School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region.
Prince of Wales Clinical School, UNSW Medicine, UNSW Sydney, New South Wales, Australia.
PLoS Genet. 2020 Feb 3;16(2):e1008572. doi: 10.1371/journal.pgen.1008572. eCollection 2020 Feb.
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.
具有聚合酶 ε (POLE) 外切酶结构域突变的癌症基因组表现出极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。然而，不同 POLE 突变体引起的全基因组突变模式和驱动突变形成仍不清楚。在这里，我们从已发表的研究和公共可用数据库中整理了 7345 例结直肠癌样本的体细胞突变调用。这些包括 44 个 POLE 突变样本，其中 9 个具有全基因组测序数据。根据存在的特定 POLE 突变，将 POLE 突变样本进行分类。在不同的 POLE 突变体中，检查了体细胞突变与表观基因组特征的关联以及与特定驱动突变的共发生。我们发现，不同的 POLE 突变体表现出不同的突变谱，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，这种 C>T 突变频率的增加不依赖于 DNA 甲基化，与其他基因组特征无关，因此仅单独由于 DNA 序列背景。值得注意的是，我们发现 TP53 R213*突变与 POLE P286R 突变体之间存在很强的关联。这种截断突变发生在 TT[C>T]GA 序列背景中。对于 C>T 突变，与其他 POLE 外切酶结构域突变体相比，POLE P286R 突变体中这种序列背景更有可能发生突变。这项研究深化了我们对 DNA 聚合酶保真度的理解，并强调了 POLE 突变癌症中观察到的全基因组突变谱和特定癌症驱动突变形成。
