Genome-wide mapping of somatic mutation rates uncovers drivers of cancer.
Genome-wide mapping of somatic mutation rates uncovers drivers of cancer.
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DOI：
10.1038/s41587-022-01353-8
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发表时间：
2022-11
影响因子：
46.9
通讯作者：
Berger, Bonnie
中科院分区：
文献类型：
--
作者：
Sherman, Maxwell A.;Yaari, Adam U.;Priebe, Oliver;Dietlein, Felix;Loh, Po-Ru;Berger, Bonnie
鉴定赋予增殖优势的癌症驱动突变是理解癌症的核心;然而，由于对在肿瘤基因组中观察到的高度可变的体细胞突变率进行建模的挑战，搜索通常限于蛋白质编码序列和特定的非编码元件（例如，启动子）。在这里，我们提出了Dig，一种在基因组中搜索驱动元件和突变的方法。我们使用深度神经网络以千碱基级分辨率在全基因组范围内绘制癌症特异性突变率。然后，通过比较观察到的突变计数与预期的突变计数，对这些估计值进行细化，以在整个基因组中搜索正选择下的驱动突变的证据。我们绘制了37种癌症类型的突变率，并应用这些图谱来识别内含子隐蔽剪接区、5′非翻译区和不常突变基因中的推定驱动因子。我们的高分辨率突变率地图，可用于基于网络的探索，是一个资源，使驱动程序发现全基因组。通过预测整个基因组的中性突变率来识别癌症驱动突变。
Identification of cancer driver mutations that confer a proliferative advantage is central to understanding cancer; however, searches have often been limited to protein-coding sequences and specific non-coding elements (for example, promoters) because of the challenge of modeling the highly variable somatic mutation rates observed across tumor genomes. Here we present Dig, a method to search for driver elements and mutations anywhere in the genome. We use deep neural networks to map cancer-specific mutation rates genome-wide at kilobase-scale resolution. These estimates are then refined to search for evidence of driver mutations under positive selection throughout the genome by comparing observed to expected mutation counts. We mapped mutation rates for 37 cancer types and applied these maps to identify putative drivers within intronic cryptic splice regions, 5′ untranslated regions and infrequently mutated genes. Our high-resolution mutation rate maps, available for web-based exploration, are a resource to enable driver discovery genome-wide. Cancer driver mutations are identified by predicting neutral mutation rates across the entire genome.
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影响因子：
64.8
作者：
Ghandi, Mahmoud;Huang, Franklin W.;Sellers, William R.
通讯作者：
Sellers, William R.
影响因子：
4.8
作者：
Chan, Michael;Huang, Yi-Wen;Lin, Huey-Jen L.
通讯作者：
Lin, Huey-Jen L.
影响因子：
64.8
作者：
Karczewski, Konrad J;Francioli, Laurent C;MacArthur, Daniel G
通讯作者：
MacArthur, Daniel G
DOI：
10.1016/j.jbc.2021.100374
发表时间：
2021-01
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Kang TZE;Zhu L;Yang D;Ding D;Zhu X;Wan YCE;Liu J;Ramakrishnan S;Chan LL;Chan SY;Wang X;Gan H;Han J;Ishibashi T;Li Q;Chan KM
通讯作者：
Chan KM
影响因子：
30.8
作者：
Dietlein, Felix;Weghorn, Donate;Sunyaev, Shamil R.
通讯作者：
Sunyaev, Shamil R.