CCNE1 Amplification May Precede Centrosome Number Abnormality in Progression from Serous Tubal Intraepithelial Carcinoma to High-Grade Ovarian Serous Carcinoma
Elisabetta Kuhn, Asli Bahadirli-Talbott, Robert Kurman, Ann Smith Sehdev, Tian-Li Wang, Ie-Ming Shih. Johns Hopkins Medical Institutions, Baltimore, MD; Legacy Health Systems, Portland, OR
Background: Genomic instability is the hallmark of most cancer cells, and has profound biological significance in tumor development. Overexpression of cyclin E, often due to amplification of the encoding gene CCNE1, facilitates genomic instability. Moreover, centrosome - the primary microtubule-organizing center in human cells - plays a critical role in chromosome segregation, and abnormalities of centrosome number result in genomic instability. Therefore, increased centrosome number (also called centrosome amplification) has been used as a surrogate marker of chromosomal instability. In this study we asked whether CCNE1 and centrosome amplification occur early during tumor progression from serous tubal intraepithelial carcinoma (STIC) to ovarian high-grade serous carcinoma (HGSC).
Design: A total of 37 STIC and 43 HGSC were investigated for CCNE1 copy number alterations using a fluorescence in situ hybridization (FISH) assay. CCNE1 amplification and high polysomy were considered FISH positive (+). A double-color immunofluorescence for γ-tubulin and α-tubulin was performed to simultaneously visualize centrosomes and microtubules, respectively.
Results: We found that 8 (22%) of 37 STICs were CCNE1 FISH +, of which 2 had high polysomy and 6 amplification. Interestingly, one out of 3 STICs not associated with HGSC showed CCNE1 high polysomy. 12 (28%) of 43 HGSCs were CCNE1 FISH +, including 2 high polysomy and 10 amplification. In this series, 30 STICs were associated with HGSC, of which 11 were bifocal. We found a significant concordance in CCNE1 copy number between STIC and HGSC from the same patient (p-value <0.001). There was no significant difference in the percentage of CCNE1 FISH + cases between STIC and HGSC (p=0.613, Chi square). On the other hand, centrosome amplification was recorded in only 3 (14%) of 21 STICs, but in 8 (47%) of 17 HGSCs. There was a significant increase in the percentage of cells with centrosome amplification in HGSC as compared to STIC (p= 0.0006, Wilcoxon rank test).
Conclusions: Our findings suggest that CCNE1 copy number gain occurs early in tumor progression while centrosome amplification may likely represent a later molecular event. Therefore, these two markers associated with genomic instability are involved at different stages of tumor progression in HGSC carcinogenesis.
Category: Gynecologic & Obstetrics
Tuesday, March 5, 2013 1:30 PM
Proffered Papers: Section B, Tuesday Afternoon