The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
Cell. 2012 Jul 20;150(2):251-63. doi: 10.1016/j.cell.2012.06.024.
Despite recent insights into melanoma genetics, systematic surveys for driver mutations are challenged by an abundance of passenger mutations caused by carcinogenic UV light exposure. We developed a permutation-based framework to address this challenge, employing mutation data from intronic sequences to control for passenger mutational load on a per gene basis. Analysis of large-scale melanoma exome data by this approach discovered six novel melanoma genes (PPP6C, RAC1, SNX31, TACC1, STK19, and ARID2), three of which-RAC1, PPP6C, and STK19-harbored recurrent and potentially targetable mutations. Integration with chromosomal copy number data contextualized the landscape of driver mutations, providing oncogenic insights in BRAF- and NRAS-driven melanoma as well as those without known NRAS/BRAF mutations. The landscape also clarified a mutational basis for RB and p53 pathway deregulation in this malignancy. Finally, the spectrum of driver mutations provided unequivocal genomic evidence for a direct mutagenic role of UV light in melanoma pathogenesis.
尽管最近对黑色素瘤遗传学有了深入的了解,但由于致癌 UV 光暴露导致的大量乘客突变,系统地寻找驱动突变仍然具有挑战性。我们开发了一种基于排列的框架来解决这一挑战,该框架利用内含子序列中的突变数据,根据每个基因的基础来控制乘客突变负荷。通过这种方法对大规模黑色素瘤外显子组数据的分析发现了六个新的黑色素瘤基因(PPP6C、RAC1、SNX31、TACC1、STK19 和 ARID2),其中三个基因(RAC1、PPP6C 和 STK19)存在反复出现的潜在可靶向突变。与染色体拷贝数数据的整合使驱动突变的景观具体化,为 BRAF 和 NRAS 驱动的黑色素瘤以及没有已知 NRAS/BRAF 突变的黑色素瘤提供了致癌见解。该景观还阐明了 RB 和 p53 通路在这种恶性肿瘤中失调的突变基础。最后,驱动突变的频谱为 UV 光在黑色素瘤发病机制中的直接诱变作用提供了明确的基因组证据。