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Inverse Relationship between Vitiligo-Related Genes and Skin Cancer Risk

  • Wenting Wu
    Affiliations
    Department of Epidemiology, Fairbanks School of Public Health, Indiana University, Indianapolis, Indiana, USA

    Melvin and Bren Simon Cancer Center, Indiana University, Indianapolis, Indiana, USA
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  • the
    Affiliations
    23andMe Inc., Mountain View, California, USA
  • Christopher I. Amos
    Affiliations
    Community and Family Medicine, Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire, USA
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  • Jeffrey E. Lee
    Affiliations
    Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA
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  • Qingyi Wei
    Affiliations
    Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina, USA

    Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA
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  • Author Footnotes
    9 These authors jointly supervised this work.
    Kavita Y. Sarin
    Footnotes
    9 These authors jointly supervised this work.
    Affiliations
    Department of Dermatology, Stanford University School of Medicine, Stanford, California, USA
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  • Author Footnotes
    9 These authors jointly supervised this work.
    Jiali Han
    Correspondence
    Corresponding author
    Footnotes
    9 These authors jointly supervised this work.
    Affiliations
    Department of Epidemiology, Fairbanks School of Public Health, Indiana University, Indianapolis, Indiana, USA

    Melvin and Bren Simon Cancer Center, Indiana University, Indianapolis, Indiana, USA
    Search for articles by this author
  • Author Footnotes
    9 These authors jointly supervised this work.
Open AccessPublished:March 26, 2018DOI:https://doi.org/10.1016/j.jid.2018.03.1511

      Abbreviations:

