Patterns of genomic evolution in advanced melanoma
Patterns of genomic evolution in advanced melanoma
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DOI：
10.1038/s41467-018-05063-1
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发表时间：
2018-07-10
影响因子：
16.6
通讯作者：
Lonning, P. E.
中科院分区：
文献类型：
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作者：
Birkeland, E.;Zhang, S.;Lonning, P. E.
在黑色素瘤进展过程中发生的基因组改变和由此产生的转移性沉积物之间的基因组异质性仍然不完全清楚。通过全外显子组测序（WES）分析了53例患者的86个转移性黑色素瘤沉积物，我们发现分支突变与主干突变的比例较低，转移间异质性很小，病灶之间几乎完全共享驱动突变。与紫外线损伤一致的分支突变表明转移可能来自原发肿瘤中的不同亚克隆。突变的BRAF等位基因的选择性获得作为早期事件发生，而全基因组重复（WGD）在约40%的情况下作为晚期主干事件发生。1例患者显示突变多样性升高，可能与既往化疗和DNA修复缺陷有关。在另一名接受放射治疗的淋巴结转移患者中，我们在随后的两次远处复发中检测到放射治疗相关的突变特征，与继发性转移播种一致。我们的发现增加了对转移性黑色素瘤基因组进化的理解。
Genomic alterations occurring during melanoma progression and the resulting genomic heterogeneity between metastatic deposits remain incompletely understood. Analyzing 86 metastatic melanoma deposits from 53 patients with whole-exome sequencing (WES), we show a low branch to trunk mutation ratio and little intermetastatic heterogeneity, with driver mutations almost completely shared between lesions. Branch mutations consistent with UV damage indicate that metastases may arise from different subclones in the primary tumor. Selective gain of mutated BRAF alleles occurs as an early event, contrasting whole-genome duplication (WGD) occurring as a late truncal event in about 40% of cases. One patient revealed elevated mutational diversity, probably related to previous chemotherapy and DNA repair defects. In another patient having received radiotherapy toward a lymph node metastasis, we detected a radiotherapy-related mutational signature in two subsequent distant relapses, consistent with secondary metastatic seeding. Our findings add to the understanding of genomic evolution in metastatic melanomas.