Genome-wide association study identifies novel alleles associated with risk of cutaneous basal cell carcinoma and squamous cell carcinoma

Nan, Hongmei; Xu, Mousheng; Kraft, Peter; Qureshi, Abrar A.; Chen, Constance; Guo, Qun; Hu, Frank B.; Curhan, Gary C.; Amos, Christopher I.; Wang, Li E.; Lee, Jeffrey E.; Wei, Qingyi; Hunter, David J.; Han, Jiali

doi:10.1093/hmg/ddr287

Cited by 94 publications

(85 citation statements)

References 24 publications

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“…13 The increased risk is consistent with recent epidemiological data of an increased risk of BCC in individuals with red hair. 17 This emphasizes that individuals with Gorlin syndrome with type 1 skin, and in particular red hair colour, need to take extra care with sun exposure to minimize their BCC risk.…”

Section: Discussionsupporting

confidence: 90%

“…The 1.64-fold increased risk associated with the MC1R variant for BCC age of onset in individuals with Gorlin syndrome is similar to that observed for the increased risk of sporadic BCC conferred by this variant. 13 The variant at the TERT-CLPTM1L locus has been associated with multiple cancer types including lung, bladder and prostate cancers. 18 Individuals with the variant have a propensity to shortened telomeres with increasing age.…”

Section: Discussionmentioning

confidence: 99%

“…Nine SNPs, previously published as being associated with increased BCC risk [13][14][15] (rs1805007 chr16.hg19:89919709C4T, rs12210050 chr6.hg19:475489C4T, rs7335046 chr13.hg19:99389484G4C, rs7538876 chr1.hg19:17395867G4A, rs801114 chr1.hg19:228862088G4A, rs401681 chr5.hg19:1321972G4A, rs2151280 chr9.hg19:22034720G4A, rs157935 chr7.hg19:130900794T4G and rs11170164 chr12.hg19:52913668G4T), were genotyped using pre-designed Taqman SNP genotyping allelic discrimination assays (Applied Biosystems, Warrington, UK). SNPs can be found on dbSNP (URL: http://www.ncbi.nlm.nih.gov/SNP/).…”

Section: Methodsmentioning

confidence: 99%

“…12 A genome-wide association study (GWAS) of over 2000 BCC cases of European ancestry in the United States replicated the strong association with the MC1R p.(Arg151Cys) missense variant (rs1805007). 13 A noncoding variant at the chromosome 6p25 locus near EXOC (rs12210050) and a variant at the 13q32 locus near UBAC2, which encodes ubiquitin-associated domain containing protein 2 (rs7335046), also reached genome-wide significance. 13 An independent GWAS of over 2000 BCC cases of Icelandic and Eastern European origin reported two loci at 1p36 (rs7538876) and 1q42 (rs801114) associated with BCC susceptibility.…”

Section: Introductionmentioning

confidence: 99%

“…13 A noncoding variant at the chromosome 6p25 locus near EXOC (rs12210050) and a variant at the 13q32 locus near UBAC2, which encodes ubiquitin-associated domain containing protein 2 (rs7335046), also reached genome-wide significance. 13 An independent GWAS of over 2000 BCC cases of Icelandic and Eastern European origin reported two loci at 1p36 (rs7538876) and 1q42 (rs801114) associated with BCC susceptibility. 14 In a follow-up GWAS of over 3000 BCC cases, by the same group, further variants including keratin 5 (KRT5, rs11170164), and the 9p21 (rs2151280), 7q32 (rs157935) and TERT-CLPTM1L (rs401681) loci were associated with an increased BCC risk.…”

Section: Introductionmentioning

confidence: 99%

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Common variants modify the age of onset for basal cell carcinomas in Gorlin syndrome

et al. 2014

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Gorlin syndrome is an autosomal dominant disorder, characterized by multiple early-onset basal cell carcinomas (BCCs) and jaw keratocysts. Through association studies in cohorts of sporadic BCC, nine genetic variants have previously been identified to increase the risk of BCC. The nine SNPs were genotyped by Taqman allelic discrimination in 125 individuals with Gorlin syndrome. Kaplan-Meier survival curves and Cox proportional-Hazard regression analysis were applied to determine the association between genotypes and age of first BCC in individuals with Gorlin syndrome. The p.(Arg151Cys) variant in MC1R (rs1805007) was associated with an earlier median age of onset of BCC of 27 years (95% CI: 20-34) compared with 34 years (95% CI: 30-40) for wild-type individuals (hazard ratio (HR) ¼ 1.64, 95% CI: 1.04-2.58, P ¼ 0.034). The risk allele of the variant at the chromosome 5p15 locus encompassing TERT-CLPTM1L (rs401681) was also associated with an earlier median onset of BCC, 31 years (95% CI: 28-37) compared with 41 years (95% CI: 32-48, HR ¼ 1.44, 95% CI: 1.08-1.93, P ¼ 0.014). In individuals with a risk allele at either rs1805007 or rs401681 the median time to BCC was 31 years of age (95% CI: 28-34) compared with 44 years of age (95% CI: 38-53) in wild-type individuals (HR ¼ 2.48, 95% CI: 1.47-4.17, P ¼ 0.0002). Our findings may have implications for future personalized risk estimates and BCC screening strategies in individuals with Gorlin syndrome.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Common variants modify the age of onset for basal cell carcinomas in Gorlin syndrome

