Endometrial carcinoma (EC) molecular classification based on four molecular subclasses identified in The Cancer Genome Atlas (TCGA) has gained relevance in recent years due to its prognostic utility and potential to predict benefit from adjuvant treatment. While most ECs can be classified based on a single classifier (POLE exonuclease domain mutations - POLEmut, MMR deficiency - MMRd, p53 abnormal - p53abn), a small but clinically relevant group of tumours harbour more than one molecular classifying feature and are referred to as 'multiple-classifier' ECs. We aimed to describe the clinicopathological and molecular features of multiple-classifier ECs with abnormal p53 (p53abn). Within a cohort of 3518 molecularly profiled ECs, 107 (3%) tumours displayed p53abn in addition to another classifier(s), including 64 with MMRd (MMRd-p53abn), 31 with POLEmut (POLEmut-p53abn), and 12 with all three aberrations (MMRd-POLEmut-p53abn). MMRd-p53abn ECs and POLEmut-p53abn ECs were mostly grade 3 endometrioid ECs, early stage, and frequently showed morphological features characteristic of MMRd or POLEmut ECs. 18/28 (60%) MMRd-p53abn ECs and 7/15 (46.7%) POLEmut-p53abn ECs showed subclonal p53 overexpression, suggesting that TP53 mutation was a secondary event acquired during tumour progression. Hierarchical clustering of TCGA ECs by single nucleotide variant (SNV) type and somatic copy number alterations (SCNAs) revealed that MMRd-p53abn tumours mostly clustered with single-classifier MMRd tumours (20/23) rather than single-classifier p53abn tumours (3/23), while POLEmut-p53abn tumours mostly clustered with single-classifier POLEmut tumours (12/13) and seldom with single-classifier p53abn tumours (1/13) (both p ≤ 0.001, chi-squared test). Finally, the clinical outcome of patients with MMRd-p53abn and POLEmut-p53abn ECs [stage I 5-year recurrence-free survival (RFS) of 92.2% and 94.1%, respectively] was significantly different from single-classifier p53abn EC (stage I RFS 70.8%, p = 0.024 and p = 0.050, respectively). Our results support the classification of MMRd-p53abn EC as MMRd and POLEmut-p53abn EC as POLEmut. © 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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“多分类”子宫内膜癌的临床病理学和分子特征。


近年来，基于癌症基因组图谱 (TCGA) 中确定的四个分子亚类的子宫内膜癌 (EC) 分子分类因其预后效用和预测辅助治疗获益的潜力而获得相关性。虽然大多数 EC 可以根据单一分类器（POLE 核酸外切酶结构域突变 - POLEmut、MMR 缺陷 - MMRd、p53 异常 - p53abn）进行分类，但一小部分但临床相关的肿瘤具有多个分子分类特征，被称为“多分类器”EC。我们的目的是描述具有异常 p53 (p53abn) 的多分类 EC 的临床病理学和分子特征。在 3518 个分子分析 EC 队列中，107 个 (3%) 肿瘤除其他分类器外还显示 p53abn，其中 64 个肿瘤具有 MMRd (MMRd-p53abn)，31 个肿瘤具有 POLEmut (POLEmut-p53abn)，12 个肿瘤具有所有三种分类器像差（MMRd-POLEmut-p53abn）。 MMRd-p53abn ECs 和 POLEmut-p53abn ECs 大多是 3 级子宫内膜样 ECs，处于早期阶段，并且经常表现出 MMRd 或 POLEmut ECs 的形态特征。 18/28 (60%) MMRd-p53abn ECs 和 7/15 (46.7%) POLEmut-p53abn ECs 显示亚克隆 p53 过度表达，表明 TP53 突变是肿瘤进展过程中获得的继发事件。按单核苷酸变异 (SNV) 类型和体细胞拷贝数改变 (SCNA) 对 TCGA EC 进行层次聚类显示，MMRd-p53abn 肿瘤大多与单分类器 MMRd 肿瘤聚类 (20/23)，而不是与单分类器 p53abn 肿瘤聚类 (3/ 23），而 POLEmut-p53abn 肿瘤大多与单分类器 POLEmut 肿瘤聚集（12/13），很少与单分类器 p53abn 肿瘤聚集（1/13）（均 p ≤ 0.001，卡方检验）。 最后，MMRd-p53abn 和 POLEmut-p53abn EC 患者的临床结果 [I 期 5 年无复发生存率 (RFS) 分别为 92.2% 和 94.1%] 与单分类器 p53abn EC（I 期）显着不同RFS 70.8%，分别为 p = 0.024 和 p = 0.050）。我们的结果支持将 MMRd-p53abn EC 分类为 MMRd，将 POLEmut-p53abn EC 分类为 POLEmut。 © 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。