文章：

一系列错误：癌症中的聚合酶校对结构域突变

A panoply of errors: polymerase proofreading domain mutations in cancer

原文发布日期：2016-01-29

DOI: 10.1038/nrc.2015.12

类型: Review Article

开放获取: 否

要点：

1. The proofreading exonuclease domains of the replicative DNA polymerases Pol δ and Pol ε perform an essential function in ensuring accurate DNA replication by proofreading and removing mispaired bases from the newly synthesized DNA strand.
2. Recent studies have shown that mutations in the proofreading domains of POLD1 and POLE (which encode the catalytic subunits of Pol δ and Pol ε, respectively, in humans) predispose to colonic polyposis and cancer, and that somatic POLE proofreading domain mutations occur in several tumour types, most commonly those of the endometrium and colorectum. Interestingly, somatic POLD1 proofreading domain mutations seem to be uncommon.
3. In several cases, the pathogenicity of these germline and somatic DNA polymerase proofreading domain mutations has been supported by studies using cell-free assays and Saccharomyces cerevisiae mutants, which confirm that they reduce or abolish exonuclease activity and increase the mutation rate.
4. Consistent with these studies, the most striking feature of tumours with somatic POLE proofreading domain mutations is their exceptional burden of base substitution mutations — 'ultramutation'. Other notable features are their characteristic mutation spectrum, with overrepresentation of C→A transversions and, in general, a strong tendency to microsatellite stability.
5. Endometrial cancers with somatic POLE proofreading domain mutations have an excellent prognosis, which may be because their ultramutation causes an abundance of antigenic neoepitopes, which in turn stimulate a potent antitumour immune response. The prognostic and immunological consequences of somatic POLE proofreading domain mutations in other tumour types await definition.
6. Future studies of DNA polymerase proofreading domain mutations in cancer may provide further insights into the mechanisms and consequences of a mutator phenotype in cancer, and help to improve care for patients with endometrial, colorectal and other cancers.

要点翻译：

1. 复制性DNA聚合酶Pol δ和Pol ε的校对外切核酸酶结构域通过校对并移除新合成DNA链中的错配碱基，在确保DNA复制准确性方面发挥重要作用。
2. 近期研究表明，人类POLD1和POLE基因（分别编码Pol δ和Pol ε的催化亚基）的校对结构域突变易导致结肠息肉病和癌症，且体细胞POLE校对结构域突变见于多种肿瘤类型，最常见于子宫内膜和结直肠肿瘤。值得注意的是，体细胞POLD1校对结构域突变似乎较为罕见。
3. 通过无细胞实验体系和酿酒酵母突变体的研究，这些生殖系和体细胞DNA聚合酶校对结构域突变的致病性已得到验证，研究证实这些突变会降低或消除外切核酸酶活性，并提高突变率。
4. 与这些研究一致的是，携带体细胞POLE校对结构域突变的肿瘤最显著特征是存在异常高负荷的碱基置换突变——即“超突变”。其他显著特征包括其特征性突变谱系，其中C→A颠换过度呈现，且通常表现出强烈的微卫星稳定性倾向。
5. 携带体细胞POLE校对结构域突变的子宫内膜癌预后极佳，这可能是因为其超突变状态产生了大量抗原性新表位，进而刺激了强烈的抗肿瘤免疫反应。而在其他肿瘤类型中，体细胞POLE校对结构域突变的预后及免疫学影响仍有待明确。
6. 未来对癌症中DNA聚合酶校对结构域突变的研究，可能进一步揭示突变表型在癌症中的机制及影响，并有助于改善子宫内膜癌、结直肠癌及其他癌症患者的诊疗。

英文摘要：

Although it has long been recognized that the exonucleolytic proofreading activity intrinsic to the replicative DNA polymerases Pol δ and Pol ε is essential for faithful replication of DNA, evidence that defective DNA polymerase proofreading contributes to human malignancy has been limited. However, recent studies have shown that germline mutations in the proofreading domains of Pol δ and Pol ε predispose to cancer, and that somatic Pol ε proofreading domain mutations occur in multiple sporadic tumours, where they underlie a phenotype of 'ultramutation' and favourable prognosis. In this Review, we summarize the current understanding of the mechanisms and consequences of polymerase proofreading domain mutations in human malignancies, and highlight the potential utility of these variants as novel cancer biomarkers and therapeutic targets.

摘要翻译： 

尽管早已认识到复制性DNA聚合酶Pol δ和Pol ε固有的外切核酸校对活性对DNA忠实复制至关重要，但DNA聚合酶校对缺陷导致人类恶性肿瘤的证据一直有限。然而，近期研究表明，Pol δ和Pol ε校对区的胚系突变易诱发癌症，且体细胞Pol ε校对区突变可见于多种散发性肿瘤，这些突变导致“超突变”表型并与良好预后相关。本综述总结了当前对人类恶性肿瘤中聚合酶校对区突变机制及后果的认识，并强调这些变异作为新型癌症生物标志物和治疗靶点的潜在价值。

原文链接：

A panoply of errors: polymerase proofreading domain mutations in cancer