The landscape and driver potential of site-specific hotspots across cancer genomes.
The landscape and driver potential of site-specific hotspots across cancer genomes.
复制标题
DOI：
10.1038/s41525-021-00197-6
复制
发表时间：
2021-05-13
影响因子：
5.3
通讯作者：
Pedersen JS
中科院分区：
文献类型：
--
作者：
Juul RI;Nielsen MM;Juul M;Feuerbach L;Pedersen JS
大量的癌症全基因组使研究全基因组突变热点成为可能。在这里，我们使用来自泛癌症全基因组分析项目的2279个全癌症基因组来检测、分类和表征位点特异性热点，并提供全基因组注释热点资源。我们研究了蛋白质编码区和基因调控区热点的过剩，并制定了对个体热点的正选择和功能影响的措施。利用癌症等位基因分数、表达畸变、突变特征和各种基因组特征，如转录因子结合位点的潜在增益或损失，我们注释并优先考虑所有高度突变的热点。在全基因组范围内，我们发现高频SNV和indel热点比给定突变背景模型的预期要多。与其他区域相比，SNV热点的蛋白质编码区通常富集。基因调控热点显示出潜在的同患者二击错义突变的富集，与单个基因相比，热点驱动突变的富集是一致的。对于蛋白质编码区、剪接位点、启动子和增强子，我们看到了与癌症基因相关的过量热点。有趣的是，肿瘤抑制因子的错义热点突变与表达升高相关，表明局部氨基酸变化具有功能影响。对于单个非编码热点，只有少数显示出明确的正选择迹象，包括TERT启动子和TP53的5 ' UTR中的已知位点。大多数新的候选基因几乎没有突变，驱动证据也有限。然而，癌基因POU2AF1增强子中的一个热点可能会产生转录因子结合位点，这提供了多条与驱动因素一致的证据。
Large sets of whole cancer genomes make it possible to study mutation hotspots genome-wide. Here we detect, categorize, and characterize site-specific hotspots using 2279 whole cancer genomes from the Pan-Cancer Analysis of Whole Genomes project and provide a resource of annotated hotspots genome-wide. We investigate the excess of hotspots in both protein-coding and gene regulatory regions and develop measures of positive selection and functional impact for individual hotspots. Using cancer allele fractions, expression aberrations, mutational signatures, and a variety of genomic features, such as potential gain or loss of transcription factor binding sites, we annotate and prioritize all highly mutated hotspots. Genome-wide we find more high-frequency SNV and indel hotspots than expected given mutational background models. Protein-coding regions are generally enriched for SNV hotspots compared to other regions. Gene regulatory hotspots show enrichment of potential same-patient second-hit missense mutations, consistent with enrichment of hotspot driver mutations compared to singletons. For protein-coding regions, splice-sites, promoters, and enhancers, we see an excess of hotspots associated with cancer genes. Interestingly, missense hotspot mutations in tumor suppressors are associated with elevated expression, suggesting localized amino-acid changes with functional impact. For individual non-coding hotspots, only a small number show clear signs of positive selection, including known sites in the TERT promoter and the 5’ UTR of TP53. Most of the new candidates have few mutations and limited driver evidence. However, a hotspot in an enhancer of the oncogene POU2AF1, which may create a transcription factor binding site, presents multiple lines of driver-consistent evidence.
登录
查看更多内容
影响因子：
9.9
作者：
Buljan M;Blattmann P;Aebersold R;Boutros M
通讯作者：
Boutros M
影响因子：
8.8
作者：
Jayasinghe RG;Cao S;Gao Q;Wendl MC;Vo NS;Reynolds SM;Zhao Y;Climente-González H;Chai S;Wang F;Varghese R;Huang M;Liang WW;Wyczalkowski MA;Sengupta S;Li Z;Payne SH;Fenyö D;Miner JH;Walter MJ;Cancer Genome Atlas Research Network;Vincent B;Eyras E;Chen K;Shmulevich I;Chen F;Ding L
通讯作者：
Ding L
DOI：
10.1038/nrc1299
发表时间：
2004-03
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
--
影响因子：
4
作者：
Alexandrov, Ludmil B.;Stratton, Michael R.
通讯作者：
Stratton, Michael R.
弥漫性大 B 细胞淋巴瘤中超级增强子相关依赖性的发现和表征。
影响因子：
50.3
作者：
Chapuy B;McKeown MR;Lin CY;Monti S;Roemer MG;Qi J;Rahl PB;Sun HH;Yeda KT;Doench JG;Reichert E;Kung AL;Rodig SJ;Young RA;Shipp MA;Bradner JE
通讯作者：
Bradner JE