et al. 2014

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Systematic evaluation of cancer‐specific genetic risk score for 11 types of cancer in The Cancer Genome Atlas and Electronic Medical Records and Genomics cohorts

Shi

et al. 2019

Cancer Medicine

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Background Genetic risk score (GRS) is an odds ratio (OR)‐weighted and population‐standardized method for measuring cumulative effect of multiple risk‐associated single nucleotide polymorphisms (SNPs). We hypothesize that GRS is a valid tool for risk assessment of most common cancers. Methods Utilizing genotype and phenotype data from The Cancer Genome Atlas (TCGA) and Electronic Medical Records and Genomics (eMERGE), we tested 11 cancer‐specific GRSs (bladder, breast, colorectal, glioma, lung, melanoma, ovarian, pancreatic, prostate, renal, and thyroid cancer) for association with the respective cancer type. Cancer‐specific GRSs were calculated, for the first time in these cohorts, based on previously published risk‐associated SNPs using the Caucasian subjects in these two cohorts. Results Mean cancer‐specific GRS in the population controls of eMERGE approximated the expected value of 1.00 (between 0.98 and 1.02) for all 11 types of cancer. Mean cancer‐specific GRS was consistently higher in respective cancer patients than controls for all 11 types of cancer (P < 0.05). When subjects were categorized into low‐, average‐, and high‐risk groups based on cancer‐specific GRS (<0.5, 0.5‐1.5, and >1.5, respectively), significant dose‐response associations of higher cancer‐specific GRS with higher OR of respective type of cancer were found for nine types of cancer (P‐trend < 0.05). More than 64% subjects in the population controls of eMERGE can be classified as high risk for at least one type of these cancers. Conclusion Validity of GRS for predicting cancer risk is demonstrated for most types of cancer. If confirmed in larger studies, cancer‐specific GRS may have the potential for developing personalized cancer screening strategy.

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Explicit Modeling of Ancestry Improves Polygenic Risk Scores and BLUP Prediction

Chen

Han

Hunter

et al. 2015

Genetic Epidemiology

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Polygenic prediction using genome-wide SNPs can provide high prediction accuracy for complex traits. Here, we investigate the question of how to account for genetic ancestry when conducting polygenic prediction. We show that the accuracy of polygenic prediction in structured populations may be partly due to genetic ancestry. However, we hypothesized that explicitly modeling ancestry could improve polygenic prediction accuracy. We analyzed three GWAS of hair color, tanning ability and basal cell carcinoma (BCC) in European Americans (sample size from 7,440 to 9,822) and considered two widely used polygenic prediction approaches: polygenic risk scores (PRS) and Best Linear Unbiased Prediction (BLUP). We compared polygenic prediction without correction for ancestry to polygenic prediction with ancestry as a separate component in the model. In 10-fold cross-validation using the PRS approach, the R2 for hair color increased by 66% (0.0456 to 0.0755; p<10−16), the R2 for tanning ability increased by 123% (0.0154 to 0.0344; p<10−16) and the liability-scale R2 for BCC increased by 68% (0.0138 to 0.0232; p<10−16) when explicitly modeling ancestry, which prevents ancestry effects from entering into each SNP effect and being over-weighted. Surprisingly, explicitly modeling ancestry produces a similar improvement when using the BLUP approach, which fits all SNPs simultaneously in a single variance component and causes ancestry to be underweighted. We validate our findings via simulations, which show that the differences in prediction accuracy will increase in magnitude as sample sizes increase. In summary, our results show that explicitly modeling ancestry can be important in both PRS and BLUP prediction.

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Genome-wide association study identifies novel alleles associated with risk of cutaneous basal cell carcinoma and squamous cell carcinoma

Cited by 94 publications

References 24 publications

Common variants modify the age of onset for basal cell carcinomas in Gorlin syndrome

Common variants modify the age of onset for basal cell carcinomas in Gorlin syndrome

Systematic evaluation of cancer‐specific genetic risk score for 11 types of cancer in The Cancer Genome Atlas and Electronic Medical Records and Genomics cohorts

Explicit Modeling of Ancestry Improves Polygenic Risk Scores and BLUP Prediction

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