Department of Pathology, Hospital de la Santa Creu i Sant Pau, Autonomous University of Barcelona, Barcelona, Spain.
Mod Pathol. 2010 May;23(5):694-702. doi: 10.1038/modpathol.2010.44. Epub 2010 Feb 19.
Previously, we showed that PIK3CA and p53 alterations in uterine endometrial carcinomas correlate with poor prognosis. However, the contribution of phosphatidylinositol 3-kinase (PI3K) -AKT deregulation to endometrial carcinogenesis is not completely understood. The purpose of this study was to analyze alterations of this pathway in endometrial carcinomas and correlate them with the most common genetic abnormalities. Expression profiling of 22 genes involved in PI3K-AKT signaling pathway was analyzed in 38 endometrial carcinomas using TaqMan low-density array (TLDA) analysis. The gene expression pattern was analyzed by hierarchical clustering analysis. Unsupervised clustering divided the high-grade endometrial carcinomas into two clusters. One cluster identified tumors with alterations in the PI3K-AKT signaling pathway (exon 20 PIK3CA mutations and/or PTEN mutations 9/15; 60%), and p16 protein overexpression (8/13; 62%). Almost all non-endometrioid adenocarcinomas (serous and clear cell adenocarcinomas) were segregated into this cluster. In contrast, the other cluster identified tumors with p53 alterations (6/6; 100%), p16 protein overexpression (5/5; 100%), and exon 9 PIK3CA mutations (2/6; 33%). Exon 20 PIK3CA and PTEN mutations were not found in this subgroup. Low-grade endometrial carcinomas clustered in a third subgroup characterized by high frequency of PTEN mutations (10/17; 59%) and microsatellite instability (6/17; 35%). Our results show that gene expression profile differences in the PI3K-AKT signaling pathway identify two subgroups of high-grade endometrial carcinomas with different molecular alterations (PI3K-AKT pathway vs p53 alterations) that may have distinct roles in endometrial carcinogenesis. Identification of these subgroups can provide insight into the biology of these tumors and may facilitate the development of future treatments.
先前，我们表明，在子宫子宫内膜癌中 PIK3CA 和 p53 的改变与预后不良相关。然而，磷脂酰肌醇 3-激酶（PI3K）-AKT 失调对子宫内膜癌发生的贡献还不完全清楚。本研究的目的是分析该通路在子宫内膜癌中的改变，并将其与最常见的遗传异常相关联。使用 TaqMan 低密度阵列（TLDA）分析，对 38 例子宫内膜癌中涉及 PI3K-AKT 信号通路的 22 个基因的表达谱进行了分析。通过层次聚类分析对基因表达模式进行了分析。无监督聚类将高级别子宫内膜癌分为两个亚群。一个亚群确定了具有 PI3K-AKT 信号通路改变的肿瘤（外显子 20 PIK3CA 突变和/或 PTEN 突变 9/15；60%）和 p16 蛋白过表达（8/13；62%）。几乎所有非子宫内膜样腺癌（浆液性和透明细胞腺癌）均被归为这一亚群。相比之下，另一个亚群确定了具有 p53 改变的肿瘤（6/6；100%）、p16 蛋白过表达（5/5；100%）和外显子 9 PIK3CA 突变（2/6；33%）。在该亚群中未发现外显子 20 PIK3CA 和 PTEN 突变。低级别子宫内膜癌聚集在第三个亚群中，其特点是 PTEN 突变（10/17；59%）和微卫星不稳定（6/17；35%）的频率较高。我们的结果表明，PI3K-AKT 信号通路中基因表达谱的差异可识别出具有不同分子改变（PI3K-AKT 通路与 p53 改变）的两个高级别子宫内膜癌亚群，这些改变可能在子宫内膜癌发生中具有不同的作用。这些亚群的鉴定可以深入了解这些肿瘤的生物学特性，并可能有助于未来治疗方法的开发。
