Oviduct-specific glycoprotein is a molecular marker for invasion in endometrial tumorigenesis identified using a relevant mouse model.

The light microscopic distinction between complex atypical hyperplasia (CAH) and invasive endometrioid carcinoma (UEC) on endometrial sampling is problematic and often has significant clinical implications. Using mouse models of endometrial tumorigenesis based on two of the most common molecular alterations found in primary human UEC we sought to characterize the transition from CAH to carcinoma to identify clinically useful biomarkers. We used the previously described Pten+/-;Mlh1-/- mouse model. DNA was isolated from microdissected lesions (CAH and carcinoma) and analyzed for LOH and mutations of Pten and additional candidate genes. In order to identify novel candidate genes associated with invasion, global gene expression profiles were compared from uteri with extensive CAH and carcinoma. The majority of CAHs as well as carcinomas, arising in this model showed biallelic inactivation of Pten mediated through LOH or intragenic mutation of the wild-type allele suggesting that complete loss of Pten is insufficient for the development of carcinoma. The global gene expression studies detected increased expression of oviduct-specific glycoprotein (OGP) in carcinoma as compared to CAHs. This finding was validated using immunohistochemical staining in a collection of primary human UECs and CAHs. Our studies identify a molecular marker for invasive endometrial cancer that may have clinical significance, and highlight the usefulness of this mouse model in not only understanding the genetic underpinnings of endometrial carcinoma, but as a tool to develop clinically relevant biomarkers.

在子宫内膜取样中，复杂非典型增生（CAH）和浸润性子宫内膜样癌（UEC）在光学显微镜下的区分存在问题，且往往具有重大的临床意义。基于在原发性人类UEC中发现的两种最常见的分子改变，我们利用子宫内膜肿瘤发生的小鼠模型，试图描述从CAH到癌的转变，以确定具有临床应用价值的生物标志物。我们使用了先前描述的Pten+/-；Mlh1-/-小鼠模型。从显微切割的病变（CAH和癌）中分离DNA，并分析Pten及其他候选基因的杂合性缺失（LOH）和突变情况。为了确定与浸润相关的新候选基因，我们比较了具有广泛CAH和癌的子宫的整体基因表达谱。在该模型中产生的大多数CAH以及癌都显示出通过野生型等位基因的LOH或基因内突变介导的Pten双等位基因失活，这表明Pten的完全缺失不足以导致癌的发生。整体基因表达研究发现，与CAH相比，癌中输卵管特异性糖蛋白（OGP）的表达增加。这一发现在一组原发性人类UEC和CAH中通过免疫组织化学染色得到了验证。我们的研究确定了一种浸润性子宫内膜癌的分子标志物，可能具有临床意义，并强调了该小鼠模型不仅在理解子宫内膜癌的遗传基础方面，而且在作为开发临床相关生物标志物的工具方面的有用性。