Clinical Significance of CTNNB1 Mutation and Wnt Pathway Activation in Endometrioid Endometrial Carcinoma
Clinical Significance of CTNNB1 Mutation and Wnt Pathway Activation in Endometrioid Endometrial Carcinoma
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DOI：
10.1093/jnci/dju245
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发表时间：
2014-09-01
影响因子：
10.3
通讯作者：
Zhang, Wei
中科院分区：
文献类型：
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作者：
Liu, Yuexin;Patel, Lalit;Zhang, Wei
背景 子宫内膜样子宫内膜癌（EEC）是子宫内膜癌最常见的形式。 EEC 的异质临床病程是个体化患者护理的障碍。方法我们对多维数据类型进行了综合分析，包括全外显子组和 RNA 测序、RPPA 分析以及癌症基因组图谱 (TCGA) 中 271 个 EEC 病例的临床数据，以确定可能解释这种临床异质性的分子指纹。微阵列的显着性分析用于鉴定进行路径分析的每个亚型的标记基因。通过 Mann Whitney、卡方、Fisher 精确检验和 Kruskal-Wallis 检验分析分子亚型与临床特征和突变数据的关联。通过对数秩检验评估生存分析。所有统计检验都是双面的。 结果 从 TCGA 数据集中鉴定出具有不同临床病理特征和突变谱的四种转录组亚型，并在 184 例 EEC 病例的独立样本队列中进行验证。第二组由年轻、肥胖、患有低级别 EEC 但生存率降低的患者组成。 CTNNB1 外显子 3 突变存在于 Cluster II 的 87.0% (47/54) 中 (P < .001)，总体突变率较低；这与 Wnt/β-连环蛋白信号传导激活具有统计学显着相关性 (P < .001)。 CTNNB1 (P = .001)、MYC (P = .01) 和 CCND1 (P = .01) 的高表达水平与低级别 EEC 肿瘤较差的总体生存率相关。结论 CTNNB1 外显子 3 突变可能是年轻女性中发生的低级别和低阶段 EEC 侵袭性子集的驱动因素。
Background Endometrioid endometrial carcinoma (EEC) is the most common form of endometrial carcinoma. The heterogeneous clinical course of EEC is an obstacle to individualized patient care.Methods We performed an integrated analysis on the multiple-dimensional data types including whole-exome and RNA sequencing, RPPA profiling, and clinical data from 271 EEC cases in The Cancer Genome Atlas (TCGA) to identify molecular fingerprints that may account for this clinical heterogeneity. Significance analysis of microarray was used to identify marker genes of each subtype that were subject to pathway analysis. Association of molecular subtypes with clinical features and mutation data was analyzed with the Mann Whitney, Chi-square, Fisher's exact, and Kruskal-Wallis tests. Survival analysis was evaluated with log-rank test. All statistical tests were two-sided.Results Four transcriptome subtypes with distinct clinicopathologic characteristics and mutation spectra were identified from the TCGA dataset and validated in an independent sample cohort of 184 EEC cases. Cluster II consisted of younger, obese patients with low-grade EEC but diminished survival. CTNNB1 exon 3 mutations were present in 87.0% (47/54) of Cluster II (P < .001) that exhibited a low overall mutation rate; this was statistically significantly associated with Wnt/beta-catenin signaling activation (P < .001). High expression levels of CTNNB1 (P = .001), MYC (P = .01), and CCND1 (P = .01) were associated with poorer overall survival in low-grade EEC tumors.Conclusions CTNNB1 exon 3 mutations are likely a driver that characterize an aggressive subset of low-grade and low-stage EEC occurring in younger women.