Phenotype of POLE-mutated endometrial cancer
Phenotype of POLE-mutated endometrial cancer
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DOI：
10.1371/journal.pone.0214318
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发表时间：
2019-03-27
期刊：
影响因子：
3.7
通讯作者：
Carlson, Joseph W.
中科院分区：
文献类型：
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作者：
Imboden, Sara;Nastic, Denis;Carlson, Joseph W.
背景和目的子宫内膜癌是发达国家最常见的妇科癌症，个体化治疗的重点是识别特定的分子亚型。DNA聚合酶epsilon （POLE）基因外切酶结构域的突变定义了一种这样的亚型，它导致超突变的肿瘤表型。这些肿瘤可能有改善的无进展生存期，并且可能接受特定的治疗。然而，这些肿瘤的临床表型是未知的。本研究的目的是评估来自一大批妇女的pole突变肿瘤的临床和遗传特征，这些病例的特点是：(1)可获得详细的临床和生活方式数据；(2)突变分析；(3)长期随访。方法选择604例子宫内膜癌患者作为研究对象。来自详细问卷的数据，包括生活方式和家族史信息，为患者提供了广泛的相关信息。对POLE基因外显子9-14进行测序。收集和分析后续数据。结果599例患者中检出散点致病性POLE突变38例（6.3%）。pole突变肿瘤的患者明显更年轻，更经常是不育的，并且有吸烟史。极突变肿瘤更常是非整倍体。热点极突变肿瘤患者的预后明显优于非突变肿瘤患者；然而，仔细选择致病突变对于定义这一预后有利的群体至关重要。结论本研究表明pole突变的子宫内膜癌与以前未知的临床病理特征显著相关。在热点突变的病例中，极点突变肿瘤的预后很好。我们的研究结果表明，极点突变的EMCA病例的良好预后预测应仅限于具有热点突变的EMCA病例，直到有更多的数据表明具有未知意义的突变数量不断增加。
Background and purposeIndividualized 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.MethodsA 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.ResultsHotspot 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.ConclusionsThis 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.