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Cited by 128melanin and skin pigmentationGenetic Associations and EpidemiologyCutaneous Melanoma Detection and Management

Genome-wide association studies of pigmentation and skin cancer: a review and meta-analysis

Open access
Gerstenblith, Meg R., Shi, Jianxin, Landi, Maria Teresa·2010·Pigment Cell & Melanoma Research
DOI 10.1111/j.1755-148x.2010.00730.xPMC PMC3179913
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Abstract

Summary: Recent genome‐wide association studies (GWAS) identified genetic loci associated with pigmentation, nevi, and skin cancer. We performed a review and meta‐analysis of GWAS results, grouping them into four categories: (i) loci associated with pigmentation (hair, eye, and/or skin color), cutaneous UV‐response (sun sensitivity and/or freckling), and skin cancer; (ii) loci associated with nevi and melanoma; (iii) loci associated with pigmentation and/or cutaneous UV‐response but not skin cancer; and (iv) loci associated distinctly with skin cancer, mostly basal cell carcinoma, but not pigmentation or cutaneous UV‐response. These findings suggest at least two pathways for melanoma development (via pigmentation and via nevi), and two pathways for basal cell carcinoma development (via pigmentation and independent of pigmentation). However, further work is necessary to separate the association with skin cancer from the association with pigmentation. As with any GWAS, the identified loci may not include the causal variants and may need confirmation by direct genome sequencing.

AI snapshot

Written from the paper’s full text.

TL;DR

This review and meta-analysis of genome-wide association studies found shared and distinct genetic loci for pigmentation, nevi, and skin cancer, suggesting at least two pathways to melanoma and two to basal cell carcinoma. Meta-analysis was possible only for red hair color and melanoma and did not identify new genome-wide significant loci.

Key findings

  • Twelve genome-wide studies and four replication/expansion studies were grouped into four categories: loci associated with pigmentation/cutaneous UV-response and skin cancer; loci associated with nevi and melanoma; loci associated with pigmentation/UV-response but not skin cancer; and loci associated with skin cancer only, mostly BCC. The authors conclude there are at least two melanoma pathways (via pigmentation and via nevi) and two BCC pathways (pigmentation-dependent and pigmentation-independent).
  • GWAS confirmed known pigmentation genes including MC1R, ASIP, TYR, TYRP1, SLC45A2, and OCA2, and identified novel pigmentation loci including SLC24A4, TPCN2, IRF4/EXOC2, KITLG, and HERC2. Skin-cancer-only BCC loci included PADI6, RHOU, KLF14, and KRT5; TERT-CLPTM1L was associated with increased BCC risk but a protective effect on melanoma.
  • In the red hair color meta-analysis, the strongest signals were on chromosome 16 near MC1R, particularly the RHC alleles R151C, R160W, and D294H. In the melanoma meta-analysis, no new loci emerged as significant, and ASIP had the strongest associations, though p-values could be affected by overlapping study subjects.
  • Some melanoma associations diminished after adjustment: MTAP/PLA2G6 associations were no longer significant after adjustment for nevus count, and TYRP1, TYR, and ASIP associations were not consistently confirmed after adjustment for pigmentation in replication studies.

Methods

  • PubMed searches identified 12 studies performing genome-wide analyses of pigmentation, cutaneous UV-response, nevi, melanoma, BCC, and SCC from the first report in 2007 through November 1, 2009, plus four studies that expanded or replicated GWAS findings. All studied Caucasian individuals except one South Asian population (Stokowski et al., 2007).
  • Associations were reported if significant at a GWAS-level p-value <1×10−7 and replicated in at least one other sample; replication studies used p<0.05 unless otherwise specified.
  • Meta-analysis was possible only for red hair color and melanoma because phenotype definitions varied. It combined odds ratios under a fixed-effects model, used a p-value-combining approach for studies reporting likelihood ratio statistics, and assessed heterogeneity with Cochran’s Q and I², using random effects when I²>0%.

