Human Cancer Biology Early Telomere Shortening and Genomic Instability in Tubo-Ovarian Preneoplastic Lesions

Purpose:Genetic instability plays an important role in ovarian carcinogenesis. We investigated the level of telomere shortening and genomic instability in early andpreinvasive stages of ovarian cancer, serous tubal intraepithelial carcinoma (STIC), and tubo-ovarian dysplasia (TOD). Experimental Design: Fifty-one TOD from prophylactic salpingo-oophorectomies with BRCA1 or 2 mutation, 12 STICs, 53 tubo-ovarian high-grade serous carcinoma, and36noncancerous controlswere laser capturemicrodissected from formalin-fixed, paraffin-embedded sections, analyzedby comparative genomic hybridization (array CGH) and for telomere length (using quantitative real-time PCR based on the Cawthon’s method). TOD and STICs were defined by morphologic scores and immunohistochemical expressions of p53, Ki67, and gH2AX. Results: TOD showed marked telomere shortening compared with noncancerous controls (P < 10 ). STICs had even shorter telomeres than TOD (P 1⁄4 0.0008). Ovarian carcinoma had shorter telomeres than controls but longer than STICs and dysplasia. In TOD, telomeres were significantly shorter in those with BRCA1 mutation than in those with BRCA2 mutation (P1⁄4 0.005). In addition, gH2AX expression in TOD and STIC groups with short telomeres was significantly increased (P < 10 ). In dysplastic epithelium, we found subtle genomic alterations, in contrast to more important genomic imbalances in STICs. The total number of genetic alterations was the highest in ovarian cancers. Conclusions: These findings suggest that genetic instability occurs in early stages of ovarian tumorigenesis. STICs and noninvasive dysplasia are likely an important step in early serous ovarian neoplasia. Clin Cancer Res; 19(11); 2873–82. 2013 AACR.