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.

中文翻译：

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独特的POLE核酸外切酶结构域突变体的突变过程驱动了大肠癌中特定TP53突变的富集。

在聚合酶Epsilon（POLE）的核酸外切酶结构域中发生突变的癌症基因组呈现出异常高的体细胞突变负担。体外研究表明，不同的POLE突变体表现出不同的聚合酶活性。但是，尚不清楚由不同的POLE突变体引起的全基因组突变模式和驱动程序突变的形成。在这里，我们从已发表的研究和公开数据库中的7,345例大肠癌样本中筛选出了体细胞突变。其中包括44个POLE突变体样品，其中9个具有完整的基因组测序数据。根据存在的特定POLE突变对POLE突变体样本进行分类。在不同的POLE突变体中检查了突变谱，体细胞突变与表观基因组学特征的关联以及与特定驱动程序突变的共现。我们发现，不同的POLE突变体表现出独特的突变谱，并且在POLE V411L突变体中C> T突变的相对频率明显更高。我们的分析表明，C> T突变的这种增加频率不依赖于DNA甲基化，也不与其他基因组特征相关，因此特别是仅由于DNA序列的背景。值得注意的是，我们发现TP53 R213 *突变与POLE P286R突变体特别相关。这种截短突变发生在TT [C> T] GA环境中。对于C> T突变，与其他POLE核酸外切酶域突变体相比，该序列上下文在POLE P286R突变体中更可能发生突变。