Limitations

  • The paper states that phenotypic definitions varied across studies, limiting meta-analysis to red hair color and melanoma; manuscripts often reported only major GWAS results, creating potential reporting bias; not all studies reported the same SNPs; and redundancy of study populations in the melanoma meta-analysis could not be quantified.
  • The paper also states that all but two skin cancer GWAS did not examine or adjust for skin cancer risk factors, and that GWAS intrinsically test only a relatively small number of SNPs and may not identify causal variants.
  • Evident from the text: the review and meta-analysis rely on published summary results rather than individual-level data, and the predominantly Caucasian study populations limit generalizability to other ancestry groups.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1111/j.1755-148x.2010.00730.x

Cites

77 of 77 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 116 cited sources checked · 0 supported · 0 flagged

  • Findingcitation

    Gudbjartsson et al. (2008) identified a novel association for BCC with the ASIP haplotype.

    “Whereas Gudbjartsson et al. (2008) identified a novel association for BCC with the ASIP haplotype”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Gudbjartsson et al. (2008)

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  • Findingcitation

    In Duffy et al. (2010), there was a suggestive pattern of interaction for MC1R and ASIP.

    “In Duffy et al. (2010), there was a suggestive pattern of interaction for MC1R and ASIP, as previously observed (Landi et al., 2005).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Duffy et al. (2010)

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    • cites Landi et al., 2005

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  • Findingcitation

    In Gudbjartsson et al. (2008) and in a subset of cases and controls with 100% Northern European ancestry in Duffy et al. (2010), ASIP SNPs were associated with melanoma even after adjustment for pigmentation.

    “In Gudbjartsson et al. (2008) and in a subset of cases and controls with 100% Northern European ancestry in Duffy et al. (2010), ASIP SNPs were associated with melanoma even after adjustment for pigmentation”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Gudbjartsson et al. (2008)

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    • cites Duffy et al. (2010)

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  • Findingown data

    Twelve studies performed genome-wide analysis examining pigmentation traits, cutaneous UV-response, nevi, melanoma, BCC, and SCC in human populations from 2007 through November 1, 2009.

    “We identified twelve studies that performed genome-wide analysis examining pigmentation traits, cutaneous UV-response, nevi, melanoma, basal cell carcinoma, and squamous cell carcinoma in human populations during the time from the first reports in 2007 through November 1, 2009”
    Quote in the paperSubstantial claim
  • Findingcitation

    Duffy et al. (2010) confirmed associations with melanoma for two MC1R RHC variants, R151C and R160W.

    “Duffy et al. (2010) confirmed associations with melanoma for two MC1R RHC variants, R151C and R160W”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Duffy et al. (2010)

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  • May combine two claims. 49
  • Classified as probably not a substantial claim. 18

  • May combine two claims.

    Findingown data

    SNPs in MC1R were associated with hair color (both red and light hair color), sun sensitivity, and freckling in GWAS.

    “SNPs in MC1R were associated with hair color (both red and light hair color), sun sensitivity, and freckling in the GWAS”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    SNPs in ASIP were associated with red hair color, sun sensitivity, and freckling.

    “SNPs in ASIP were associated with red hair color, sun sensitivity, and freckling”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingreasoning

    GWAS confirmed associations already known, such as MC1R with pigmentation and skin cancer, and also identified chromosomal regions previously not known to be associated with pigmentation and/or skin cancer.

    “Using large populations with mostly Caucasian individuals, GWAS confirmed associations already known, such as MC1R with pigmentation and skin cancer, and also identified chromosomal regions previously not known to be associated with pigmentation and/or skin cancer.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    In Nan et al. (2009a), rs1015362 and rs6058017 SNPs and the ASIP haplotype had null associations with melanoma; rs4911414 had a suggestive association with melanoma risk but was not statistically significant.

    “The rs1015362 and rs6058017 SNPs and the ASIP haplotype had null associations with melanoma; rs4911414 had a suggestive association with melanoma risk but was not statistically significant.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Nan et al. (2009a)

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  • May combine two claims.

    Findingcitation

    All included studies examined Caucasian individuals except one that examined a South Asian population.

    “All studied Caucasian individuals except one that examined a South Asian population (Stokowski et al., 2007).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Stokowski et al., 2007

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  • May combine two claims.

