Nan H, Xu M, Kraft P et al.Genome-wide association study identifies novel alleles associated with risk of cutaneous basal cell carcinoma and squamous cell carcinoma. Hum Mol Genet 20:3718-3724

Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA.
Human Molecular Genetics (Impact Factor: 6.39). 06/2011; 20(18):3718-24. DOI: 10.1093/hmg/ddr287
Source: PubMed


We conducted a genome-wide association study on cutaneous basal cell carcinoma (BCC) among 2045 cases and 6013 controls of European ancestry, with follow-up replication in 1426 cases and 4845 controls. A non-synonymous SNP in the MC1R gene (rs1805007 encoding Arg151Cys substitution), a previously well-documented pigmentation gene, showed the strongest association with BCC risk in the discovery set (rs1805007[T]: OR (95% CI) for combined discovery set and replication set [1.55 (1.45-1.66); P= 4.3 × 10(-17)]. We identified that an SNP rs12210050 at 6p25 near the EXOC2 gene was associated with an increased risk of BCC [rs12210050[T]: combined OR (95% CI), 1.24 (1.17-1.31); P= 9.9 × 10(-10)]. In the locus on 13q32 near the UBAC2 gene encoding ubiquitin-associated domain-containing protein 2, we also identified a variant conferring susceptibility to BCC [rs7335046 [G]; combined OR (95% CI), 1.26 (1.18-1.34); P= 2.9 × 10(-8)]. We further evaluated the associations of these two novel SNPs (rs12210050 and rs7335046) with squamous cell carcinoma (SCC) risk as well as melanoma risk. We found that both variants, rs12210050[T] [OR (95% CI), 1.35 (1.16-1.57); P= 7.6 × 10(-5)] and rs7335046 [G] [OR (95% CI), 1.21 (1.02-1.44); P= 0.03], were associated with an increased risk of SCC. These two variants were not associated with melanoma risk. We conclude that 6p25 and 13q32 are novel loci conferring susceptibility to non-melanoma skin cancer.

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Available from: Peter Kraft
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    • "Furthermore, our data demonstrate that the associations of IRF4, MC1R, ASIP, and BNC2 with facial pigmented spots were at least partially independent of skin color. The four identified genes are known to be associated with visible skin traits in Europeans, including pigmentation variation (eye, hair, and skin color; Sulem et al., 2007; Han et al., 2008; Jacobs et al., 2013), freckling (Sulem et al., 2007; Eriksson et al., 2010), tanning response (Nan et al., 2009), and different types of skin cancer (basal cell carcinoma, squamous cell carcinoma, and melanoma; Bishop et al., 2009; Stacey et al., 2009; Nan et al., 2011; Zhang et al., 2013). However, not all skin color-associated genes have an additional effect on the development of pigmented spots, such as HERC2. "
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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:
    Full-text · Article · Feb 2015 · Human Molecular Genetics
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    • "For instance, following the identification of genetic variances at the TERT_CLPTM1L locus associated with BCC, the same region was associated with the risk of several other cancer types including melanoma (Rafnar et al., 2009). Our group also reported that the SNPs near the EXOC2 and the UBAC2 identified in GWAS on BCC risk were associated with the risk of SCC (Nan et al., 2011b). "
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    ABSTRACT: Genome-wide association studies (GWAS) have become a widely used approach for genetic association studies of various human traits. A few GWAS have been conducted with the goal of identifying novel loci for pigmentation traits, melanoma, and non-melanoma skin cancer. Nevertheless, the phenotype variation explained by the genetic markers identified so far is limited. In this review, we discuss the GWAS study design and its application in pigmentation and skin cancer research. Furthermore, we summarize recent developments in post-GWAS activities such as meta-analysis, pathway analysis, and risk prediction.
    Full-text · Article · Jul 2012 · Pigment Cell & Melanoma Research
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    ABSTRACT: Recently, a pathway-based approach has been developed to evaluate the cumulative contribution of the functionally related genes for genome-wide association studies (GWASs), which may help utilize GWAS data to a greater extent. In this study, we applied this approach for the GWAS of basal cell carcinoma (BCC) of the skin. We first conducted the BCC GWAS among 1,797 BCC cases and 5,197 controls in Caucasians with 740,760 genotyped SNPs. 115,688 SNPs were grouped into gene transcripts within 20 kb in distance and then into 174 Kyoto Encyclopedia of Genes and Genomes pathways, 205 BioCarta pathways, as well as two positive control gene sets (pigmentation gene set and BCC risk gene set). The association of each pathway with BCC risk was evaluated using the weighted Kolmogorov-Smirnov test. One thousand permutations were conducted to assess the significance. Both of the positive control gene sets reached pathway p-values<0.05. Four other pathways were also significantly associated with BCC risk: the heparan sulfate biosynthesis pathway (p  =  0.007, false discovery rate, FDR  =  0.35), the mCalpain pathway (p  =  0.002, FDR  =  0.12), the Rho cell motility signaling pathway (p  =  0.011, FDR  =  0.30), and the nitric oxide pathway (p  =  0.022, FDR  =  0.42). We identified four pathways associated with BCC risk, which may offer new insights into the etiology of BCC upon further validation, and this approach may help identify potential biological pathways that might be missed by the standard GWAS approach.
    Full-text · Article · Jul 2011 · PLoS ONE
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