RepairSig: Deconvolution of DNA damage and repair contributions to the mutational landscape of cancer
RepairSig: Deconvolution of DNA damage and repair contributions to the mutational landscape of cancer
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RepairSig：DNA 损伤的解卷积和修复对癌症突变景观的贡献
DOI：
10.1101/2020.11.21.392878
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发表时间：
2020
期刊：
影响因子：
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通讯作者：
T. Przytycka
中科院分区：
文献类型：
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作者：
Damian Wójtowicz;Jan Hoinka;Bayarbaatar Amgalan;Y. Kim;T. Przytycka
许多诱变过程在癌症基因组上留下特征性印记，称为突变标记。这些特征最近引起了人们的兴趣，因为它们在研究塑造癌症突变景观的过程中的适用性。特别是，查明DNA修复途径改变的存在可能具有重要的治疗意义。然而，DNA修复缺陷的突变特征往往很难推断。这一挑战是由于DNA修复过程缺陷通过改变其他诱变剂的结果而起作用。因此，它们表现出非加性效应，而这些非加性效应不是由当前用于将突变过程建模为独立签名的范例所描绘的。为了缩小这一差距，我们提出了RepairSig，这是一种解释DNA损伤和修复之间相互作用的方法，能够发现缺陷DNA修复过程的无偏特征。特别是，RepairSig能够取代先前提出的在乳腺癌中活跃的三个MMR缺陷签名，只有一个签名与实验得出的签名惊人相似。作为第一种对诱变过程之间的相互作用进行建模的方法，RepairSig是对癌症中的突变过程进行生物学更真实建模的重要一步。RepairSig的源代码可在https://github.com/ncbi/RepairSig上公开获得。
Many mutagenic processes leave characteristic imprints on cancer genomes known as mutational signatures. These signatures have been of recent interest regarding their applicability in studying processes shaping the mutational landscape of cancer. In particular, pinpointing the presence of altered DNA repair pathways can have important therapeutic implications. However, mutational signatures of DNA repair deficiencies are often hard to infer. This challenge emerges as a result of deficient DNA repair processes acting by modifying the outcome of other mutagens. Thus, they exhibit non-additive effects that are not depicted by the current paradigm for modeling mutational processes as independent signatures. To close this gap, we present RepairSig, a method that accounts for interactions between DNA damage and repair and is able to uncover unbiased signatures of deficient DNA repair processes. In particular, RepairSig was able to replace three MMR deficiency signatures previously proposed to be active in breast cancer, with just one signature strikingly similar to the experimentally derived signature. As the first method to model interactions between mutagenic processes, RepairSig is an important step towards biologically more realistic modeling of mutational processes in cancer. The source code for RepairSig is publicly available at https://github.com/ncbi/RepairSig.
DOI：
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发表时间：
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期刊：
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影响因子：
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作者：
Yanjiao Zhou;Hongyu Gao;K. Mihindukulasuriya;P. S. L. Rosa;K. Wylie;Tatiana Vishnivetskaya;M. Podar;B. Warner;P. Tarr;David E. Nelson;J. D. Fortenberry;Martin J Holland;S. Burr;W. Shannon;E. Sodergren;G. Weinstock;Patricio S;La Rosa;J. D. Fortenberry;Martin J Holland
通讯作者：
Yanjiao Zhou;Hongyu Gao;K. Mihindukulasuriya;P. S. L. Rosa;K. Wylie;Tatiana Vishnivetskaya;M. Podar;B. Warner;P. Tarr;David E. Nelson;J. D. Fortenberry;Martin J Holland;S. Burr;W. Shannon;E. Sodergren;G. Weinstock;Patricio S;La Rosa;J. D. Fortenberry;Martin J Holland
影响因子：
12.3
作者：
Kim, Yoo-Ah;Wojtowicz, Damian;Przytycka, Teresa M.
通讯作者：
Przytycka, Teresa M.
影响因子：
11.1
作者：
Moldovan GL;D'Andrea AD
通讯作者：
D'Andrea AD