Gene Expression Analysis of Early Stage Endometrial Cancers Reveals Unique Transcripts Associated with Grade and Histology but Not Depth of Invasion

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.

Crosstalk between PKCα and PI3K/AKT Signaling Is Tumor Suppressive in the Endometrium

“…This notion is supported by our analysis of mouse models of PI3K/AKT-driven endometrial neoplasia, which demonstrated loss of PKCα expression in pre-malignant hyperplasia regardless of the nature of PTEN dysregulation. Additional supportive evidence is provided by previous transcriptome analysis of early Type I ECs, which demonstrated a 3-fold down-regulation of PKCα mRNA in tumors relative to normal endometrium (Saghir et al, 2010; Risinger et al, 2013), by stage-specific TCGA data, and by IHC analysis of a limited set of grade 1 ECs, which revealed regions of low or undetectable PKCα protein in a subset of lesions (Haughian et al, 2009). …”

LAT1 is a putative therapeutic target in endometrioid endometrial carcinoma

“…Gene expression data was downloaded from GEO (http://www.ncbi.nlm.nih.gov/geo/; GDS4589) and cBioPortal . Survival analysis was performed using cBioPortal website (http://www.cbioportal.org/) on the TCGA cohort…”

MicroRNAs in endometrial cancers from black and white patients

“…[11][12][13][14] Although we have consistently observed unique transcript expression patterns in various histologic types of endometrial cancer, we have not identified global differences in transcript expression between black and white endometrial cancer patients when corrected (matched) for histology, stage, and grade. 15,16 Recent data suggest that microRNAs (miRNAs) play important roles in regulating posttranscriptional events 14 thereby potentially leading to functional changes not evident from assessment of mRNA abundance levels. Our current study aimed to identify differences in miRNA expression in tumor cells from endometrioid endometrial cancers from black and white patients.…”