      BCC (basal cell carcinoma), NMSC (nonmelanoma skin cancer), SCC (squamous cell carcinoma)
      To the Editor
      Vitiligo, the most common cutaneous depigmentation disorder, affects up to 2% of the population and is characterized by immune-mediated destruction of melanocytes, causing depigmentation of the skin, hair, and oral mucosa (
      • Kruger C.
      • Schallreuter K.U.
      A review of the worldwide prevalence of vitiligo in children/adolescents and adults.
      ). Affected skin lacks melanin, which plays a critical role in protecting against UV-mediated mutagenesis (
      • Jin Y.
      • Birlea S.A.
      • Fain P.R.
      • Ferrara T.M.
      • Ben S.
      • Riccardi S.L.
      • et al.
      Genome-wide association analyses identify 13 new susceptibility loci for generalized vitiligo.
      ). Because UV exposure is a well-established risk factor for skin cancers, vitiligo was initially presumed to confer increased risk for both melanoma and nonmelanoma skin cancer (NMSC) (
      • Rodrigues M.
      Skin cancer risk (nonmelanoma skin cancers/melanoma) in vitiligo patients.
      ). Surprisingly, a number of studies have instead found that vitiligo is associated with a lower risk of melanoma and NMSC, via unknown mechanisms (
      • Paradisi A.
      • Tabolli S.
      • Didona B.
      • Sobrino L.
      • Russo N.
      • Abeni D.
      Markedly reduced incidence of melanoma and nonmelanoma skin cancer in a nonconcurrent cohort of 10,040 patients with vitiligo.
      ,
      • Rodrigues M.
      Skin cancer risk (nonmelanoma skin cancers/melanoma) in vitiligo patients.
      ). To date, genome-wide association studies have identified 58 genetic loci associated with vitiligo (
      • Birlea S.A.
      • Gowan K.
      • Fain P.R.
      • Spritz R.A.
      Genome-wide association study of generalized vitiligo in an isolated European founder population identifies SMOC2, in close proximity to IDDM8.
      ,
      • Jin Y.
      • Birlea S.A.
      • Fain P.R.
      • Gowan K.
      • Riccardi S.L.
      • Holland P.J.
      • et al.
      Variant of TYR and autoimmunity susceptibility loci in generalized vitiligo.
      ,
      • Jin Y.
      • Birlea S.A.
      • Fain P.R.
      • Ferrara T.M.
      • Ben S.
      • Riccardi S.L.
      • et al.
      Genome-wide association analyses identify 13 new susceptibility loci for generalized vitiligo.
      ,
      • Jin Y.
      • Andersen G.
      • Yorgov D.
      • Ferrara T.M.
      • Ben S.
      • Brownson K.M.
      • et al.
      Genome-wide association studies of autoimmune vitiligo identify 23 new risk loci and highlight key pathways and regulatory variants.
      ,
      • Quan C.
      • Ren Y.Q.
      • Xiang L.H.
      • Sun L.D.
      • Xu A.E.
      • Gao X.H.
      • et al.
      Genome-wide association study for vitiligo identifies susceptibility loci at 6q27 and the MHC.
      ). We investigated the role of these vitiligo-associated genetic loci in risk of melanoma, basal cell carcinoma (BCC), and squamous cell carcinoma (SCC), using genome-wide association study data on 6,628 melanoma cases, 12,945 BCC cases, 6,579 SCC cases, and more than 274,000 controls of European ancestry.
      We performed the analysis in three studies. Melanoma analysis (study 1) was based on a two-stage meta-analysis. 23andMe (Mountain View, CA) provided free access to aggregated genetic and phenotypic information for study 1 (Supplementary Figure S1a online). Study 2 participants were from a hospital-based case-control study of melanoma recruited at the MD Anderson Cancer Center (
      • Ransohoff K.J.
      • Wu W.
      • Cho H.G.
      • Chahal H.C.
      • Lin Y.
      • Dai H.J.
      • et al.
      Two-stage genome-wide association study identifies a novel susceptibility locus associated with melanoma.
      ; Supplementary Figure S2 online). The nonmelanoma skin cancer study (study 3), including both BCC and SCC, was limited to 23andMe research participants (
      • Chahal H.S.
      • Lin Y.
      • Ransohoff K.J.
      • Hinds D.A.
      • Wu W.
      • Dai H.J.
      • et al.
      Genome-wide association study identifies novel susceptibility loci for cutaneous squamous cell carcinoma.
      ,
      • Chahal H.S.
      • Wu W.
      • Ransohoff K.J.
      • Yang L.
      • Hedlin H.
      • Desai M.
      • et al.
      Genome-wide association study identifies 14 novel risk alleles associated with basal cell carcinoma.
