Frequent CCNE1 amplification in endometrial intraepithelial carcinoma and uterine serous carcinoma

Abstract

Uterine serous carcinoma accounts for only 10% of all uterine epithelial cancers, but is the leading cause of death among them. The pathogenesis of this aggressive neoplasm has been largely elusive until recently, when comprehensive genome-wide analyses of uterine serous carcinoma have been performed. Among amplified cancer-related genes, CCNE1, encoding for cyclin E1, is frequently amplified in uterine serous carcinoma. In the current study we applied fluorescence in situ hybridization (FISH) to determine CCNE1 copy number in uterine serous carcinoma and concurrent endometrial intraepithelial carcinoma, the noninvasive component of uterine serous carcinoma, and the results were correlated with clinicopathological and molecular features. We found that 20 (45%) of 44 uterine serous carcinomas and 11 (41%) of 27 endometrial intraepithelial carcinomas showed CCNE1 amplification. Overall, we found high concordance in CCNE1 copy number in concurrent uterine serous carcinoma and endometrial intraepithelial carcinoma pairs (P-value ¼ 0.0003). No correlation was observed between CCNE1 copy number and clinicopathological features, as well as common mutations previously reported in uterine serous carcinoma. In summary, we confirm that amplification of CCNE1 is a frequent molecular genetic change in uterine serous carcinoma. Moreover, the identification of CCNE1 amplification in many endometrial intraepithelial carcinomas suggests that this genetic event occurs early during tumor progression.

The history and future of targeting cyclin-dependent kinases in cancer therapy

“…Cyclin E1 or cyclin E2 amplifications are key oncogenic events in multiple cancers, particularly in uterine and ovarian cancers 75-77 (FIG. 4).…”

Characterization of the 19q12 amplification including CCNE1 and URI in different epithelial ovarian cancer subtypes

“…Both parameters are detectable on one slide and appear as black (19q12) and red (chr19) dots. A sample was considered amplified if the ratio of 19q12/INSR was found being equal to or greater 2.0 (Kuhn et al, 2014). Examples are shown in Fig.…”

“…The FISH signals were analyzed with a Zeiss fluorescence microscope, AXIO Imager Z1. CCNE1 amplification was defined as the ratio of CCNE1 to CEN19p ≥ 2 or high polysomy with ≥4 copies in N 40% cells (Kuhn et al, 2014). The URI amplification status was previously assessed by FISH (Theurillat et al, 2011).…”

The mutational landscape of endometrial cancer

“…Nonetheless it is noteworthy that the MYC and CCNE1 oncogenes [7,9], which encode oncoproteins regulated by the SCF FBXW7 ubiquitin ligase, as well as CHD4 and MBD3 which encode two subunits of the NuRD chromatin remodeling complex [9], and PIK3CA , which encodes the catalytic subunit of PI3-kinase [9] reside with statistically significant regions of copy number alteration. Because mutations in FBXW7 , CHD4 , and the PIK3CA have been implicated in serous EC [8,14–16], copy number alterations affecting components of the associated pathways or processes may also point to driver events.…”