Roberts M R, Asgari M M, Toland A E
Department of Dermatology, Massachusetts General Hospital, Boston, MA, U.S.A.
Department of Population Medicine, Harvard Pilgrim Healthcare Institute, Boston, MA, U.S.A.
Br J Dermatol. 2019 Dec;181(6):1146-1155. doi: 10.1111/bjd.17917. Epub 2019 Jul 7.
Genome-wide association studies (GWAS) have identified thousands of susceptibility variants, although most have been associated with small individual risk estimates that offer little predictive value. However, combining multiple variants into polygenic risk scores (PRS) may be more informative. Multiple studies have developed PRS composed of GWAS-identified variants for cutaneous cancers. This review highlights data from these studies.
To review published GWAS and PRS studies for melanoma, cutaneous squamous cell carcinoma (cSCC) and basal cell carcinoma (BCC), and discuss their potential clinical utility.
We searched PubMed and the National Human Genome Research Institute-European Bioinformatics Institute GWAS catalogue to identify relevant studies.
Results from 21 GWAS (11 melanoma, 3 cSCC, 7 BCC) and 11 PRS studies are summarized. Six loci in pigmentation genes overlap between these three cancers (ASIP/RALY, IRF4, MC1R, OCA2, SLC45A2 and TYR). Additional loci overlap for cSCC/BCC and BCC/melanoma, but no other loci are shared between cSCC and melanoma. PRS for melanoma show roughly two-to-threefold increases in risk and modest improvements in risk prediction (2-7% increases). PRS are associated with twofold and threefold increases in risk of cSCC and BCC, respectively, with small improvements (2% increase) in predictive ability.
Existing data indicate that PRS may offer small, but potentially meaningful, improvements to risk prediction. Additional research is needed to clarify the potential utility of PRS in cutaneous carcinomas. Clinical translation will require well-powered validation studies incorporating known risk factors to evaluate PRS as tools for screening. What's already known about this topic? Over 50 susceptibility loci for melanoma, basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC) have been identified in genome-wide association studies (GWAS). Polygenic risk scores (PRS) using variants identified from GWAS have also been developed for melanoma, BCC and cSCC, and investigated with respect to clinical risk prediction. What does this study add? This review provides an overview of GWAS findings and the potential clinical utility of PRS for melanoma, BCC and cSCC.
全基因组关联研究（GWAS）已鉴定出数千个易感性变异，尽管大多数变异与个体风险估计值较小相关，几乎没有预测价值。然而，将多个变异组合成多基因风险评分（PRS）可能更具信息性。多项研究已开发出由GWAS鉴定的变异组成的用于皮肤癌的PRS。本综述重点介绍这些研究的数据。
回顾已发表的关于黑色素瘤、皮肤鳞状细胞癌（cSCC）和基底细胞癌（BCC）的GWAS和PRS研究，并讨论其潜在的临床应用价值。
我们检索了PubMed和国家人类基因组研究所 - 欧洲生物信息学研究所GWAS目录，以识别相关研究。
总结了21项GWAS（11项黑色素瘤、3项cSCC、7项BCC）和11项PRS研究的结果。这三种癌症在色素沉着基因中有6个位点重叠（ASIP/RALY、IRF4、MC1R、OCA2、SLC45A2和TYR）。cSCC/BCC和BCC/黑色素瘤之间还有其他重叠位点，但cSCC和黑色素瘤之间没有其他共享位点。黑色素瘤的PRS显示风险大致增加两到三倍，风险预测有适度改善（增加2 - 7%）。PRS分别与cSCC和BCC的风险增加两倍和三倍相关，预测能力有小幅改善（增加2%）。
现有数据表明，PRS可能会对风险预测有小幅但潜在有意义的改善。需要更多研究来阐明PRS在皮肤癌中的潜在应用价值。临床转化将需要有充分效力的验证研究，纳入已知风险因素以评估PRS作为筛查工具的效用。关于这个主题已经知道了什么？在全基因组关联研究（GWAS）中已鉴定出超过50个黑色素瘤、基底细胞癌（BCC）和皮肤鳞状细胞癌（cSCC）的易感位点。也已开发出使用从GWAS鉴定的变异的多基因风险评分（PRS）用于黑色素瘤、BCC和cSCC，并就临床风险预测进行了研究。这项研究增加了什么？本综述概述了GWAS的研究结果以及PRS对黑色素瘤、BCC和cSCC的潜在临床应用价值。
