Johanna Kögl, Teresa L Pan, Christian Marth, Alain G Zeimet
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An additional six \"non-hotspot\" <i>POLE</i>-EDM EC mutations are also considered pathogenic, and they also confer a favorable prognosis. Currently, de-escalation of adjuvant treatment is recommended for patients with EC with stage I-II tumors involving any of these 11 EDM mutations, even in patients with other clinicopathological risk factors. The high tumor mutational burden and the consequent increased infiltration of immune cells due to the overexpression of different neoantigens are probably responsible for the improved prognosis. Ongoing studies are examining <i>POLE</i> hotspot mutations among many non-gynecologic tumors, although the impact of such mutations on clinical outcomes is still a topic of debate. Therapeutic modalities for these hypermutated tumors are also an important consideration, including the need for or de-escalation of adjuvant treatments and the response to immune therapy. 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In EC, there are five confirmed pathogenic somatic <i>POLE</i>-EDM mutations that are located at codons 286, 411, 297, 456, and 459, and these are called \\\"hotspot\\\" mutations. <i>POLE</i> mutant tumors are ultramutated entities with a frequency of base substitution mutations that is among the highest in human tumors. Interestingly, these mutations are associated with excellent clinical outcome in EC. An additional six \\\"non-hotspot\\\" <i>POLE</i>-EDM EC mutations are also considered pathogenic, and they also confer a favorable prognosis. Currently, de-escalation of adjuvant treatment is recommended for patients with EC with stage I-II tumors involving any of these 11 EDM mutations, even in patients with other clinicopathological risk factors. The high tumor mutational burden and the consequent increased infiltration of immune cells due to the overexpression of different neoantigens are probably responsible for the improved prognosis. 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引用次数: 0
摘要
DNA 聚合酶 Pol ϵ(POLE)基因外切酶校对结构域(EDM)内的体细胞突变在卵巢癌、结直肠癌、泌尿系统癌,尤其是子宫内膜癌(EC)中的发现越来越多,这些病例的比例高达 10%。在子宫内膜癌中,有五种已证实的致病性体细胞 POLE-EDM 突变位于密码子 286、411、297、456 和 459,这些突变被称为 "热点 "突变。POLE 突变肿瘤是超突变实体,其碱基置换突变的频率是人类肿瘤中最高的。有趣的是,这些突变与 EC 的良好临床预后有关。另外六种 "非热点 "POLE-EDM EC 基因突变也被认为是致病性的,它们也会带来良好的预后。目前,对于肿瘤涉及这11种EDM突变中任何一种突变的I-II期EC患者,即使患者具有其他临床病理危险因素,也建议放弃辅助治疗。高肿瘤突变负荷以及不同新抗原过度表达导致的免疫细胞浸润增加可能是预后改善的原因。目前正在对许多非妇科肿瘤中的 POLE 热点突变进行研究,但这些突变对临床预后的影响仍是一个争论不休的话题。对这些高突变肿瘤的治疗方式也是一个重要的考虑因素,包括是否需要或减少辅助治疗以及对免疫疗法的反应。本综述探讨了 POLE 基因突变在妇科肿瘤学和一般肿瘤学中的关键作用,重点关注定义、变异、潜在的致病机制、该领域的最新进展以及与此类基因突变相关的临床表现。
The game-changing impact of POLE mutations in oncology-a review from a gynecologic oncology perspective.
Somatic mutations within the exonuclease proofreading domain (EDM) of the DNA polymerase Pol ϵ (POLE) gene are increasingly being discovered in ovarian, colorectal, urological, and, especially, endometrial carcinoma (EC), where these are found in up to 10% of the cases. In EC, there are five confirmed pathogenic somatic POLE-EDM mutations that are located at codons 286, 411, 297, 456, and 459, and these are called "hotspot" mutations. POLE mutant tumors are ultramutated entities with a frequency of base substitution mutations that is among the highest in human tumors. Interestingly, these mutations are associated with excellent clinical outcome in EC. An additional six "non-hotspot" POLE-EDM EC mutations are also considered pathogenic, and they also confer a favorable prognosis. Currently, de-escalation of adjuvant treatment is recommended for patients with EC with stage I-II tumors involving any of these 11 EDM mutations, even in patients with other clinicopathological risk factors. The high tumor mutational burden and the consequent increased infiltration of immune cells due to the overexpression of different neoantigens are probably responsible for the improved prognosis. Ongoing studies are examining POLE hotspot mutations among many non-gynecologic tumors, although the impact of such mutations on clinical outcomes is still a topic of debate. Therapeutic modalities for these hypermutated tumors are also an important consideration, including the need for or de-escalation of adjuvant treatments and the response to immune therapy. This review addresses the critical role of POLE mutations in gynecologic oncology and oncology in general, focusing on definitions, variants, underlying pathogenic mechanisms, upcoming developments in the field, and the clinic behavior associated with such mutations.
期刊介绍:
Cancer Imaging and Diagnosis is dedicated to the publication of results from clinical and research studies applied to cancer diagnosis and treatment. The section aims to publish studies from the entire field of cancer imaging: results from routine use of clinical imaging in both radiology and nuclear medicine, results from clinical trials, experimental molecular imaging in humans and small animals, research on new contrast agents in CT, MRI, ultrasound, publication of new technical applications and processing algorithms to improve the standardization of quantitative imaging and image guided interventions for the diagnosis and treatment of cancer.