PDF(Pubmed)
Abstract：
DNA repair deficiencies in cancers may result in characteristic mutational patterns, as exemplified by deficiency of BRCA1/2 and efficacy prediction for PARP inhibitors. We trained and evaluated predictive models for loss-of-function (LOF) of 145 individual DNA damage response genes based on genome-wide mutational patterns, including structural variants, indels, and base-substitution signatures. We identified 24 genes whose deficiency could be predicted with good accuracy, including expected mutational patterns for BRCA1/2, MSH3/6, TP53, and CDK12 LOF variants. CDK12 is associated with tandem duplications, and we here demonstrate that this association can accurately predict gene deficiency in prostate cancers (area under the receiver operator characteristic curve = 0.97). Our novel associations include mono- or biallelic LOF variants of ATRX, IDH1, HERC2, CDKN2A, PTEN, and SMARCA4, and our systematic approach yielded a catalogue of predictive models, which may provide targets for further research and development of treatment, and potentially help guide therapy.
Many different aspects of the environment – such as ultraviolet radiation, carcinogens in food and drink, and the ageing process itself – damage the DNA in human cells. Normally, cells can repair these sites by activating a mechanism known as the DNA damage response. However, the hundreds of genes that orchestrate this response are also themselves often lost or damaged, allowing the unrepaired sites to turn into permanent mutations that accumulate across the genome of the cancer cell. By studying the DNA of cancer cells, it has been possible to identify characteristic patterns of mutations, called mutational signatures, that appear in different types of cancer. One specific pattern has been linked to the loss of either the BRCA1 or BRCA2 gene, both of which are part of the DNA damage response. However, it remained unclear how many other genes involved in the DNA damage response also lead to detectable mutational signatures when lost. To investigate, Sørensen et al. computationally analysed data from over six thousand cancer patients. They looked for associations between over 700 DNA damage response genes and 80 different mutational signatures. As expected, the analysis revealed a strong connection between the loss of BRCA1/BRCA2 and their known mutational signature. However, it also found 23 other associations between DNA damage response genes that had been lost or damaged and particular patterns of mutations in a variety of cancers. These findings suggest that mutational signatures could be used more widely to predict which DNA damage response genes are no longer functioning in the genome of cancer cells. The mutational signature caused by the loss of BRAC1/BRAC2 has been shown to make patients more responsive to a certain type of chemotherapy. Further experiments are needed to determine whether the connections identified by Sørensen et al. could also provide information on which treatment would benefit a cancer patient the most. In the future, this might help medical practitioners provide more personalized treatment.
Many different aspects of the environment – such as ultraviolet radiation, carcinogens in food and drink, and the ageing process itself – damage the DNA in human cells. Normally, cells can repair these sites by activating a mechanism known as the DNA damage response. However, the hundreds of genes that orchestrate this response are also themselves often lost or damaged, allowing the unrepaired sites to turn into permanent mutations that accumulate across the genome of the cancer cell. By studying the DNA of cancer cells, it has been possible to identify characteristic patterns of mutations, called mutational signatures, that appear in different types of cancer. One specific pattern has been linked to the loss of either the BRCA1 or BRCA2 gene, both of which are part of the DNA damage response. However, it remained unclear how many other genes involved in the DNA damage response also lead to detectable mutational signatures when lost. To investigate, Sørensen et al. computationally analysed data from over six thousand cancer patients. They looked for associations between over 700 DNA damage response genes and 80 different mutational signatures. As expected, the analysis revealed a strong connection between the loss of BRCA1/BRCA2 and their known mutational signature. However, it also found 23 other associations between DNA damage response genes that had been lost or damaged and particular patterns of mutations in a variety of cancers. These findings suggest that mutational signatures could be used more widely to predict which DNA damage response genes are no longer functioning in the genome of cancer cells. The mutational signature caused by the loss of BRAC1/BRAC2 has been shown to make patients more responsive to a certain type of chemotherapy. Further experiments are needed to determine whether the connections identified by Sørensen et al. could also provide information on which treatment would benefit a cancer patient the most. In the future, this might help medical practitioners provide more personalized treatment.
摘要：
癌症中的DNA修复缺陷可能会导致特征性的突变模式，例如BRCA1/2缺乏和PARP抑制剂的疗效预测。我们训练并评估了基于全基因组突变模式的145个个体DDR基因的功能丧失（LOF）的预测模型。包括结构变体，indels,和碱基替换签名。我们确定了24个基因，其缺陷可以很好地预测，包括BRCA1/2、MSH3/6、TP53和CDK12LOF变体的预期突变模式。CDK12与串联复制相关，我们在这里证明了这种关联可以准确预测前列腺癌的基因缺陷（ROC曲线下面积=0.97）。我们的新关联包括ATRX的单-或双等位基因LOF变体，IDH1,HERC2,CDKN2A,PTEN,和SMARCA4，我们的系统方法产生了一系列预测模型，这可能为进一步的治疗研究和发展提供目标，并可能帮助指导治疗。