    Findingcitation

    Nan et al. (2009a) found rs4911414 and rs6058017 were nearly significantly associated with risk of BCC in opposite directions; neither was significant after Bonferroni correction.

    “rs4911414 and rs6058017 were nearly significantly associated with risk of BCC (in opposite directions); however, neither was significant after Bonferroni correction for multiple testing.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Nan et al. (2009a)

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  • May combine two claims.

    Findingcitation

    Both Duffy et al. (2010) and Gathany et al. (2009) replicated the significant association with dark hair color; Duffy et al. also replicated significant associations with light eye and skin color for IRF4, but these associations were not significant in Gathany et al.

    “Both studies replicated the significant association with dark hair color; Duffy et al. (2010) also replicated the significant associations with light eye and skin color for IRF4, but these associations were not significant in Gathany et al. (2009) perhaps due to the smaller sample size”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Duffy et al. (2010)

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    • cites Gathany et al. (2009)

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  • May combine two claims.

    Findingcitation

    In Nan et al. (2009a), SLC45A2 SNP rs13289 was associated with melanoma risk, but not significant after Bonferroni correction.

    “Nan et al. (2009a) also tested the association of SLC45A2 SNPs and melanoma; one SNP, rs13289, was associated with melanoma risk, but the association was not significant after Bonferroni correction.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Nan et al. (2009a)

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  • May combine two claims.

    Findingcitation

    In a replication study, OCA2 SNP rs1800407 was associated with melanoma but was not statistically significant after Bonferroni correction.

    “In a replication study, the OCA2 SNP rs1800407 was associated with melanoma but was not statistically significant after Bonferroni correction for multiple testing (Duffy et al., 2010).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Duffy et al., 2010

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  • May combine two claims.

    Findingcitation

    SNPs in SLC24A5 were associated with skin color but were not tested for association with skin cancers in these GWAS.

    “SNPs in SLC24A5 were associated with skin color but were not tested for association with skin cancers in these GWAS”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    In Nan et al. (2009a) and Duffy et al. (2010), the association of the same TYRP1 SNP with melanoma was confirmed, but not statistically significant after Bonferroni correction in Nan et al. and after adjustment for hair, eye, and skin color in Duffy et al.

    “In Nan et al. (2009a) and Duffy et al. (2010), the association of the same TYRP1 SNP with melanoma was confirmed, but the association was not statistically significant after Bonferroni correction for multiple comparisons in Nan et al. (2009a) and after adjustment for hair, eye, and skin color in Duffy et al. (2010).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Nan et al. (2009a)

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    • cites Duffy et al. (2010)

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  • May combine two claims.

    Findingcitation

    The rs4911414 SNP was associated with SCC and there was a suggestive association of rs6058017 with SCC, but these associations were not significant after Bonferroni correction.

    “The rs4911414 SNP was associated with SCC and there a suggestive association of rs6058017 with SCC, but these associations were not significant after Bonferroni correction (Nan et al. 2009a).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Nan et al. 2009a

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    SNPs in TYRP1 were associated with eye color, and a novel association with melanoma was found in GWAS.

    “SNPs in TYRP1 were associated with eye color, and a novel association with melanoma was found in GWAS”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    The TYR SNP rs1042602 was marginally associated with SCC, but the association was further diminished after Bonferroni correction.

    “The TYR SNP rs1042602 was marginally associated with SCC, but the association was further diminished after Bonferroni correction (Nan et al., 2009a).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Nan et al., 2009a

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  • May combine two claims.

    Findingown data

    In GWAS, SNPs in TYR were associated with eye color, skin color, sun sensitivity, and freckling; a novel association with melanoma was found.

    “In GWAS, SNPs in TYR were associated with eye color, skin color, sun sensitivity, and freckling; in addition, a novel association with melanoma was found”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    In Nan et al. (2009a), OCA2 SNP rs1800407 was associated with BCC, but not statistically significant after Bonferroni correction.

    “In Nan et al. (2009a), this OCA2 SNP was associated with BCC, but the association was not statistically significant after Bonferroni correction.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Nan et al. (2009a)

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    The association of SLC24A4 SNPs with light hair color was replicated by Duffy et al. (2010), and a new association with blue eye color was reported in that study.

