Talhouk Aline, McConechy Melissa K, Leung Samuel, Yang Winnie, Lum Amy, Senz Janine, Boyd Niki, Pike Judith, Anglesio Michael, Kwon Janice S, Karnezis Anthony N, Huntsman David G, Gilks C Blake, McAlpine Jessica N
Department of Pathology and Laboratory Medicine, University of British Columbia and British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
Department of Human Genetics, McGill University, Research Institute of the McGill University Health Network, Montreal, Quebec, Canada.
Cancer. 2017 Mar 1;123(5):802-813. doi: 10.1002/cncr.30496. Epub 2017 Jan 6.
Classification of endometrial carcinomas (ECs) by morphologic features is irreproducible and imperfectly reflects tumor biology. The authors developed the Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE), a molecular classification system based on The Cancer Genome Atlas genomic subgroups, and sought to confirm both feasibility and prognostic ability in a new, large cohort of ECs.
Immunohistochemistry (IHC) for the presence or absence of mismatch repair (MMR) proteins (to identify MMR deficiency [MMR-D]), sequencing for polymerase-ɛ (POLE) exonuclease domain mutations (POLE EDMs), and IHC for tumor protein 53 (p53) (wild type vs null/missense mutations; p53 wt and p53 abn, respectively) were performed on 319 new EC samples. Subgroups were characterized and assessed relative to outcomes. The prognostic ability of ProMisE was compared with that of current risk-stratification systems (European Society of Medical Oncology [ESMO]).
ProMisE decision-tree classification achieved categorization of all cases and identified 4 prognostic subgroups with distinct overall, disease-specific, and progression-free survival (P < .001). Tumors with POLE EDMs had the most favorable prognosis, and those with p53 abn the worst prognosis, and separation of the 2 middle survival curves (p53 wt and MMR-D) was observed. There were no significant differences in survival between the ESMO low-risk and intermediate-risk groups. ProMisE improved the ability to discriminate outcomes compared with ESMO risk stratification. There was substantial overlap (89%) between the p53 abn and high-risk ESMO subgroups; but, otherwise, there were no predictable associations between molecular and ESMO risk groups.
Molecular classification of ECs can be achieved using clinically applicable methods and provides independent prognostic information beyond established clinicopathologic risk factors available at diagnosis. Consistent, biologically relevant categorization enables stratification for clinical trials and/or targeted therapy, identification of women who are at increased risk of having Lynch syndrome, and may guide clinical management. Cancer 2017;123:802-13. © 2016 American Cancer Society.
根据形态学特征对子宫内膜癌（EC）进行分类是不可重复的，且不能完美反映肿瘤生物学特性。作者开发了子宫内膜癌前瞻性分子风险分类器（ProMisE），这是一种基于癌症基因组图谱基因组亚组的分子分类系统，并试图在一个新的大型EC队列中证实其可行性和预后能力。
对319例新的EC样本进行免疫组织化学（IHC）检测错配修复（MMR）蛋白的有无（以识别MMR缺陷[MMR-D]），对聚合酶ɛ（POLE）核酸外切酶结构域突变（POLE EDMs）进行测序，并对肿瘤蛋白53（p53）进行IHC检测（野生型与无效/错义突变；分别为p53 wt和p53 abn）。对亚组进行特征分析并评估其与预后的关系。将ProMisE的预后能力与当前风险分层系统（欧洲医学肿瘤学会[ESMO]）进行比较。
ProMisE决策树分类实现了所有病例的分类，并确定了4个预后亚组，其总生存期、疾病特异性生存期和无进展生存期均有显著差异（P＜0.001）。具有POLE EDMs的肿瘤预后最佳，具有p53 abn的肿瘤预后最差，观察到两条中间生存曲线（p53 wt和MMR-D）的分离。ESMO低风险组和中风险组之间的生存期无显著差异。与ESMO风险分层相比，ProMisE提高了区分预后的能力。p53 abn亚组与ESMO高风险亚组之间存在大量重叠（89%）；但除此之外，分子亚组与ESMO风险组之间没有可预测的关联。
使用临床适用的方法可以实现EC的分子分类，并提供超出诊断时可用的既定临床病理风险因素之外的独立预后信息。一致的、生物学相关的分类能够为临床试验和/或靶向治疗进行分层，识别患林奇综合征风险增加的女性，并可能指导临床管理。《癌症》2017年；123：802 - 13。©2016美国癌症协会
