Correlation of homologous recombination deficiency induced mutational signatures with sensitivity to PARP inhibitors and cytotoxic agents
Correlation of homologous recombination deficiency induced mutational signatures with sensitivity to PARP inhibitors and cytotoxic agents
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DOI：
10.1186/s13059-019-1867-0
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发表时间：
2019-11-14
期刊：
影响因子：
12.3
通讯作者：
Szuets, David
中科院分区：
文献类型：
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作者：
Poti, Adam;Gyergyak, Hella;Szuets, David
由BRCA1或BRCA2缺陷引起的同源重组（HR）修复缺陷与体细胞突变的特征模式有关。在这项遗传研究中，我们询问HR通路的其他基因或DNA损伤检查点的失活突变是否也会产生可用于治疗预测的体细胞突变模式。结果通过对一个等基因敲除细胞系进行全基因组测序，我们发现了一个普遍的HR缺陷特异性碱基替换特征，与COSMIC特征3相似。相反，我们检测到不同的缺失表型对应于特定的HR突变。与BRCA1、RAD51或RAD54的破坏相比，BRCA2或PALB2的失活导致更大的缺失，通常具有微同源性。与Cas9切割位点的缺失谱比较表明，大多数自发产生的基因组缺失不是双链断裂的结果。令人惊讶的是，检查点激酶ATM和CHK2的失活没有致突变后果。研究基因中双等位基因失活突变的肿瘤外显子组分析证实了细胞系模型的有效性。我们提出了研究突变体对13种治疗药物的敏感性的综合分析，目的是将基因组诱变表型与药物敏感性联系起来。我们的研究结果表明，没有单一的基因组突变类别与常见治疗的敏感性完全相关，但COSMIC特征3对碱基取代的贡献，或不同特征的组合测量，可能相当好地预测铂和PARP抑制剂的敏感性。
BackgroundHomologous recombination (HR) repair deficiency arising from defects in BRCA1 or BRCA2 is associated with characteristic patterns of somatic mutations. In this genetic study, we ask whether inactivating mutations in further genes of the HR pathway or the DNA damage checkpoint also give rise to somatic mutation patterns that can be used for treatment prediction.ResultsUsing whole genome sequencing of an isogenic knockout cell line panel, we find a universal HR deficiency-specific base substitution signature that is similar to COSMIC signature 3. In contrast, we detect different deletion phenotypes corresponding to specific HR mutants. The inactivation of BRCA2 or PALB2 leads to larger deletions, typically with microhomology, when compared to the disruption of BRCA1, RAD51 paralogs, or RAD54. Comparison with the deletion spectrum of Cas9 cut sites suggests that most spontaneously arising genomic deletions are not the consequence of double-strand breaks. Surprisingly, the inactivation of checkpoint kinases ATM and CHK2 has no mutagenic consequences. Analysis of tumor exomes with biallelic inactivating mutations in the investigated genes confirms the validity of the cell line models. We present a comprehensive analysis of sensitivity of the investigated mutants to 13 therapeutic agents for the purpose of correlating genomic mutagenic phenotypes with drug sensitivity.ConclusionOur results suggest that no single genomic mutational class shows perfect correlation with sensitivity to common treatments, but the contribution of COSMIC signature 3 to base substitutions, or a combined measure of different features, may be reasonably good at predicting platinum and PARP inhibitor sensitivity.