    “The association of SLC24A4 SNPs with light hair color was replicated by Duffy et al. (2010), and a new association with blue eye color was reported in that study.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Duffy et al. (2010)

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  • May combine two claims.

    Findingcitation

    In one replication study, the TYR SNP rs1126809 was significantly associated with BCC; in Nan et al. (2009a) the association with BCC followed the same direction but was not significant.

    “In one replication study, the TYR SNP rs1126809 was significantly associated with BCC (Gudbjartsson et al., 2008) (Table IIb), while in Nan et al. (2009a) the association with BCC followed the same direction but was not significant.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Gudbjartsson et al., 2008

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    • cites Nan et al. (2009a)

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  • May combine two claims.

    Findingcitation

    In Duffy et al. (2010), three SLC45A2 SNPs showed significant associations with melanoma; after adjustment for pigmentation and Bonferroni correction, rs16891982 remained significantly associated with melanoma.

    “These results were confirmed in Duffy et al. (2010), with three SNPs showing significant associations with melanoma; after adjustment for pigmentation and Bonferroni correction, the SLC45A2 SNP rs16891982 remained significantly associated with melanoma.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Duffy et al. (2010)

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  • May combine two claims.

    Findingcitation

    Stacey et al. (2009) identified novel associations of SLC45A2 SNP rs16891982 with BCC and SCC; results of the association with skin cancer were not adjusted for pigmentation.

    “Stacey et al. (2009) identified novel associations of the SLC45A2 SNP rs16891982 with BCC and SCC (Table IIb; Supplementary Table Ig); in this study, the SLC45A2 SNP rs16891982 was associated with pigmentation factors, but results of the association with skin cancer were not adjusted for pigmentation.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Stacey et al. (2009)

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    The IRF4 minor variant rs12203592 [T] was associated with dark hair color but light eye and skin color and sun sensitivity in GWAS.

    “the IRF4 minor variant rs12203592 [T] was associated with dark hair color but light eye and skin color and sun sensitivity in GWAS”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingreasoning

    SNPs around ASIP had the strongest associations with melanoma, but the p-values could be affected by inclusion of the same subjects in some studies contributing to the meta-analysis.

    “For example, SNPs around ASIP had the strongest associations with melanoma (Figure 1), but the p-values could be affected by the inclusion of the same subjects in some of the studies contributing to the meta-analysis.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Few new SNPs reached genome-wide significance in the meta-analysis and previous associations were refined, but no new loci emerged as significant in the meta-analysis for either phenotype.

    “Although few new SNPs reached genome-wide significance in the meta-analysis and previous associations were refined, no new loci emerged as significant in the meta-analysis for either phenotype.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingreasoning

    There are two main subsets of SNPs associated with melanoma risk: one associated with melanoma and pigmentation, and one associated with melanoma and nevus count.

    “There are two main subsets of SNPs associated with melanoma risk, one associated with melanoma and pigmentation and one associated with melanoma and nevus count.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    In GWAS, a SNP around TERT-CLPTM1L was associated with an increased risk of BCC and a protective effect on melanoma.

    “In GWAS, a SNP around telomerase reverse transcriptase-CLPTM1-like protein (TERT-CLPTM1L) was also associated with an increased risk of BCC and a protective effect on melanoma.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingreasoning

    Genome-wide association studies of pigmentation, sun sensitivity, and skin cancer phenotypes have identified new loci associated with these phenotypes, some shared and some distinct.

    “Genome-wide association studies of pigmentation, sun sensitivity, and skin cancer phenotypes have identified new loci associated with these phenotypes, some of which are shared and some of which are distinct.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    In all GWAS reviewed here, a signal on chromosome 16 near MC1R prompted further genotyping of the RHC alleles and multivariable analyses demonstrating that the signals were due to RHC alleles.

    “in all GWAS reviewed here, a signal on chromosome 16 near MC1R prompted further genotyping of the RHC alleles and multivariable analyses demonstrating that the signals were due to RHC alleles (Han et al., 2008; Nan et al., 2009b; Sulem et al., 2007; and Sulem et al., 2008).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Han et al., 2008

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    • cites Nan et al., 2009b

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    • cites Sulem et al., 2007

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  • May combine two claims.

