Laboratorio Internacional de Investigación sobre el Genoma Humano, Universidad Nacional Autónoma de México, Santiago de Querétaro, México 76230, USA.
Cancer, Ageing and Somatic Mutation, Wellcome Sanger Institute, Hinxton, Cambridgeshire CB101SA, UK.
Hum Mol Genet. 2022 Aug 25;31(17):2845-2856. doi: 10.1093/hmg/ddac074.
A number of genomic regions have been associated with melanoma risk through genome-wide association studies; however, the causal variants underlying the majority of these associations remain unknown. Here, we sequenced either the full locus or the functional regions including exons of 19 melanoma-associated loci in 1959 British melanoma cases and 737 controls. Variant filtering followed by Fisher's exact test analyses identified 66 variants associated with melanoma risk. Sequential conditional logistic regression identified the distinct haplotypes on which variants reside, and massively parallel reporter assays provided biological insights into how these variants influence gene function. We performed further analyses to link variants to melanoma risk phenotypes and assessed their association with melanoma-specific survival. Our analyses replicate previously known associations in the melanocortin 1 receptor (MC1R) and tyrosinase (TYR) loci, while identifying novel potentially causal variants at the MTAP/CDKN2A and CASP8 loci. These results improve our understanding of the architecture of melanoma risk and outcome.
一些基因组区域已经通过全基因组关联研究与黑色素瘤风险相关联；然而，这些关联中的大多数潜在的因果变异仍然未知。在这里，我们对 1959 名英国黑色素瘤病例和 737 名对照者的 19 个黑色素瘤相关基因座的全长基因座或包括外显子在内的功能区域进行了测序。经过变体过滤和 Fisher 精确检验分析，鉴定出与黑色素瘤风险相关的 66 个变体。连续条件逻辑回归确定了变异所在的独特单倍型，并通过大规模平行报告基因分析提供了关于这些变异如何影响基因功能的生物学见解。我们进行了进一步的分析，将变异与黑色素瘤风险表型联系起来，并评估了它们与黑色素瘤特异性生存的关联。我们的分析复制了在黑素皮质素 1 受体（MC1R）和酪氨酸酶（TYR）基因座中已知的关联，同时在 MTAP/CDKN2A 和 CASP8 基因座中鉴定出了新的潜在因果变异。这些结果提高了我们对黑色素瘤风险和结果的结构的理解。
