RESUMEN
Most genetic susceptibility to cutaneous melanoma remains to be discovered. Meta-analysis genome-wide association study (GWAS) of 36,760 cases of melanoma (67% newly genotyped) and 375,188 controls identified 54 significant (P < 5 × 10-8) loci with 68 independent single nucleotide polymorphisms. Analysis of risk estimates across geographical regions and host factors suggests the acral melanoma subtype is uniquely unrelated to pigmentation. Combining this meta-analysis with GWAS of nevus count and hair color, and transcriptome association approaches, uncovered 31 potential secondary loci for a total of 85 cutaneous melanoma susceptibility loci. These findings provide insights into cutaneous melanoma genetic architecture, reinforcing the importance of nevogenesis, pigmentation and telomere maintenance, together with identifying potential new pathways for cutaneous melanoma pathogenesis.
Asunto(s)
Predisposición Genética a la Enfermedad/genética , Melanoma/genética , Neoplasias Cutáneas/genética , Femenino , Sitios Genéticos/genética , Estudio de Asociación del Genoma Completo/métodos , Genotipo , Humanos , Masculino , Fenotipo , Pigmentación/genética , Polimorfismo de Nucleótido Simple/genética , Melanoma Cutáneo MalignoRESUMEN
Thirteen common susceptibility loci have been reproducibly associated with cutaneous malignant melanoma (CMM). We report the results of an international 2-stage meta-analysis of CMM genome-wide association studies (GWAS). This meta-analysis combines 11 GWAS (5 previously unpublished) and a further three stage 2 data sets, totaling 15,990 CMM cases and 26,409 controls. Five loci not previously associated with CMM risk reached genome-wide significance (P < 5 × 10(-8)), as did 2 previously reported but unreplicated loci and all 13 established loci. Newly associated SNPs fall within putative melanocyte regulatory elements, and bioinformatic and expression quantitative trait locus (eQTL) data highlight candidate genes in the associated regions, including one involved in telomere biology.
Asunto(s)
Melanoma/genética , Neoplasias Cutáneas/genética , Estudios de Casos y Controles , Cromosomas Humanos/genética , Sitios Genéticos , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Polimorfismo de Nucleótido Simple , Melanoma Cutáneo MalignoRESUMEN
At least 17 genomic regions are established as harboring melanoma susceptibility variants, in most instances with genome-wide levels of significance and replication in independent samples. Based on genome-wide single nucleotide polymorphism (SNP) data augmented by imputation to the 1,000 Genomes reference panel, we have fine mapped these regions in over 5,000 individuals with melanoma (mainly from the GenoMEL consortium) and over 7,000 ethnically matched controls. A penalized regression approach was used to discover those SNP markers that most parsimoniously explain the observed association in each genomic region. For the majority of the regions, the signal is best explained by a single SNP, which sometimes, as in the tyrosinase region, is a known functional variant. However in five regions the explanation is more complex. At the CDKN2A locus, for example, there is strong evidence that not only multiple SNPs but also multiple genes are involved. Our results illustrate the variability in the biology underlying genome-wide susceptibility loci and make steps toward accounting for some of the "missing heritability."
Asunto(s)
Predisposición Genética a la Enfermedad , Melanoma/genética , Polimorfismo de Nucleótido Simple , Mapeo Cromosómico , Ciclina D1/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Sitios Genéticos , Humanos , Telomerasa/genéticaRESUMEN
Telomere length has been associated with risk of many cancers, but results are inconsistent. Seven single nucleotide polymorphisms (SNPs) previously associated with mean leukocyte telomere length were either genotyped or well-imputed in 11108 case patients and 13933 control patients from Europe, Israel, the United States and Australia, four of the seven SNPs reached a P value under .05 (two-sided). A genetic score that predicts telomere length, derived from these seven SNPs, is strongly associated (P = 8.92x10(-9), two-sided) with melanoma risk. This demonstrates that the previously observed association between longer telomere length and increased melanoma risk is not attributable to confounding via shared environmental effects (such as ultraviolet exposure) or reverse causality. We provide the first proof that multiple germline genetic determinants of telomere length influence cancer risk.
Asunto(s)
Mutación de Línea Germinal , Melanoma/genética , Polimorfismo de Nucleótido Simple , Neoplasias Cutáneas/genética , Proteínas de Unión a Telómeros/genética , Telómero/genética , Australia , Factores de Confusión Epidemiológicos , ADN Helicasas/genética , Europa (Continente) , Humanos , Israel , Valor Predictivo de las Pruebas , ARN/genética , Proyectos de Investigación , Ribonucleoproteínas/genética , Telomerasa/genética , Estados Unidos , Dedos de Zinc/genéticaRESUMEN
The highly polymorphic melanocortin 1 receptor (MC1R) gene plays a crucial role in pigmentation. Variants of the gene have been implicated in risk of cutaneous squamous cell carcinoma (SCC) in the general population. In renal transplant (RT) recipients these cancers are more aggressive and very common. To evaluate the risk of SCC relative to MC1R and the pigmentation-associated genes ASIP, TYR, and TYRP1, a group of 217 RT recipients with and without SCC was genotyped. Associations with SCC risk were indicated in carriers of the red hair color associated MC1R variant p.Arg151Cys (OR = 1.99; 1.05-3.75), and in carriers of two of any of the MC1R variants disclosed (OR = 2.36; 1.08-5.15). These associations appeared independent of traditionally protective phenotypes, also supported by the stratifications from skin phototype and hair color. A tendency towards an increased SCC risk was observed for a specific ASIP haplotype (OR = 1.87; 0.91-3.83), while no such associations were observed for the TYR and TYRP1 variants. Thus, the risk of developing SCC in RT patients is modulated by MC1R variation irrespective of phenotypes considered to be protective. Heterozygous combinations of MC1R variants appear to be more relevant in assessing SCC risk than the effects of variants individually.
RESUMEN
Allelic variants of the low-penetrance melanoma gene MC1R increase the risk of both melanoma and non-melanoma skin cancer. Common variants of the genes ASIP, TYR, and TYRP1, which regulate the melanogenic pathway, have also been shown to associate with melanoma. In this population-based study, we investigated SNPs of MC1R, ASIP, TYR, and TYRP1 as risk factors for development of multiple primary melanomas (MPM) in 388 Norwegian cases. The MPM patients had a significantly higher likelihood of carrying any MC1R variant than the control group of 420 blood donors [86.8 vs. 78.3%, OR = 1.73, and confidence intervals (CI) 1.18-2.52]. When MC1R variants were analyzed individually, Asp84Glu and Arg151Cys were significantly more frequent among the MPM cases than among the controls (OR = 5.77, CI 1.97-16.90, and OR = 1.80, CI 1.36-2.37, respectively). In addition, there was an allele dose-dependent increase in MPM risk for carriers of red hair color (RHC) MC1R variants. The AH haplotype of ASIP was also a significant risk factor for MPM development (OR = 1.72 and CI 1.12-2.49), whereas no association was observed for previously reported risk variants of the TYR and TYRP1 genes. In summary, by using a population-based material of high-risk melanoma cases, we demonstrate a significant effect of both MC1R RHC variants and an ASIP haplotype, but could not replicate an association with postulated risk SNPs of TYR and TYRP1.
