Phenotype of POLE-mutated endometrial cancer

Background and purpose
Individualized therapy in endometrial cancer, the most common gynaecologic cancer in the developed world, focuses on identifying specific molecular subtypes. Mutations in the exonuclease domain of the DNA polymerase epsilon (POLE) gene define one such subtype, which causes an ultra-mutated tumour phenotype. These tumours may have an improved progression-free survival and may be receptive to specific therapies. However, the clinical phenotype of these tumours is unknown. The objective of this study was to evaluate the clinical and genetic features of POLE-mutated tumours from a large cohort of women whose cases are characterized by: (1) the availability of detailed clinical and lifestyle data; (2) mutation analysis; and (3) long-term follow-up.
Methods
A total of 604 patients with endometrial cancer were included in the study. Data from a detailed questionnaire, including lifestyle and family history information, provided extensive pertinent information on the patients. Sequencing of exons 9–14 of the POLE gene was performed. Follow-up data were gathered and analysed.
Results
Hotspot pathogenic POLE mutations were identified in N = 38/599 patients (6.3%). Patients with a POLE-mutated tumour were significantly younger, were more often nulliparous, and had a history of smoking. POLE-mutated tumours were more frequently aneuploid. Prognosis for patients with hotspot POLE-mutated tumours was significantly better in comparison with patients with non-mutated tumours; however careful selection of pathogenic mutations is essential to the definition of this prognostically favourable group.
Conclusions
This study demonstrates that POLE-mutated endometrial cancer is significantly associated with previously unknown clinicopathologic characteristics. Outcome in POLE-mutated tumours was excellent in cases with hotspot mutations. Our results suggest that prediction of excellent outcome in cases of POLE-mutated EMCA should be restricted to cases of EMCA with hotspot mutations until further data are available on the rising number of mutations with unknown significance.

### 背景与目的
子宫内膜癌是发达国家最常见的妇科恶性肿瘤，其个体化治疗的核心目标是识别特定分子亚型。DNA聚合酶ε（POLE）基因外切酶结构域的突变即为其中一类亚型，可引发超突变肿瘤表型。此类肿瘤的无进展生存期更优，且对特定治疗方案敏感，但目前其临床表型尚未明确。本研究旨在从一大组女性患者队列中评估POLE突变肿瘤的临床与遗传特征，该队列具备以下特点：(1) 留存详细的临床及生活方式数据；(2) 可开展突变分析；(3) 具备长期随访数据。

### 研究方法
本研究共纳入604例子宫内膜癌患者。通过详细问卷收集了涵盖生活方式与家族史在内的丰富相关患者信息。对POLE基因的第9至14号外显子进行测序。收集并分析随访数据。

### 研究结果
在599例可评估患者中，共检出38例（6.3%）存在热点致病性POLE突变。携带POLE突变肿瘤的患者年龄显著更轻，未生育比例更高，且有吸烟史。POLE突变肿瘤更易出现非整倍体。与携带非突变肿瘤的患者相比，热点POLE突变肿瘤患者的预后显著更佳，但需谨慎筛选致病性突变，方可准确界定这一预后良好的亚型。

### 结论
本研究证实，POLE突变型子宫内膜癌与此前未被报道的临床病理特征显著相关。携带热点突变的POLE突变肿瘤患者预后极佳。本研究结果提示，在获得更多意义未明突变的相关数据前，POLE突变型子宫内膜癌（EMCA）的良好预后预测应仅局限于携带热点突变的病例。