      ; Supplementary Figure S1b, S1c online). 23andMe research participants provided written informed consent, in accordance with the company’s human subjects protocol (reviewed and approved by Ethical and Independent Review Services, an Association for the Accreditation of Human Research Protection Programs (AAHRPP)–accredited Institutional Review Board). Study protocols for study 2 were approved by the Institutional Review Board at MD Anderson, and written informed consent was obtained from all participants. Further information on methodology is presented in Supplementary Material online.
      A combined analysis of melanoma study 1 and study 2, totaling 6,628 melanoma cases and 287,591 controls (Supplementary Table S1 online), identified four vitiligo-susceptibility loci reaching a Bonferroni-adjusted P-value threshold (P < 8.6 × 10–4 for 58 single-nucleotide polymorphisms), with three loci also reaching genome-wide significance (P < 5 × 10-8): RALY-EIF252-ASIP-AHCY-ITCH, IRF4, TYR, and MC1R (Table 1, Supplementary Table S2 online).
      Table 1Loci reaching statistical significance after Bonferroni correction for melanoma risk
      SNPRegionGeneMin/MajMAF
      MAF = minor allele frequency in study 1 controls.
      23andMe (study 1)MD Anderson (study 2)Meta-Analysis
      Meta-analysis = Combined 23andMe + MD Anderson.
      Previous reported (
      • Jin Y.
      • Andersen G.
      • Yorgov D.
      • Ferrara T.M.
      • Ben S.
      • Brownson K.M.
      • et al.
      Genome-wide association studies of autoimmune vitiligo identify 23 new risk loci and highlight key pathways and regulatory variants.
      )
      OR with P-value for risk of vitiligo in a previous report by Jin et al. (2016), associated with the minor allele.
      OR95% CI
      CI = 95% confidence interval.
      POR95% CI
      CI = 95% confidence interval.
      POR95% CI
      CI = 95% confidence interval.
      PORP
      rs605965520q11.22RALY-EIF252-ASIP-AHCY-ITCHA/G0.071.37(1.28–1.46)1.69 × 10–181.44(1.2–1.74)1.02 × 10–41.38(1.29–1.47)5.04 × 10–230.611.04 × 10–19
      rs122035926p25.3IRF4T/C0.171.21(1.15–1.27)1.47 × 10–121.16(1.01–1.33)3.71 × 10–21.20(1.14–1.26)8.29 × 10–140.792.95 × 10–10
      rs112680911q14.3TYRA/G0.281.16(1.11–1.21)4.62 × 10–111.23(1.09–1.39)6.32 × 10–41.17(1.12–1.22)1.26 × 10–130.671.16 × 10–43
      rs4268748
      Meta-analysis odds ratios calculated with the random-effects method.
      16q24.3MC1RC/T0.271.26(1.2–1.31)1.25 × 10–231.40(1.25-1–.58)1.29 × 10–81.31(1.18–1.46)6.23 × 10–70.712.88 × 10–33
      SNPs that met Bonferroni-adjusted significance (P < 8.6×10−4) in the overall meta-analysis are listed. In addition, we report genetic locus, nearest genes, major allele, minor allele, MAF in study 1 controls, average imputation r2 (a measure of imputation quality) for study 1, and OR with P-value for each stage, calculated with respect to the minor allele. Study 1 included 4,842 melanoma cases and 286,565 controls from 23andMe. Study 2 included 1,804 melanoma cases and 1,026 controls from the MD Anderson Cancer Center. The combined fixed-effect meta-analysis totaling 6,628 melanoma cases and 287,591 controls. Statistics for effect heterogeneity (Phet and I2) are included in Supplementary Table S2. All subjects lived in the USA and were of European ancestry.
      Abbreviations: CI, confidence interval; OR, odds ratio; SNP, single-nucleotide polymorphism.
      1 MAF = minor allele frequency in study 1 controls.
      2 Meta-analysis = Combined 23andMe + MD Anderson.
      3 CI = 95% confidence interval.
      4 OR with P-value for risk of vitiligo in a previous report by
      • Jin Y.
      • Andersen G.
      • Yorgov D.
      • Ferrara T.M.
      • Ben S.
      • Brownson K.M.
      • et al.
      Genome-wide association studies of autoimmune vitiligo identify 23 new risk loci and highlight key pathways and regulatory variants.
      , associated with the minor allele.
      5 Meta-analysis odds ratios calculated with the random-effects method.
      All 58 loci were investigated for BCC (12,945 cases and 274,252 controls) (
      • Chahal H.S.
      • Wu W.
      • Ransohoff K.J.
      • Yang L.
      • Hedlin H.
      • Desai M.
      • et al.
      Genome-wide association study identifies 14 novel risk alleles associated with basal cell carcinoma.
      ) and SCC (6,579 cases and 280,558 controls) (
      • Chahal H.S.
      • Lin Y.
      • Ransohoff K.J.
      • Hinds D.A.
      • Wu W.
      • Dai H.J.
      • et al.
      Genome-wide association study identifies novel susceptibility loci for cutaneous squamous cell carcinoma.