    Findingnone given

    Four novel loci identified from GWAS were distinctly associated with BCC and one with BCC and melanoma, but not with pigmentation, sun sensitivity, freckling, or other skin cancers.

    “Four novel loci identified from GWAS were distinctly associated with BCC and one with BCC and melanoma, but not with pigmentation, sun sensitivity, freckling, or other skin cancers.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingnone given

    CDKN2A/B was associated with BCC but not melanoma in GWAS.

    “Cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) was associated with BCC but not melanoma in GWAS.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingnone given

    Both studies reported many of the same SNPs.

    “Both studies reported many of the same SNPs.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Findingnone given

    The p-values under the fixed effects model and the random effects model are very different when there is strong evidence of heterogeneity.

    “As expected, the p-values under the fixed effects model and the random effects model are very different when there is strong evidence of heterogeneity.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationnone given

    The identified GWAS loci may not include the causal variants and need confirmation by direct genome sequencing.

    “As with any GWAS, the identified loci may not include the causal variants and need confirmation by direct genome sequencing.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Studies of oculocutaneous albinism identified additional pigmentation genes including TYR, TYRP1, OCA2, and SLC45A2.

    “Studies of the four types of oculocutaneous albinism, disorders of melanin synthesis characterized by light skin, hair, and eye pigmentation among other features, have identified additional pigmentation genes, including tyrosinase (TYR), tyrosinase-related protein 1 (TYRP1), oculocutaneous albinism type 2 gene (OCA2, previously called P gene), and solute carrier family 45, member 2 (SLC45A2, previ”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Tomita and Suzuki, 2004

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  • May combine two claims.

    Interpretationcitation

    MC1R contributes to melanoma risk beyond the pigmentary phenotype, or residual confounding from pigmentation cannot be completely ruled out.

    “suggesting that MC1R contributes to melanoma risk beyond the pigmentary phenotype or that residual confounding from pigmentation cannot be completely ruled out”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    MC1R variants are associated with melanoma, BCC, and SCC.

    “MC1R variants are indeed associated with melanoma, BCC, and SCC”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Bastiaens et al., 2001

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    • cites Box et al., 2001

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    • cites Kennedy et al., 2001

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  • May combine two claims.

    Premisecitation

    Animal studies identified associations with pigmentation for ASIP and SLC24A5 genes, and candidate gene studies in humans confirmed these associations with pigmentation.

    “Animal studies identified associations with pigmentation for the agouti signaling protein (ASIP) and solute carrier family 24, member 5 (SLC24A5) genes; candidate gene studies in humans confirmed these associations with pigmentation”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Graf et al., 2005

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    • cites Kanetsky et al., 2002

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    • cites Lamason et al., 2005

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  • May combine two claims.

    Premisecitation

    Patients with certain types of oculocutaneous albinism experience sun sensitivity and are at increased risk of skin cancer, particularly nonmelanoma skin cancers; melanomas are much less commonly reported.

    “Patients with certain types of oculocutaneous albinism experience sun sensitivity and are at increased risk of skin cancer, particularly nonmelanoma skin cancers; melanomas, often amelanotic, are much less commonly reported”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Luande et al. 1985

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    • cites Perry and Silverberg, 2001

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    • cites Terenziani et al. 2003

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  • May combine two claims.

    Premisecitation

    CDK4 and PTCH1-related NBCCS account for only a small percentage of melanomas and BCCs, respectively.

    “CDK4 and PTCH1-related NBCCS only account for a small percentage of melanomas (Goldstein et al., 2006) and BCCs (Epstein 2008), respectively.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Goldstein et al., 2006

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    • cites Epstein 2008

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Prior to GWAS, KITLG was known to have a role in pigmentation.

    “Prior to GWAS, KITLG was known to have a role in pigmentation.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    TPCN2 encodes a protein also involved in calcium transport.

    “Interestingly, TPCN2 encodes a protein also involved in calcium transport (Sulem et al., 2008).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Sulem et al., 2008

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    SLC24A4 is in the same solute carrier family as SLC45A2 and SLC24A5, which are potassium-dependent sodium/calcium exchangers.

