Pathogenic somatic missense mutations within the DNA polymerase epsilon (POLE) exonuclease domain define the important subtype of ultramutated tumours ('POLE-ultramutated') within the novel molecular classification of endometrial carcinoma (EC). However, clinical implementation of this classifier requires systematic evaluation of the pathogenicity of POLE mutations. To address this, we examined base changes, tumour mutational burden (TMB), DNA microsatellite instability (MSI) status, POLE variant frequency, and the results from six in silico tools on 82 ECs with whole-exome sequencing from The Cancer Genome Atlas (TCGA). Of these, 41 had one of five known pathogenic POLE exonuclease domain mutations (EDM) and showed characteristic genomic alterations: C>A substitution > 20%, T>G substitutions > 4%, C>G substitutions < 0.6%, indels < 5%, TMB > 100 mut/Mb. A scoring system to assess these alterations (POLE-score) was developed; based on their scores, 7/18 (39%) additional tumours with EDM were classified as POLE-ultramutated ECs, and the six POLE mutations present in these tumours were considered pathogenic. Only 1/23 (4%) tumours with non-EDM showed these genomic alterations, indicating that a large majority of mutations outside the exonuclease domain are not pathogenic. The infrequent combination of MSI-H with POLE EDM led us to investigate the clinical significance of this association. Tumours with pathogenic POLE EDM co-existent with MSI-H showed genomic alterations characteristic of POLE-ultramutated ECs. In a pooled analysis of 3361 ECs, 13 ECs with DNA mismatch repair deficiency (MMRd)/MSI-H and a pathogenic POLE EDM had a 5-year recurrence-free survival (RFS) of 92.3%, comparable to previously reported POLE-ultramutated ECs. Additionally, 14 cases with non-pathogenic POLE EDM and MMRd/MSI-H had a 5-year RFS of 76.2%, similar to MMRd/MSI-H, POLE wild-type ECs, suggesting that these should be categorised as MMRd, rather than POLE-ultramutated ECs for prognostication. This work provides guidance on classification of ECs with POLE mutations, facilitating implementation of POLE testing in routine clinical care. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

中文翻译：

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子宫内膜癌体细胞 POLE 突变的解释。


DNA聚合酶ε（POLE）核酸外切酶结构域内的致病性体细胞错义突变定义了子宫内膜癌（EC）新分子分类中超突变肿瘤（“POLE超突变”）的重要亚型。然而，该分类器的临床实施需要对 POLE 突变的致病性进行系统评估。为了解决这个问题，我们检查了碱基变化、肿瘤突变负荷 (TMB)、DNA 微卫星不稳定性 (MSI) 状态、POLE 变异频率，以及来自癌症基因组图谱的全外显子组测序的 82 个 EC 上的 6 个计算机工具的结果（ TCGA）。其中，41 个具有五种已知致病性 POLE 核酸外切酶结构域突变 (EDM) 之一，并显示出特征性基因组改变：C>A 替换 > 20%、T>G 替换 > 4%、C>G 替换 < 0.6%、插入缺失 < 5 %，TMB > 100 mut/Mb。开发了评估这些改变的评分系统（POLE-score）；根据他们的评分，7/18 (39%) 的其他 EDM 肿瘤被归类为 POLE 超突变 EC，这些肿瘤中存在的 6 个 POLE 突变被认为是致病性的。只有 1/23 (4%) 的非 EDM 肿瘤显示出这些基因组改变，表明核酸外切酶结构域之外的绝大多数突变不是致病性的。 MSI-H 与 POLE EDM 的罕见组合促使我们研究这种关联的临床意义。具有致病性 POLE EDM 并与 MSI-H 共存的肿瘤表现出 POLE 超突变 EC 的基因组改变特征。在对 3361 个 EC 的汇总分析中，13 个具有 DNA 错配修复缺陷 (MMRd)/MSI-H 和致病性 POLE EDM 的 EC 的 5 年无复发生存率 (RFS) 为 92.3%，与之前报道的 POLE 超突变的情况相当EC。 此外，14 例非致病性 POLE EDM 和 MMRd/MSI-H 病例的 5 年 RFS 为 76.2%，与 MMRd/MSI-H、POLE 野生型 EC 相似，表明这些病例应归类为 MMRd，而不是比 POLE 超突变 EC 的预测效果更好。这项工作为具有 POLE 突变的 EC 分类提供了指导，有助于在常规临床护理中实施 POLE 检测。 © 2019 作者。 《病理学杂志》由 John Wiley & Sons Ltd 代表大不列颠及爱尔兰病理学会出版。