Abstract
Endometrial cancer is the most common gynecologic malignancy in the United States but it remains poorly understood at the molecular level. This investigation was conducted to specifically assess whether gene expression changes underlie the clinical and pathologic factors traditionally used for determining treatment regimens in women with stage I endometrial cancer. These include the effect of tumor grade, depth of myometrial invasion and histotype. We utilized oligonucleotide microarrays to assess the transcript expression profile in epithelial glandular cells laser microdissected from 79 endometrioid and 12 serous stage I endometrial cancers with a heterogeneous distribution of grade and depth of myometrial invasion, along with 12 normal post-menopausal endometrial samples. Unsupervised multidimensional scaling analyses revealed that serous and endometrioid stage I cancers have similar transcript expression patterns when compared to normal controls where 900 transcripts were identified to be differentially expressed by at least fourfold (univariate t-test, p < 0.001) between the cancers and normal endometrium. This analysis also identified transcript expression differences between serous and endometrioid cancers and tumor grade, but no apparent differences were identified as a function of depth of myometrial invasion. Four genes were validated by quantitative PCR on an independent set of cancer and normal endometrium samples. These findings indicate that unique gene expression profiles are associated with histologic type and grade, but not myometrial invasion among early stage endometrial cancers. These data provide a comprehensive perspective on the molecular alterations associated with stage I endometrial cancer, particularly those subtypes that have the worst prognosis.
Highlights
The majority of endometrial malignancies are carcinomas, which historically have been characterized as Type I or Type II on the basis of both clinical presentation as well as histopathologic variables (Deligdisch and Holinka, 1987)
TISSUE SPECIMENS Stage I endometrial cancers utilized for this study were collected from patients that enrolled on one of two different protocols: (1) a tissue and data collection protocol approved by the Institutional Review Board (IRB) at Duke University Medical Center; and (2) a tissue and data collection protocol (GOG-136) managed by the Gynecologic Oncology Group which was approved by the IRB of each institution that provided specimens to the central repository
We further evaluated the expression of six of these genes [Retinoic Acid Related (RAR) orphan receptor B (RORB), PEG3, TRH, S100A8, maternal embryonic leucine zipper kinase (MELK), and DLG7 ] using real-time quantitative PCR to validate the methodology of our array processing
Summary
The majority of endometrial malignancies are carcinomas, which historically have been characterized as Type I or Type II on the basis of both clinical presentation as well as histopathologic variables (Deligdisch and Holinka, 1987) Based on these criteria, Type I endometrial carcinomas are usually endometrioid in histology, present with early stage disease at diagnosis, are well-differentiated with respect to grade, and are often associated with a hyper-estrogenic milieu (Berchuck and Boyd, 1995). Type I endometrial carcinomas are usually endometrioid in histology, present with early stage disease at diagnosis, are well-differentiated with respect to grade, and are often associated with a hyper-estrogenic milieu (Berchuck and Boyd, 1995) These cancers display a high incidence of loss of function alterations in the PTEN tumor suppressor gene as well as defects in DNA mismatch repair resulting in microsatellite instability (Risinger et al, 1993, 1997; Tashiro et al, 1997). The definition of Type I and Type II is imprecise when high www.frontiersin.org
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