    “SLC24A4 is in the same solute carrier family as the other ‘pigmentation genes’ SLC45A2 and SLC24A5, which are potassium-dependent sodium/calcium exchangers”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Lamason et al., 2005

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    • cites Sulem et al., 2007

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    KITLG functions in melanogenesis and was found to affect pigmentation in animal models.

    “KITLG functions in melanogenesis and was found to affect pigmentation in animal models (Hultman et al., 2007; reviewed in Wehrle-Haller, 2003).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Hultman et al., 2007

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    • cites Wehrle-Haller, 2003

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Gain of function mutations in KITLG cause Familial Progressive Hyperpigmentation.

    “gain of function mutations in KITLG were recently found to cause Familial Progressive Hyperpigmentation, an autosomal dominant syndrome characterized by hyperpigmented patches of the skin that expand and increase with age (Wang et al., 2009).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Wang et al., 2009

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  • May combine two claims.

    Premisecitation

    In one study, short telomeres were associated with an increased risk of BCC while long telomeres were associated with an increased risk of melanoma.

    “in one study, short telomeres were associated with an increased risk of BCC while long telomeres were associated with an increased risk of melanoma (Han et al., 2009).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Han et al., 2009

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    GWAS have a major intrinsic limitation: the identified loci may not be the causal variants, so associated SNPs are not necessarily causally related to the examined phenotype.

    “Second, the identified loci may not be the causal variants, so associated SNPs are not necessarily causally related to the examined phenotype.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    CDKN2A is a high penetrance melanoma susceptibility gene, and in some families with CDKN2A mutations, there is an increased risk of pancreatic cancer, breast cancer, and neural tumors in addition to melanoma.

    “However, CDKN2A is a high penetrance melanoma susceptibility gene, as discussed previously, and in some families with CDKN2A mutations, there is an increased risk of pancreatic cancer, breast cancer, and neural tumors in addition to melanoma”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Bahuau et al., 1998

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    • cites Borg et al., 2000

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    • cites Goldstein et al., 2006

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  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    It was difficult to perform a meta-analysis given varying phenotypic definitions of pigmentation and sun sensitivity traits.

    “It was difficult to perform a meta-analysis given varying phenotypic definitions of pigmentation and sun sensitivity traits”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The mechanisms by which these BCC-only loci increase the risk for BCC are unknown, but these findings suggest a pathway or pathways independent of pigmentation and sun sensitivity.

    “The mechanisms by which these loci increase the risk for BCC are unknown, but these findings suggest a pathway or pathways independent of pigmentation and sun sensitivity.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The four categories of loci grouped by associated phenotypes correspond to distinct biological pathways.

  • Classified as probably not a substantial claim.

    Premisecitation

    Under the null hypothesis of no heterogeneity, Cochran's Q statistic follows a χ2 distribution with N-1 degree of freedom, where N is the number of studies to be combined.

    “Under the null hypothesis of no heterogeneity, the Cochran’s Q statistic follows a χ2 distribution with N-1 degree of freedom, where N is the number of studies to be combined.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Cochran, 1954

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Associations were reported if they were significant at a GWAS level corresponding to a p-value<1×10−7 and replicated in at least one other sample.

    “We reported associations that were significant at a GWAS level corresponding to a p-value<1×10−7 and replicated in at least one other sample.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductreasoning

    Due to the fact that for some SNPs only p-values were reported, the direction of the association could not be inferred; therefore, the meta-analysis for red hair color was possible for most but not all reported significant SNPs.

    “due to the fact that for some SNPs only p-values were reported, the direction of the association could not be inferred; therefore, the meta-analysis for red hair color was possible for most but not all reported significant SNPs.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The reviewed GWAS studies are sufficiently comparable in phenotype definitions and study design to combine in the meta-analysis for red hair color and melanoma.

  • Classified as probably not a substantial claim.

    Premisenone given

    The approach is appropriate if the p-values were derived from Wald-tests based on ORs and their SDs.

