Medical Genetics Division, Shizuoka Cancer Center Research Institute, Sunto-gun, Shizuoka, 411-8777, Japan.
Cancer Diagnostics Research Division, Shizuoka Cancer Center Research Institute, Sunto-gun, Shizuoka, 411-8777, Japan.
Sci Rep. 2018 Jun 7;8(1):8700. doi: 10.1038/s41598-018-26967-4.
Defective DNA polymerase ε (POLE) proofreading leads to extensive somatic mutations that exhibit biased mutational properties; however, the characteristics of POLE-mutated tumours remain unclear. In the present study, we describe a molecular profile using whole exome sequencing based on the transition of somatic mutations in 10 POLE-mutated solid tumours that were obtained from 2,042 Japanese patients. The bias of accumulated variations in these mutants was quantified to follow a pattern of somatic mutations, thereby classifying the sequential mutation shift into three periods. During the period prior to occurrence of the aberrant POLE, bare accumulation of mutations in cancer-related genes was observed, whereas PTEN was highly mutated in conjunction with or subsequent to the event, suggesting that POLE and PTEN mutations were responsible for the development of POLE-mutated tumours. Furthermore, homologous recombination was restored following the occurrence of PTEN mutations. Our strategy for estimation of the footprint of somatic mutations may provide new insight towards the understanding of mutation-driven tumourigenesis.
DNA 聚合酶 ε（POLE）校对功能缺陷会导致广泛的体细胞突变，并表现出偏倚的突变特征；然而，POLE 突变肿瘤的特征仍不清楚。在本研究中，我们描述了一种基于 10 个 POLE 突变实体瘤体细胞突变的外显子组测序的分子谱，这些肿瘤来自 2042 名日本患者。对这些突变体中积累变异的偏倚进行了量化，以遵循体细胞突变的模式，从而将序贯突变转移分为三个时期。在发生异常 POLE 之前的时期，观察到与癌症相关基因的突变积累，而在该事件发生时或之后，PTEN 发生高频突变，提示 POLE 和 PTEN 突变是 POLE 突变肿瘤发生的原因。此外，PTEN 突变后同源重组得到恢复。我们估计体细胞突变足迹的策略可能为理解突变驱动的肿瘤发生提供新的见解。
