Abstract：
OBJECTIVE: Molecular classification according to The Cancer Genome Atlas (TCGA) improves endometrial endometrioid carcinoma (EEC) prognostication and has specific treatment implications; however, original data were skewed towards low-grade and low-stage tumours. Herein, we molecularly classify EECs metastatic at the time of diagnosis or with subsequently documented recurrent/metastatic disease to examine correlation with clinical outcomes.
METHODS: TCGA categories include POLE-mutated, microsatellite instability (MSI), p53 abnormal (p53 abnl) and no specific molecular profile (NSMP). POLE targeted sequencing at exons 9, 11, 13 and 14 and immunohistochemistry (IHC) for PMS2, MSH6 and p53 were performed to establish molecular classification.
RESULTS: The distribution in our cohort of 141 EECs was similar to that generally reported in EEC, with nine POLE-mutated (6%), 45 MSI (32%), 16 p53 abnl (11%) and 71 NSMP (50%), with similar distributions between low- and high-stage cohorts. We demonstrate that when stratified by molecular subtype, disease-specific survival from the time of high-stage (stages III-IV) presentation or time of recurrence in low-stage (stages I-II) disease among metastatic and/or recurrent EEC is strongly associated with TCGA classification (high-stage P = 0.02, low-stage P = 0.017). Discordant molecular classification between primary and metastatic/recurrent tumours occurred in four of 105 (3.8%) patients, two related to PMS2/MSH6 IHC and two related to p53 IHC.
CONCLUSIONS: We demonstrate that molecular classification is prognostically relevant not only at the time of diagnosis, but also at the time of recurrence and in the metastatic setting. Rare subclonal alterations occur and suggest a role for confirming TCGA classification in recurrent/metastatic tumours.
METHODS: TCGA categories include POLE-mutated, microsatellite instability (MSI), p53 abnormal (p53 abnl) and no specific molecular profile (NSMP). POLE targeted sequencing at exons 9, 11, 13 and 14 and immunohistochemistry (IHC) for PMS2, MSH6 and p53 were performed to establish molecular classification.
RESULTS: The distribution in our cohort of 141 EECs was similar to that generally reported in EEC, with nine POLE-mutated (6%), 45 MSI (32%), 16 p53 abnl (11%) and 71 NSMP (50%), with similar distributions between low- and high-stage cohorts. We demonstrate that when stratified by molecular subtype, disease-specific survival from the time of high-stage (stages III-IV) presentation or time of recurrence in low-stage (stages I-II) disease among metastatic and/or recurrent EEC is strongly associated with TCGA classification (high-stage P = 0.02, low-stage P = 0.017). Discordant molecular classification between primary and metastatic/recurrent tumours occurred in four of 105 (3.8%) patients, two related to PMS2/MSH6 IHC and two related to p53 IHC.
CONCLUSIONS: We demonstrate that molecular classification is prognostically relevant not only at the time of diagnosis, but also at the time of recurrence and in the metastatic setting. Rare subclonal alterations occur and suggest a role for confirming TCGA classification in recurrent/metastatic tumours.
摘要：
目的：根据癌症基因组图谱（TCGA）的分子分类可改善子宫内膜子宫内膜样癌（EEC）的预后，并具有特定的治疗意义；然而，原始数据向低级别和低阶段肿瘤倾斜.在这里，我们对诊断时转移的EECs或随后记录的复发/转移疾病进行分子分类,以检查与临床结局的相关性.
方法：TCGA类别包括POLE突变，微卫星不稳定性（MSI），p53异常(p53abnl)和无特异性份子谱(NSMP)。在外显子9、11、13和14处进行POLE靶向测序以及PMS2、MSH6和p53的免疫组织化学(IHC)以建立分子分类。
结果：我们的141个EEC队列中的分布与EEC中通常报道的相似，有9个波兰人突变（6%），45MSI（32%），16p53abnl（11％）和71NSMP（50％），低阶段和高阶段队列之间的分布相似。我们证明，当按分子亚型分层时，在转移性和/或复发性EEC中,从高阶段(III-IV期)出现时间或低阶段(I-II期)疾病复发时间开始的疾病特异性生存率与TCGA分类密切相关(高阶段P=0.02,低阶段P=0.017).原发性和转移性/复发性肿瘤的分子分类不一致发生在105例患者中有4例(3.8%)。两个与PMS2/MSH6IHC有关，两个与p53IHC有关。
结论：我们证明分子分类不仅在诊断时具有预后相关性，而且在复发时和转移背景下也是如此。发生罕见的亚克隆改变，并提示在确认复发/转移性肿瘤中TCGA分类的作用。
方法：TCGA类别包括POLE突变，微卫星不稳定性（MSI），p53异常(p53abnl)和无特异性份子谱(NSMP)。在外显子9、11、13和14处进行POLE靶向测序以及PMS2、MSH6和p53的免疫组织化学(IHC)以建立分子分类。
结果：我们的141个EEC队列中的分布与EEC中通常报道的相似，有9个波兰人突变（6%），45MSI（32%），16p53abnl（11％）和71NSMP（50％），低阶段和高阶段队列之间的分布相似。我们证明，当按分子亚型分层时，在转移性和/或复发性EEC中,从高阶段(III-IV期)出现时间或低阶段(I-II期)疾病复发时间开始的疾病特异性生存率与TCGA分类密切相关(高阶段P=0.02,低阶段P=0.017).原发性和转移性/复发性肿瘤的分子分类不一致发生在105例患者中有4例(3.8%)。两个与PMS2/MSH6IHC有关，两个与p53IHC有关。
结论：我们证明分子分类不仅在诊断时具有预后相关性，而且在复发时和转移背景下也是如此。发生罕见的亚克隆改变，并提示在确认复发/转移性肿瘤中TCGA分类的作用。
