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Abstract:
: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.
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最新影响因子:9.883 | 期刊ISSN:0022-3417 | CiteScore:5.86 |
出版周期:Monthly | 是否OA:YES | 出版年份:1969 |
期刊官方网址:http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1096-9896
自引率:2.20% | 研究方向:医学-病理学 |
出版地区:ENGLAND |
SCI期刊coverage:Science Citation Index Expanded(科学引文索引扩展)
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The main interests of the Journal of Pathology lie in the pathophysiological and pathogenetic mechanisms of human disease and in the application of such knowledge to diagnosis and prognosis. In determining content the primary considerations are excellence relevance and novelty. The Journal welcomes investigative studies on human tissues experimental studies in vitro and in vivo and investigations based on animal models with a clear relevance to human disease including transgenic systems. Methodological improvements in investigative and diagnostic pathology are also of interest. Correlative studies of pathological data and clinical outcomes are encouraged but purely descriptive papers on diagnostic pathology are not considered central to the Journal's purpose. In general studies which appropriately employ multiple investigative techniques are preferred over those which rely on a single methodology. Illustrations must be of the highest quality to be acceptable for publication. As well as original research papers the Journal seeks to provide rapid publication in a variety of other formats including editorials review articles and other features both contributed and solicited. Papers covering significant developments in teaching methods and in the practice of pathology may be acceptable if they are of international scope and relevance. Correspondence from readers will be published if it is of general interest. In summary the Journal aims to serve as a bridge between basic biomedical science and clinical medicine. As a Journal of the Pathological Society of Great Britain and Ireland it seeks to reflect the broad scientific interests of the Society's membership but its ethos authorship content and purpose are those expected of a leading publication in the international scientific literature.
《病理学杂志》的主要兴趣在于人类疾病的病理生理和发病机制,以及这些知识在诊断和预后中的应用。在确定内容时,主要考虑的是卓越的相关性和新颖性。该杂志欢迎对人体组织的研究,体外和体内的实验研究,以及基于与人类疾病(包括转基因系统)有明确关联的动物模型的研究。研究性和诊断性病理学的方法改进也很有趣。鼓励对病理学数据和临床结果进行相关研究,但关于诊断病理学的纯描述性论文并不被认为是该杂志的核心目的。一般来说,适当采用多种调查方法的研究比依赖单一方法的研究更为可取。插图必须具有最高质量,才能出版。除了最初的研究论文,该杂志还寻求以各种其他形式提供快速出版,包括社论评论文章和其他既有贡献又有索取的特色。如果论文涉及到教学方法和病理学实践的重大发展,并且具有国际范围和相关性,则可以接受。如果读者的信件符合一般利益,将予以公布。总之,该杂志的目标是成为基础生物医学科学和临床医学之间的桥梁。作为大不列颠和爱尔兰病理学会的一本杂志,它试图反映该学会成员的广泛科学利益,但它的精神、作者内容和目的是国际科学文献的主要出版物。
大类(学科) | 小类(学科) | 学科排名 |
医学 |
PATHOLOGY (病理学) 2区 ONCOLOGY (肿瘤学) 2区 |
32/223 5/79 |
年度总发文量 | 年度论文发表量 | 年度综述发表量 |
142 | 137 | 5 |
引文计数(2018)
文献(2015-2017)
2919次引用
498篇文献
序号 | 类别 | 排名 | 百分位 |
1 |
大类(学科):Medicine
小类(学科):Pathology and Forensic Medicine
|
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发表一篇学和医学成像类SCI论文
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