CCNE1 Amplification and Centrosome Number Abnormality in Serous Tubal Intraepithelial Carcinoma- Further Evidence Supporting its Role as a Precursor of Ovarian High-Grade Serous Carcinoma

Aberration in chromosomal structure characterizes almost all cancers and has profound biological significance in tumor development. It can be facilitated by various mechanisms including overexpression of cyclin E1 and centrosome amplification. Since ovarian high-grade serous carcinoma has pronounced chromosomal instability, in this study we sought to determine if increased copy number of CCNE1 which encodes cyclin E1 and centrosome amplification (> 2 copies) occur in its putative precursor, serous tubal intraepithelial carcinoma. We found CCNE1 copy number gain/amplification in 8 (22%) of 37 serous tubal intraepithelial carcinomas and 12 (28%) of 43 high-grade serous carcinomas. There was a correlation in CCNE1 copy number between serous tubal intraepithelial carcinoma and high-grade serous carcinoma in the same patient (p <0.001). There was no significant difference in the percentage of CCNE1 gain/amplification between serous tubal intraepithelial carcinoma and high-grade serous carcinoma (p= 0.61). Centrosome amplification was recorded in only 5 (14%) of 37 serous tubal intraepithelial carcinomas, and in 10 (40%) of 25 high-grade serous carcinomas. The percentage of cells with centrosome amplification was higher in high-grade serous carcinoma than serous tubal intraepithelial carcinoma (p< 0.001). Induced expression of cyclin E1 increased the percentage of fallopian tube epithelial cells showing centrosome amplification. Our findings suggest that gain/amplification of CCNE1 copy number occurs early in tumor progression and precedes centrosome amplification. The more prevalent centrosome amplification in high-grade serous carcinoma than serous tubal intraepithelial carcinoma supports the view that serous tubal intraepithelial carcinoma precedes the development of many high-grade serous carcinomas.