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首页> 外文期刊>PLoS Genetics >Mutational processes of distinct POLE exonuclease domain mutants drive an enrichment of a specific TP53 mutation in colorectal cancer
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Mutational processes of distinct POLE exonuclease domain mutants drive an enrichment of a specific TP53 mutation in colorectal cancer

机译：不同杆外切核酸酶域突变体的突变过程驱动了结直肠癌中特异性TP53突变的富集

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Cancer genomes with mutations in the exonuclease domain of Polymerase Epsilon (POLE) present with an extraordinarily high somatic mutation burden. In vitro studies have shown that distinct POLE mutants exhibit different polymerase activity. Yet, genome-wide mutation patterns and driver mutation formation arising from different POLE mutants remains unclear. Here, we curated somatic mutation calls from 7,345 colorectal cancer samples from published studies and publicly available databases. These include 44 POLE mutant samples including 9 with whole genome sequencing data available. The POLE mutant samples were categorized based on the specific POLE mutation present. Mutation spectrum, associations of somatic mutations with epigenomics features and co-occurrence with specific driver mutations were examined across different POLE mutants. We found that different POLE mutants exhibit distinct mutation spectrum with significantly higher relative frequency of C&T mutations in POLE V411L mutants. Our analysis showed that this increase frequency in C&T mutations is not dependent on DNA methylation and not associated with other genomic features and is thus specifically due to DNA sequence context alone. Notably, we found strong association of the TP53 R213* mutation specifically with POLE P286R mutants. This truncation mutation occurs within the TT[C&T]GA context. For C&T mutations, this sequence context is significantly more likely to be mutated in POLE P286R mutants compared with other POLE exonuclease domain mutants. This study refines our understanding of DNA polymerase fidelity and underscores genome-wide mutation spectrum and specific cancer driver mutation formation observed in POLE mutant cancers.
机译：具有聚合酶ε（极）的外切核酸酶域（极）的癌症基因组，存在具有极高的体细胞突变负担。体外研究表明，不同的极突变体表现出不同的聚合酶活性。然而，由不同杆突变体产生的基因组 - 范围突变模式和驾驶员突变形成仍然不清楚。在这里，我们从发布的研究和公开的数据库中策划了来自7,345种结肠直肠癌样本的体细胞突变呼叫。这些包括44极突变体样本，包括具有全基因组测序数据的9。杆突变体样品基于存在的特定极突变分类。在不同的极突变体中检查突变谱，细胞突变与表观瘤特征和与特定驾驶员突变的共发生的缔合。我们发现不同的极突变体表现出明显的突变光谱，具有显着高于C＆GT的相对频率的磁共振突变突变突变。我们的分析表明，C＆GT突变中的这种增加频率不依赖于DNA甲基化并且与其他基因组特征无关，因此特别是单独的DNA序列上下文。值得注意的是，我们发现TP53 R213 *突变的强烈关联，具体地用杆P286R突变体。此截断突变发生在TT [C＆GT; T] GA上下文中。对于C＆GT; T突变，与其他杆外切核酸酶结构域突变体相比，该序列环境显着更容易在极P286R突变体中突变。本研究改善了我们对DNA聚合酶保真度的理解，并且在极突变癌中观察到的基因组范围的突变谱和特异性癌症驱动突变形成。

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