Telomeres and Genomic Instability from Precancerous Lesions to Advanced Cancer – Understanding Through Ovarian Cancer

Genetic instability plays an important role in ovarian carcinogenesis. Genetic instability is one of the characteristics shared by most human cancers and seems to exist (at various levels) at all stages of the disease, from precancerous lesions to advanced cancer. It is possible that this instability is one of the first trigger events, which would facilitate the subsequent establishment of all the other cancer hallmarks. Telomere shortening appears to take place in most human preinvasive epithelial lesions: short telomeres are found in up to 88% of early precancerous conditions of the bladder, cervix, colon, esophagus, or prostate. However, little is known about ovarian carcinogenesis and telomere shortening. Recent evidence has shown that the fallopian tube may be the origin of ovarian cancer. A new tubal carcinogenic sequence has been described with precancerous lesions that could metastasize to the ovary and result in invasive ovarian cancer. In this review, we will describe the degree of telomere shortening and genomic instability (estimated by the expression of DNA damage response proteins, such as H2AX, Chk2, ATM, 53BP1, p53, and TRF2, and by array comparative genomic hybridization) in early preinvasive stages of ovarian cancer (serous tubal intraepithelial carcinoma (STIC)), ovarian high-grade serous carcinoma, and benign controls. Given that STICs have the shortest telomeres, they could be in a telomere crisis phase preceding genomic stabilization due to telomerase activation (see appended diagram). Concordant results were obtained in immunohistochemical and molecular studies. The expression of all DNA damage proteins increased from benign fallopian tubes to STICs suggesting an early activation of the DNA damage response (DDR) pathways in STICs and indicating that genomic instability may occur early in the precancerous lesions of high-grade serous ovarian cancer (HGSC). In this chapter, we propose to review current knowledge about the function of human telomeres and telomerase and their relevance in genomic instability in cancer and to focus on specific results for ovarian cancer