR12 (rs13014235[C], OR=1.15, P=1.5 × 10(-9)), 8q21 ZFHX4 (rs28727938[G], OR=0.70, P=3.5 × 10(-12)) and 10p14 GATA3 (rs73635312[A], OR=0.74, P=2.4 × 10(-16)). Fine mapping reveals that two variants correlated with rs73635312[A] occur in conserved binding sites for the GATA3 transcription factor. In addition, expression microarrays and RNA-seq show that rs13014235[C] and a related SNP rs700635[C] are associated with expression of CASP8 splice variants in which sequences from intron 8 are retained.
    Nature Communications 01/2015; 6:6825. DOI:10.1038/ncomms7825 · 10.74 Impact Factor


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