The Genetic Evolution of Melanoma from Precursor Lesions
The Genetic Evolution of Melanoma from Precursor Lesions
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DOI：
10.1056/nejmoa1502583
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发表时间：
2015-11-12
影响因子：
158.5
通讯作者：
Bastian, Boris C.
中科院分区：
文献类型：
--
作者：
Shain, A. Hunter;Yeh, Iwei;Bastian, Boris C.
背景黑色素瘤的致病基因突变已被很大程度地分类，但其发生的顺序尚不清楚。方法我们对37个原发黑色素瘤及其邻近的前驱病变的150个区域的293个癌相关基因进行了测序。这些区域的组织病理图谱包括明确的良性病变、中间病变和表皮内或侵袭性黑色素瘤。结果复发病变是由已知激活丝裂原活化蛋白激酶途径的基因突变引起的。明确的良性病变专门含有BRAF V600E突变，而那些被归类为中间病变的病变富含NRAS突变和额外的驱动突变。共有77%的中间病变和黑色素瘤原位区域存在TERT启动子突变，这一发现表明这些突变是在肿瘤进展的出人意料的早期阶段选择的。CDKN2A双等位基因失活仅见于侵袭性黑色素瘤。仅在进展期原发性黑色素瘤中发现PTEN和TP53突变。从良性病变到中间病变再到黑色素瘤，点突变的负担增加，在所有进化阶段都能检测到紫外线辐射的强烈影响。拷贝数改变仅在侵袭性黑色素瘤中流行。随着黑色素瘤的进展，肿瘤异质性变得明显，表现为遗传上不同的亚群。结论本研究定义了黑色素瘤进展过程中的基因变化序列，显示了不同黑色素瘤亚型的不同进化轨迹。它确定了一种中间类型的黑素细胞肿瘤，其特征是存在一种以上的致病基因改变和独特的组织病理学特征。最后，我们的研究表明紫外线辐射是黑色素瘤发生和发展的主要因素。(由美国国立卫生研究院和其他机构资助。)
BACKGROUNDThe pathogenic mutations in melanoma have been largely catalogued; however, the order of their occurrence is not known.METHODSWe sequenced 293 cancer-relevant genes in 150 areas of 37 primary melanomas and their adjacent precursor lesions. The histopathological spectrum of these areas included unequivocally benign lesions, intermediate lesions, and intraepidermal or invasive melanomas.RESULTSPrecursor lesions were initiated by mutations of genes that are known to activate the mitogen-activated protein kinase pathway. Unequivocally benign lesions harbored BRAF V600E mutations exclusively, whereas those categorized as intermediate were enriched for NRAS mutations and additional driver mutations. A total of 77% of areas of intermediate lesions and melanomas in situ harbored TERT promoter mutations, a finding that indicates that these mutations are selected at an unexpectedly early stage of the neoplastic progression. Biallelic inactivation of CDKN2A emerged exclusively in invasive melanomas. PTEN and TP53 mutations were found only in advanced primary melanomas. The point-mutation burden increased from benign through intermediate lesions to melanoma, with a strong signature of the effects of ultraviolet radiation detectable at all evolutionary stages. Copy-number alterations became prevalent only in invasive melanomas. Tumor heterogeneity became apparent in the form of genetically distinct subpopulations as melanomas progressed.CONCLUSIONSOur study defined the succession of genetic alterations during melanoma progression, showing distinct evolutionary trajectories for different melanoma subtypes. It identified an intermediate category of melanocytic neoplasia, characterized by the presence of more than one pathogenic genetic alteration and distinctive histopathological features. Finally, our study implicated ultraviolet radiation as a major factor in both the initiation and progression of melanoma. (Funded by the National Institutes of Health and others.)