    “The approach is appropriate if the p-values were derived from Wald-tests based on ORs and their SDs.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    For SNPs with suggestive evidence of heterogeneity (I2>0%), a meta-analysis was performed under a random effects model.

    “For SNPs with suggestive evidence of heterogeneity (I2>0%), we performed a meta-analysis under a random effects model (Higgins and Thompson, 2002).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Higgins and Thompson, 2002

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    In studies replicating GWAS findings, a p-value<0.05 was considered significant unless otherwise specified in the study.

    “In studies replicating GWAS findings, a p-value<0.05 was considered significant unless otherwise specified in the study.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductreasoning

    The deCODE Genetics studies reported p-values adjusted by GC values because of strong evidence of cryptic relatedness and substructure, and the reported GC-corrected test results were used in the meta-analysis.

    “The studies performed by deCODE Genetics (Gudbjartsson et al., 2008; Rafnar et al., 2009; Stacey et al., 2008; Stacey et al., 2009; Sulem et al., 2007; and Sulem et al., 2008) reported p-values adjusted by GC values because of strong evidence of cryptic relatedness and substructure. We have used the reported, GC-corrected test results in the meta-analysis.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Gudbjartsson et al., 2008

      Not checked in the free run.

    • cites Rafnar et al., 2009

      Not checked in the free run.

    • cites Stacey et al., 2008

      Not checked in the free run.

    • Rests on an assumption: The reported odds ratios and p-values from the original studies are accurate and suitable for the meta-analysis after GC correction.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    Only SNPs with novel and/or significant associations for melanoma are included in Supplementary Table Ig, and only SNPs reported in at least three studies are included in Figure 1.

    “Only SNPs with novel and/or significant associations for melanoma are included in Supplementary Table Ig, and only SNPs reported in at least three studies are included in Figure 1.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The SNPs reported in at least three studies are representative of the genetic associations for melanoma.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisenone given

    The natural weights used for combining ORs are their standard deviations, which were derived from the reported CIs.

    “The natural weights used for combining ORs are their standard deviations (SDs), which were derived from the reported CIs.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductreasoning

    Not all studies included in the meta-analysis reported data on all of the same SNPs; thus, only SNPs reported in more than one study could be combined.

    “Another limitation is that not all studies included in the meta-analysis reported data on all of the same SNPs; thus, we could only combine the SNPs that were reported in more than one study.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The reviewed GWAS studies are sufficiently comparable in phenotype definitions and study design to combine in the meta-analysis for red hair color and melanoma.

  • May combine two claims.

    Study design and conductreasoning

    There were six studies that performed melanoma GWAS and four replication studies; however, for most SNPs, data could be combined across only a few studies since these studies did not report data on all of the same SNPs.

    “there were six studies that performed melanoma GWAS (Bishop et al., 2009; Brown et al., 2008; Falchi et al., 2009; Rafnar et al., 2009; Stacey et al., 2008; and Stacey et al., 2009), and four replication studies (Duffy et al. 2009; Gathany et al. 2009; Gudbjartsson et al. 2008; and Nan et al. 2009a); however, for most SNPs, we could combine data across only a few of the studies since these studies”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Bishop et al., 2009

      Not checked in the free run.

    • cites Brown et al., 2008

      Not checked in the free run.

    • cites Falchi et al., 2009

      Not checked in the free run.

    • Rests on an assumption: The reviewed GWAS studies are sufficiently comparable in phenotype definitions and study design to combine in the meta-analysis for red hair color and melanoma.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductreasoning

    For a given SNP reported here, one or more GWAS may have failed to report the test results because the SNP was not genotyped, because the association between the SNP and the disease had been previously demonstrated to be significant, or because the SNP was not among the most significant in that study.

    “For a given SNP reported here, one or more GWAS may have failed to report the test results because the SNP was not genotyped, because the association between the SNP and the disease had been previously demonstrated to be significant, or because the SNP was not among the most significant in that study.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    For all studies reviewed, with the exception of six deCODE studies, there was no strong evidence of cryptic relatedness or substructure based on genome control (GC) values; hence, original odds ratios and p-values were used in the meta-analysis.

