New common variants affecting susceptibility to basal cell carcinoma

Stacey, Simon; Sulem, Patrick; Másson, Gísli; Gudjonsson, Sigurjon A.; Þorleifsson, Guðmar; Jakobsdottir, Margret; Sigurðsson, Ásgeir; Guðbjartsson, Daníel F.; Sigurgeirsson, Bárður; Benediktsdóttir, Kristrún R.; Thorisdottir, Kristin; Ragnarsson, Rafn; Scherer, Dominique; Hemminki, Kari; Rudnai, Péter; Gurzău, Eugen; Koppová, Kvetoslava; Botella‐Estrada, Rafael; Soriano, Virtudes; Juberías, Pablo; Sáez, Berta; Gilaberte, Yolanda; Fuentelsaz, Victoria; Corredera, Cristina; Grasa, Matilde; Höiom, Veronica; Lindblom, Annika; Bonenkamp, Johannes J.; Rossum, Michelle M. van; Aben, Katja K.H.; Vries, Esther de; Santinami, Mario; Mauro, Maria Gaetana Di; Maurichi, Andrea; Wendt, Judith; Hochleitner, Pia; Pehamberger, Hubert; Guðmundsson, Jūlı́us; Magnúsdóttir, Droplaug N; Grétarsdóttir, Sólveig; Hólm, Hilma; Steinthórsdóttir, Valgerður; Frigge, Michael L.; Blöndal, Thórarinn; Saemundsdottir, Jona; Bjarnason, Hjördis; Kristjánsson, Kristleifur; Björnsdóttir, Gyða; Okamoto, Ichiro; Rivoltini, Licia; Rodolfo, Monica; Kiemeney, Lambertus A.; Hansson, Johan; Nagore, Eduardo; Mayordomo, J. I.; Kumar, Rajiv; Karagas, Margaret R.; Nelson, Heather H.; Gulcher, Jeffrey R.; Rafnar, Thorunn; Þorsteinsdóttir, Unnur; Ólafsson, Jón; Kong, Augustine; Stefánsson, Kāri

doi:10.1038/ng.412

Cited by 295 publications

(255 citation statements)

References 30 publications

Supporting

Mentioning

246

Contrasting

Order By: Relevance

“…18 The increased risk conferred by the TERT-CLPTM1L variant in Gorlin syndrome is comparable to that in sporadic BCC. 15 The median time to BCC was reduced by over 10 years with the presence of one or both risk alleles for either variant in MC1R or at TERT-CLPTM1L.…”

Section: Discussionmentioning

confidence: 94%

“…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%

“…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. 15 In this study, we genotyped nine variants previously associated with increased BCC risk, in a cohort of individuals with Gorlin syndrome, to assess their effect on the age of BCC onset.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

et al. 2014

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 94%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

et al. 2014

View full text Add to dashboard Cite

show abstract

“…Using large populations with mostly Caucasian individuals, GWAS have produced sufficient evidence of the genetic associations with BCC risk (Stokowski et al, 2007;Sulem et al, 2007;Brown et al, 2008;Han et al, 2008;Stacey et al, 2008;Sulem et al, 2008;Falchi et , 2009b;Rafnar et al, 2009;Stacey et al, 2009;Duffy et al, 2010). However, a paucity of studies based on data from non-Caucasian deals with the genetic associations with BCC risk (Cho et al, 2001;Kim et al, 2002;Kang et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Exploratory Investigation of Genetic Associations with Basal Cell Carcinoma Risk: Genome-Wide Association Study in Jeju Island, Korea

Yun

Song²,

Lee³

2014

Asian Pacific Journal of Cancer Prevention

View full text Add to dashboard Cite

Aim: Little is known about the genetic associations with Basal cell carcinoma (BCC) risk in non-Caucasian populations, in which BCC is rare, as in Korea. We here conducted a pilot genome-wide association study (GWAS) in 12 patients and 48 standard controls. Method: A total of 263,511 SNPs were analyzed with the Illumina HumanOmni1 Quad v1.0 DNA Analysis BeadChip for cases and Korean HapMap 570K for controls. Results: SNP-based analyses, based on the allele genetic model with adjustment for sex and age showed suggestive associations with BCC risk for 6 SNPs with a P-value (P < 0.0005). However, these associations were not statistically significant after Bonferroni correction: rs1040503, rs2216491, rs13407683, rs4751072, rs9891263, and rs1368474. In addition, results from gene-based analyses showed suggestive associations with BCC risk for 33 candidate genes with a P-value (P <0.0005). Consistent with previous GWAS and replication studies in Caucasian populations, PADI6, RHOU and SLC45A2 were identified as having null associations with BCC (P > 0.05), likely due to the smaller sample size. Conclusions: Although this was a small-scale negative study, to our knowledge, we have conducted the first GWAS for BCC risk in an Asian population. Further large studies in non-Caucasian populations are required to achieve statistical significance and confirm these findings.

show abstract

“…SNPs in 9p21 locus were also found to be associated with various cancers, in addition to cardiovascular diseases and T2D. [81][82][83] So far, most of the GWAS did a fast-track replication by selecting the top few or top tens of SNPs with the most significant P-values in stage 1 and proceeding to replicate those SNPs in stage 2 or stage 3 with larger sample sizes. However, other SNPs down the significance list are just as likely to be genuine, thus more SNPs need to be selected for replication in larger sample sets.…”

Section: The Recent 2 Years: 2008 and 2009mentioning

confidence: 99%

The pursuit of genome-wide association studies: where are we now?

et al. 2010

View full text Add to dashboard Cite

It is now 5 years since the first genome-wide association studies (GWAS), published in 2005, identified a common risk allele with large effect size for age-related macular degeneration in a small sample set. Following this exciting finding, researchers have become optimistic about the prospect of the genome-wide association approach. However, most of the risk alleles identified in the subsequent GWAS for various complex diseases are common with small effect sizes (odds ratio o1.5). So far, more than 450 GWAS have been published and the associations of greater than 2000 single nucleotide polymorphisms (SNPs) or genetic loci were reported. The aim of this review paper is to give an overview of the evolving field of GWAS, discuss the progress that has been made by GWAS and some of the interesting findings, and summarize what we have learned over the past 5 years about the genetic basis of human complex diseases. This review will focus on GWAS of SNPs association for complex diseases but not studies of copy number variations.

show abstract

New common variants affecting susceptibility to basal cell carcinoma

Cited by 295 publications

References 30 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

Exploratory Investigation of Genetic Associations with Basal Cell Carcinoma Risk: Genome-Wide Association Study in Jeju Island, Korea

The pursuit of genome-wide association studies: where are we now?

Contact Info

Product

Resources

About