Melanoma is a cancer of melanocytes, with multiple subtypes based on body site location. Cutaneous melanoma is associated with skin exposed to ultraviolet radiation; uveal melanoma occurs in the eyes; mucosal melanoma occurs in internal mucous membranes; and acral melanoma occurs on the palms, soles, and nail beds. Here, we present the largest whole-genome sequencing study of melanoma to date, with 570 tumors profiled, as well as methylation and RNA sequencing for subsets of tumors. Uveal melanoma is genomically distinct from other melanoma subtypes, harboring the lowest tumor mutation burden and with significantly mutated genes in the G-protein signaling pathway. Most cutaneous, acral, and mucosal melanomas share alterations in components of the MAPK, PI3K, p53, p16, and telomere pathways. However, the mechanism by which these pathways are activated or inactivated varies between melanoma subtypes. Additionally, we identify potential novel germline predisposition genes for some of the less common melanoma subtypes. Significance: This is the largest whole-genome analysis of melanoma to date, comprehensively comparing the genomics of the four major melanoma subtypes. This study highlights both similarities and differences between the subtypes, providing insights into the etiology and biology of melanoma. This article is highlighted in the In This Issue feature, p. 2711

中文翻译：

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比较基因组学为黑色素瘤亚型提供病因学和生物学见解


黑色素瘤是一种黑色素细胞癌症，根据身体部位的不同，有多种亚型。皮肤黑色素瘤与皮肤暴露于紫外线辐射有关。葡萄膜黑色素瘤发生在眼睛中；粘膜黑色素瘤发生于内粘膜；肢端黑色素瘤发生在手掌、脚底和甲床。在这里，我们提出了迄今为止最大的黑色素瘤全基因组测序研究，对 570 个肿瘤进行了分析，并对部分肿瘤进行了甲基化和 RNA 测序。葡萄膜黑色素瘤在基因组上与其他黑色素瘤亚型不同，其肿瘤突变负担最低，并且 G 蛋白信号通路中的基因显着突变。大多数皮肤、肢端和粘膜黑色素瘤的 MAPK、PI3K、p53、p16 和端粒通路成分均发生改变。然而，这些途径被激活或失活的机制因黑色素瘤亚型而异。此外，我们还发现了一些不太常见的黑色素瘤亚型的潜在新型种系易感基因。意义：这是迄今为止最大的黑色素瘤全基因组分析，全面比较了四种主要黑色素瘤亚型的基因组。这项研究强调了亚型之间的相似性和差异，为黑色素瘤的病因学和生物学提供了见解。这篇文章在本期特稿中重点介绍，第 17 页。 2711