    “For all studies reviewed in this manuscript, with the exception of Gudbjartsson et al. (2008), Rafnar et al. (2009), Stacey et al. (2008), Stacey et al. (2009), Sulem et al. (2007), and Sulem et al. (2008), there was no strong evidence of cryptic relatedness or substructure based on genome control (GC) values; hence, we have used the original odds ratios (ORs) and p-values in the meta-analysis.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Gudbjartsson et al., 2008

      Not checked in the free run.

    • cites Rafnar et al., 2009

      Not checked in the free run.

    • cites Stacey et al., 2008

      Not checked in the free run.

    • Rests on an assumption: The reported odds ratios and p-values from the original studies are accurate and suitable for the meta-analysis after GC correction.
61 of 61

  • The paper relies on this without support.

    The genes located in or near the chromosomal regions identified by GWAS are the relevant genes for the associated phenotypes.

    “Table III shows overall associations with pigmentation, sun sensitivity, freckling, nevi, and skin cancer phenotypes for the genes located in the chromosomal regions identified by GWAS and replication studies”
    “The loci associated with BCC only are located around the following genes: peptidylarginine deiminase, type VI (PADI6), ras homolog gene family, member u (RHOU), kruppel-like factor 14 (KLF14), and keratin 5 (KRT5)”

  • The paper relies on this without support.

    The four categories of loci grouped by associated phenotypes correspond to distinct biological pathways.

    “The significant loci from the GWAS were grouped into four categories: (1) loci associated with pigmentation (hair, eye, and/or skin color), cutaneous UV-response (sun sensitivity and/or freckling), and skin cancer; (2) loci associated with nevi and melanoma; (3) loci associated with pigmentation and/or cutaneous UV-response, but not skin cancer; and (4) loci associated with skin cancers, mostly B”
    “These findings suggest at least two pathways for melanoma development (via pigmentation and via nevi), and two pathways for BCC development (via pigmentation and independent of pigmentation).”

  • The paper relies on this without support.

    The reviewed GWAS studies are sufficiently comparable in phenotype definitions and study design to combine in the meta-analysis for red hair color and melanoma.

    “Given different phenotypic definitions, a meta-analysis was only possible for red hair color and melanoma phenotypes.”

  • The paper relies on this without support.

    The reported odds ratios and p-values from the original studies are accurate and suitable for the meta-analysis after GC correction.

    “We have used the reported, GC-corrected test results in the meta-analysis.”

  • The paper relies on this without support.

    The SNPs reported in at least three studies are representative of the genetic associations for melanoma.

    “only SNPs reported in at least three studies are included in Figure 1”
5 of 5

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Authors
Gerstenblith, M. R., Shi, J., & Landi, M. T.
Affiliations
National Institutes of Health (US)
Corresponding author
Landi, Maria Teresa
ORCID
Venue
Pigment Cell & Melanoma Research
Publisher
Wiley
Published
2010-09
Volume
23
Issue
5
Pages
587-606
ISSN
  • 1755-1471 (ISSN-L)
  • 1755-148X
DOI
10.1111/j.1755-148x.2010.00730.x
PMC
PMC3179913
OpenAlex
W1912033397
Cited by
128
References
77
Citations by year
2026: 2 · 2025: 6 · 2024: 6 · 2023: 5 · 2022: 5 · 2021: 9 · 2020: 1 · 2019: 9 · 2018: 9 · 2017: 5 · 2016: 7 · 2015: 10 · 2014: 13 · 2013: 13 · 2012: 10
FWCI
1.17
Type
journal article
Language
en
Open access
Licence
Locations
  • Pigment Cell & Melanoma Research (publishedVersion, public-domain)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health
  • National Cancer Institute (ZIACP010200, Z01CP010200)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › melanin and skin pigmentation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Health Sciences › Medicine › Oncology › Cutaneous Melanoma Detection and Management
Keywords
pigmentation, skin cancer, melanoma, basal cell carcinoma, nevi, sun sensitivity, freckles, hair color, eye color, skin color, genetic loci
MeSH terms
Animals, Genotype, Humans, Melanoma, Nevus, Skin Neoplasms, Skin Pigmentation, Ultraviolet Rays, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Genome-Wide Association Study

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

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