Genome-wide association study identifies 14 novel risk alleles associated with basal cell carcinoma

Chahal, Harvind S.; Wu, Wenting; Ransohoff, Katherine J.; Yang, Lingyao; Hedlin, Haley; Desai, Manisha; Lin, Yuan; Dai, Hong; Qureshi, Abrar A.; Li, Wen Qing; Kraft, Peter; Hinds, David A.; Tang, Jean Y.; Han, Jiali; Sarin, Kavita Y.

doi:10.1038/ncomms12510

Cited by 97 publications

(172 citation statements)

References 76 publications

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“…17 SNPs and associated effect sizes (in this case, log OR) that reached predefined P-value thresholds (pT; 0.0001, 1 × 10 −5 , 1 × 10 −6 , 1 × 10 −7 , 1 × 10 −8 , 1 × 10 −9 ) were extracted from the discovery GWAS results data from two previously published GWAS papers, one of SCC 13 and one of BCC, both in a nontransplant population. 13,14 Effect sizes for the SNPs that reached the given pT, along with the effect allele and associated rsID were extracted from these results. More details on accessing this data are available elsewhere.…”

Section: Polygenic Risk Scoresmentioning

confidence: 99%

“…These were tested against NMSC, as well as the two main subtypes of NMSC: BCC and SCC to evaluate subtype specific differences. There was a large degree of overlap in the SNPs that reached pT1 × 10 −5 in BCC and SCC GWASs, 13,14 with 69% of the SNPs in the SCC PRS found in the BCC PRS at this threshold (see Tables S1 and S2 for SNPs used for these scores). Although era of transplantation was not a significant predictor of skin cancer, we felt it was appropriate to include it as a covariate as to account for differences in immunosuppression regimens which are known to influence the onset of NMSC posttransplant.…”

Section: Re Sultsmentioning

confidence: 99%

“…10 Despite the increased risk of skin cancer, only one study has tested for germline genetic associations with skin cancer posttransplant on a genomic scale. [11][12][13][14] The genetic architecture of NMSC in a transplant setting would appear to mirror that of complex human traits generally, where common genetic variants individually tend to have small effect sizes and limited clinical relevance, with some notable exceptions. 7 This study had limited power (n = 388) compared to genome-wide association studies (GWAS) of SCC and BCC in nontransplant populations (n = 8058+) where robust genetic risk factors for NMSC were identified.…”

Section: Introductionmentioning

confidence: 99%

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Polygenic risk score as a determinant of risk of non-melanoma skin cancer in a European-descent renal transplant cohort

Stapleton

Birdwell

McKnight

et al. 2019

American Journal of Transplantation

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Renal transplant recipients have an increased risk of non-melanoma skin cancer (NMSC) compared to in the general population. Here, we show polygenic risk scores (PRS) calculated from genome-wide association studies (GWAS) of NMSC in a general, nontransplant setting, can predict risk of, and time to posttransplant skin cancer. Genetic variants, reaching predefined P-value thresholds were chosen from published squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) nontransplant GWAS. Using these GWAS, BCC and SCC PRS were calculated for each sample across three European ancestry renal transplant cohorts (n = 889) and tested as predictors of case:control status and time to NMSC posttransplant. BCC PRS calculated at P-value threshold 1 × 10 was the most significant predictor of case:control status of NMSC posttransplant (OR = 1.61; adjusted P = .0022; AUC [full model adjusted for clinical predictors and PRS] = 0.81). SCC PRS at P-value threshold 1 × 10 was the most significant predictor of time to posttransplant NMSC (adjusted P = 9.39 × 10 ; HR = 1.41, concordance [full model] = 0.74). PRS of nontransplant NMSC is predictive of case:control status and time to NMSC posttransplant. These results are relevant to how genomics can risk stratify patients to help develop personalized treatment regimens.

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Section: Polygenic Risk Scoresmentioning

confidence: 99%

Section: Re Sultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Polygenic risk score as a determinant of risk of non-melanoma skin cancer in a European-descent renal transplant cohort

Stapleton

Birdwell

McKnight

et al. 2019

American Journal of Transplantation

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“…The risk allele of rs11598018 ( C ) is associated with increased leukocyte telomere length thereby supporting a relationship between genotype and biology (78–80). Variation at 10q24.33 is additionally associated with risk of melanoma (81), basal cell carcinoma (82), thyroid cancer (83), and renal cell carcinoma (84). The SNPs defined by these associations do not appear to be correlated with rs11598018 ( r 2 = 0.11–0.12, D′ = 0.72–1.0).…”

Section: Chronological History Of Glioma Risk Loci Discoverymentioning

confidence: 99%

Genome-Wide Association Studies in Glioma

Kinnersley

Houlston

Bondy

2018

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Since the first reports in 2009, genome-wide association studies (GWAS) have been successful in identifying germline variants associated with glioma susceptibility. In this review, we describe a chronological history of glioma GWAS, culminating in the most recent study comprising 12,496 cases and 18,190 controls. We additionally summarize associations at the 27 glioma-risk SNPs that have been reported so far. Future efforts are likely to be principally focused on assessing association of germline-risk SNPs with particular molecular subgroups of glioma, as well as investigating the functional basis of the risk loci in tumor formation. These ongoing studies will be important to maximize the impact of research into glioma susceptibility, both in terms of insight into tumor etiology as well as opportunities for clinical translation.

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“…We were unaware of studies of associations between variations within VDR binding sites and risk of BCC. Therefore, in this study, we thoroughly examine the effects of common genetic variation across 2,776 previously identified VDR binding sites on BCC risk based on a genome‐wide association meta‐analysis …”

mentioning

confidence: 99%

Association between genetic variation within vitamin D receptor‐DNA binding sites and risk of basal cell carcinoma

Lin

Chahal

et al. 2017

Intl Journal of Cancer

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An increasing number of studies have reported a protective association between vitamin D and cancer risk. The vitamin D endocrine system regulates transcriptional programs involved in inflammation, cell growth and differentiation through the binding of vitamin D receptor (VDR) to specific VDR elements. However, limited attention has been given to the role of variation within VDR binding sites in the development of basal cell carcinoma (BCC). Across 2,776 previously identified VDR binding sites, we identified 2,540 independent single-nucleotide polymorphisms (SNPs) and examined their associations with BCC risk in a genome-wide association meta-analysis totaling 17,187 BCC cases and 287,054 controls from two data sets. After multiple testing corrections, we identified two SNPs at new loci (rs16917546 at 10q21.1: odds ratio (OR) = 1.06, p = 3.16 × 10 and rs79824801 at 12q13.3: OR = 1.10, p = 1.88 × 10 ) for the first time as independently related to BCC risk in meta-analysis; and both SNPs were nominally significant in two data sets. In addition, the SNP rs3769823 within VDR binding site at a previously reported BCC susceptibility locus (2q33.1, rs13014235) also exhibited a significant association (OR = 1.12, p = 3.99 × 10 ). A mutually adjusted model suggested that rs3769823 explained the signal in this region. Our findings support the hypothesis that inherited common variation in VDR binding sites affects the development of BCC.

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Genome-wide association study identifies 14 novel risk alleles associated with basal cell carcinoma

Cited by 97 publications

References 76 publications

Polygenic risk score as a determinant of risk of non-melanoma skin cancer in a European-descent renal transplant cohort

Polygenic risk score as a determinant of risk of non-melanoma skin cancer in a European-descent renal transplant cohort

Genome-Wide Association Studies in Glioma

Association between genetic variation within vitamin D receptor‐DNA binding sites and risk of basal cell carcinoma

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