Early telomere shortening and genomic instability in tubo-ovarian preneoplastic lesions
Cette étude évalue le niveau de raccourcissement des télomères et d'instabilité génomique dans des échantillons prélevés sur 51 patientes présentant des mutations BRCA1 ou BRCA2 et atteintes d'une dysplasie tubo-ovarienne, sur 12 patientes atteintes d'un carcinome intrépithélial tubaire séreux, 53 patientes atteintes d'un carcinome séreux tubo-ovarien de haut grade et 36 témoins
Purpose: Genetic instability plays an important role in ovarian carcinogenesis. We investigated the level of telomere shortening and genomic instability in early and pre-invasive stages of ovarian cancer, serous tubal intraepithelial carcinoma (STIC) and tubo-ovarian dysplasia (TOD). 51 TOD from prophylactic salpingo-oophorectomies with BRCA 1 or 2 mutation, 12 STICs, 53 tubo-ovarian high grade serous carcinoma and 36 non-cancerous controls were laser-capture microdissected from formalin-fixed paraffin-embedded sections, analyzed by comparative genomic hybridization (array CGH) and for telomere length (using quantitative real-time polymerase chain reaction based on the Cawthon's method). TOD and STICs were defined by morphological scores and immunohistochemical expressions of p53, Ki67 and γH2AX. Results: TOD showed marked telomere shortening compared to non-cancerous controls (p< 10-7). STICs had even shorter telomeres than TOD (p= 0.0008). Ovarian carcinoma had shorter telomeres than controls, but longer than STICs and dysplasia. In TOD, telomeres were significantly shorter in case of BRCA1 mutation than in case of BRCA2 mutation (p = 0.005). In addition, γH2AX expression in TOD and STIC groups with short telomeres was significantly increased (p < 10-7). 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 non invasive dysplasia are likely an important step in early serous ovarian neoplasia.