      ) (Supplementary Table S1). Sixteen loci for BCC and seven loci for SCC reached the Bonferroni-adjusted P-value threshold (Supplementary Table S3 online). Interestingly, all four melanoma-associated loci were also significantly associated with the risk of BCC and SCC. Three additional SCC-associated loci were also found to be significantly related to the risk of BCC.
      Within those loci with P-value ≤ 0.05, 100% (11 of 11), 80.0% (25 of 27), and 100% (19 of 19) indicated an inverse correlation between risk of vitiligo and risk of melanoma, BCC, and SCC, respectively (Figure 1, Supplementary Tables S2 and S3). Furthermore, among the loci that reached a Bonferroni-adjusted P-value threshold, we observed very consistent inverse relationships between vitiligo and risk of melanoma, BCC, and SCC (100%, 93.75%, 100% consistency). To identify possible causal genes, we interrogated publicly available Genotype-Tissue Expression Project (GTEx) expression quantitative trait loci (eQTL) v7 data sets for three tissues (Supplementary Table S4 online). Of the 58 loci, 20 were identified as eQTLs for whole blood. It was intriguing to find inverse associations for rs12203592 and IRF4 gene expression levels within whole blood and sun-exposed skin tissue. Further information on methods and imputation quality can be found in Supplementary Material and Supplementary Table S5 online.
      Figure 1
      Figure 1Effect sizes estimated in skin cancer versus vitiligo, for the 58 SNPs from a previously reported vitiligo GWAS (
      • Jin Y.
      • Andersen G.
      • Yorgov D.
      • Ferrara T.M.
      • Ben S.
      • Brownson K.M.
      • et al.
      Genome-wide association studies of autoimmune vitiligo identify 23 new risk loci and highlight key pathways and regulatory variants.
      ). Both x- and y-axes display odds ratio values associated with the minor allele. SNPs with P < 8.6 × 10-4 (significant after Bonferroni correction) are labeled with the gene name corresponding to that locus. Effect size estimated in vitiligo was reported by a previous GWAS study (
      • Jin Y.
      • Andersen G.
      • Yorgov D.
      • Ferrara T.M.
      • Ben S.
      • Brownson K.M.
      • et al.
      Genome-wide association studies of autoimmune vitiligo identify 23 new risk loci and highlight key pathways and regulatory variants.
      ). (a) Effect sizes estimated in melanoma versus vitiligo. SNPs with P < 0.5 in the meta-analysis are shown in red; the other SNPs are shown in blue. For effect sizes estimated in the melanoma meta-analysis, SNPs with heterogeneity statistics I2 ≥ 60% were calculated with a random-effects method. (b) Effect sizes estimated in basal cell carcinoma versus vitiligo. SNPs with P < 0.05 are shown in red; other SNPs are shown in blue. (c) Effect sizes estimated in squamous cell carcinoma versus vitiligo. SNPs with P < 0.05 are shown in red; other SNPs are shown in blue. GWAS, genome-wide association study; SNP, single-nucleotide polymorphism.
      Vitiligo is an autoimmune disease characterized by loss of skin pigmentation and affects approximately 0.5% to 2% of the population worldwide (
      • Rodrigues M.
      Skin cancer risk (nonmelanoma skin cancers/melanoma) in vitiligo patients.
      ). It has been associated with other autoimmune diseases such as rheumatoid arthritis and adult-onset type I diabetes (
      • Alkhateeb A.
      • Fain P.R.
      • Thody A.
      • Bennett D.C.
      • Spritz R.A.
      Epidemiology of vitiligo and associated autoimmune diseases in Caucasian probands and their families.
      ). Interestingly, although individuals with vitiligo were initially presumed to be more susceptible to UV mutagenesis and skin cancer because of their lack of melanoma, previous studies have instead highlighted an inverse relationship between vitiligo and both melanoma and NMSC (
      • Jin Y.
      • Andersen G.
      • Yorgov D.
      • Ferrara T.M.
      • Ben S.
      • Brownson K.M.
      • et al.
      Genome-wide association studies of autoimmune vitiligo identify 23 new risk loci and highlight key pathways and regulatory variants.
      ). A large retrospective study of 10,040 patients with vitiligo reported a lower risk of melanoma and NMSC in such patients. However, this association remains controversial, as another study reported a higher risk of skin cancer among patients with vitiligo who underwent phototherapy (
      • Paradisi A.
      • Tabolli S.
      • Didona B.
      • Sobrino L.
      • Russo N.
      • Abeni D.
      Markedly reduced incidence of melanoma and nonmelanoma skin cancer in a nonconcurrent cohort of 10,040 patients with vitiligo.
      ). In addition, most studies did not describe how vitiligo might influence the risk of melanoma and NMSC.
