Comprehensive Genetic Landscape of Uveal Melanoma by Whole-Genome Sequencing
Comprehensive Genetic Landscape of Uveal Melanoma by Whole-Genome Sequencing
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DOI：
10.1016/j.ajhg.2016.09.008
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发表时间：
2016-11-03
影响因子：
9.8
通讯作者：
Rivolta, Carlo
中科院分区：
文献类型：
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作者：
Royer-Bertrand, Beryl;Torsello, Matteo;Rivolta, Carlo
葡萄膜黑色素瘤(UM)是一种罕见的眼内肿瘤，类似于皮肤黑色素瘤，起源于黑素细胞。为了了解其遗传学，我们对33个样本(24个原发肿瘤和9个转移瘤)进行了非常深入的肿瘤对照对的全基因组测序。在整个基因组范围内，编码突变的数量相当低(每个肿瘤平均只有17个变异；范围为7-28)，因此与皮肤黑色素瘤截然不同，皮肤黑色素瘤通常会检测到数百种外显子DNA侮辱。此外，没有鉴定出紫外光诱导的突变特征。在已知的UM驱动基因GNAQ GNA11、BAP1、EIF1AX和SF3B1中发现了反复的编码突变。其他基因，即TP53BP1、CSMD1、TTC28、DLK2和KTN1，也被发现在一个以上的个体中含有体细胞突变，可能表明与UM的发病机制以前未被描述的关联。来自非编码DNA的未匹配读数的从头组装揭示了定义特定UM亚型的特殊拷贝数变异，这反过来可能与转移转化有关。突变驱动的与其他肿瘤类型的比较表明，UM与儿科肿瘤非常相似，特征是很少有躯体侮辱，可能还有重要的表观遗传学变化。通过对全基因组测序数据的分析，我们的发现为葡萄膜黑色素瘤的分子遗传学提供了新的线索，描述了它是一种成人的非典型肿瘤，对于这种肿瘤来说，除了外显子DNA突变之外的躯体事件塑造了它的遗传格局，并确定了它的转移潜力。
Uveal melanoma (UM) is a rare intraocular tumor that, similar to cutaneous melanoma, originates from melanocytes. To gain insights into its genetics, we performed whole-genome sequencing at very deep coverage of tumor-control pairs in 33 samples (24 primary and 9 metastases). Genome-wide, the number of coding mutations was rather low (only 17 variants per tumor on average; range 7-28), thus radically different from cutaneous melanoma, where hundreds of exonic DNA insults are usually detected. Furthermore, no UV light-induced mutational signature was identified. Recurrent coding mutations were found in the known UM drivers GNAQ GNA11, BAP1, EIF1AX, and SF3B1. Other genes, i.e., TP53BP1, CSMD1, TTC28, DLK2, and KTN1, were also found to harbor somatic mutations in more than one individual, possibly indicating a previously undescribed association with UM pathogenesis. De novo assembly of unmatched reads from non-coding DNA revealed peculiar copy-number variations defining specific UM subtypes, which in turn could be associated with metastatic transformation. Mutational-driven comparison with other tumor types showed that UM is very similar to pediatric tumors, characterized by very few somatic insults and, possibly, important epigenetic changes. Through the analysis of whole-genome sequencing data, our findings shed new light on the molecular genetics of uveal melanoma, delineating it as an atypical tumor of the adult for which somatic events other than mutations in exonic DNA shape its genetic landscape and define its metastatic potential.