      We observed a consistent inverse relationship between risk of vitiligo and skin cancers in the RALY-EIF252-ASIP-AHCY-ITCH, IRF4, TYR, and MC1R genes. A haplotype near ASIP has been associated with skin sensitivity to sun, red, and blonde hair, and was shown to confer a significant risk of melanoma and BCC (
      • Gudbjartsson D.F.
      • Sulem P.
      • Stacey S.N.
      • Goldstein A.M.
      • Rafnar T.
      • Sigurgeirsson B.
      • et al.
      ASIP and TYR pigmentation variants associate with cutaneous melanoma and basal cell carcinoma.
      ). IRF4 protein activates melanin synthesis by tyrosinase, an enzyme found in melanocytes. The genetic variant rs12203592 T allele impairs transcription factor binding and results in decreased protein expression of IRF4 and tyrosinase (
      • Asgari M.M.
      • Toland A.E.
      • Arron S.T.
      IRF4 polymorphism is associated with cutaneous squamous cell carcinoma in organ transplant recipients: a pigment-independent phenomenon.
      ). The TYR gene encodes tyrosinase, catalyzing melanin biosynthesis rate-limiting steps (
      • Jin Y.
      • Birlea S.A.
      • Fain P.R.
      • Gowan K.
      • Riccardi S.L.
      • Holland P.J.
      • et al.
      Variant of TYR and autoimmunity susceptibility loci in generalized vitiligo.
      ). The melanocortin 1 receptor is a G protein-coupled receptor protein important for melanocyte proliferation and function regulation (
      • Garcia-Borron J.C.
      • Abdel-Malek Z.
      • Jimenez-Cervantes C.
      MC1R, the cAMP pathway, and the response to solar UV: extending the horizon beyond pigmentation.
      ). In all these well-established pigmentation genes, inherited variants have been identified as the most promising loci for melanoma and NMSC (
      • Chahal H.S.
      • Lin Y.
      • Ransohoff K.J.
      • Hinds D.A.
      • Wu W.
      • Dai H.J.
      • et al.
      Genome-wide association study identifies novel susceptibility loci for cutaneous squamous cell carcinoma.
      ,
      • Ransohoff K.J.
      • Wu W.
      • Cho H.G.
      • Chahal H.C.
      • Lin Y.
      • Dai H.J.
      • et al.
      Two-stage genome-wide association study identifies a novel susceptibility locus associated with melanoma.
      ). Moreover, it is interesting to find that immune-related single-nucleotide polymorphisms located in the HLA-DRB1/DQA1, CTLA4, and PTPN22 genes, which encode important immunoregulative proteins, showed consistent inverse relationships between vitiligo and skin cancers, especially BCC. Overall, the inverse relationship might indicate that different or opposed biological pathways mediate vitiligo and skin cancer (
      • Jin Y.
      • Birlea S.A.
      • Fain P.R.
      • Gowan K.
      • Riccardi S.L.
      • Holland P.J.
      • et al.
      Variant of TYR and autoimmunity susceptibility loci in generalized vitiligo.
      ), or vitiligo might lead to enhanced immune activity against malignant melanoma and NMSC (
      • Jin Y.
      • Andersen G.
      • Yorgov D.
      • Ferrara T.M.
      • Ben S.
      • Brownson K.M.
      • et al.
      Genome-wide association studies of autoimmune vitiligo identify 23 new risk loci and highlight key pathways and regulatory variants.
      ).
      These associations suggest a possible genetic relationship between vitiligo and skin cancers. In our analysis of each of the three types of skin cancers, we did not exclude those with a history of the other skin cancer types. However, given the large sample size, those with such a history represented a small percentage of cases and controls, probably resulting in a limited bias in genetic risk estimates for each specific type of skin cancers. Further studies are warranted to understand the underlying mechanisms.

      Conflict of Interest

      The authors state no conflict of interest.

      Acknowledgments

      We would like to thank the research participants and employees of 23andMe for making this work possible. The 23andMe Research Team: Michelle Agee, Babak Alipanahi, Adam Auton, Robert K. Bell, Katarzyna Bryc, Sarah L. Elson, Pierre Fontanillas, Nicholas A. Furlotte, David A. Hinds, Karen E. Huber, Aaron Kleinman, Nadia K. Litterman, Jennifer C. McCreight, Matthew H. McIntyre, Joanna L. Mountain, Elizabeth S. Noblin, Carrie A. M. Northover, Steven J. Pitts, J. Fah Sathirapongsasuti, Olga V. Sazonova, Janie F. Shelton, Suyash Shringarpure, Chao Tian, Joyce Y. Tung, Vladimir Vacic, and Catherine H. Wilson.

      Supplementary Material

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