Importance It is known that oocytes undergo aging that is caused by exposure to an aged ovarian microenvironment. Telomere length in mouse and bovine oocytes declines with age, and age-associated telomere shortening in oocytes is considered a sign of poor development competency. Women with advanced age undergoing assisted reproductive technologies have poor outcomes because of increasing aneuploidy rates with age. Research has shown that aneuploidy is associated with DNA damage, reactive oxygen species, and telomere dysfunction. Objective In this review, we focus on the possible relationship between telomere dysfunction and aneuploidy in human early embryo development and several reproductive and perinatal outcomes, discussing the mechanism of aneuploidy caused by telomere shortening and fusion in human embryos. Evidence acquisition We reviewed the current literature evidence concerning telomere dysfunction and aneuploidy in early human embryo development. Results Shorter telomeres in oocytes, leukocytes, and granulosa cells, related to aging in women, were associated with recurrent miscarriage, trisomy 21, ovarian insufficiency, and decreasing chance of in vitro fertilization success. Telomere length and telomerase activity in embryos have been related to the common genomic instability at the cleavage stage of human development. Complications of assisted reproductive technology pregnancies, such as miscarriage, birth defects, preterm births, and intrauterine growth restriction, also might result from telomere shortening as observed in oocytes, polar body, granulosa cells, and embryos. Conclusions and relevance Telomere length clearly plays an important role in the development of the embryo and fetus, and the abnormal shortening of telomeres is likely involved in embryo loss during early human development. However, telomere fusion studies have yet to be performed in early human development.

Telomere Shortening and Fusions: A Link to Aneuploidy in Early Human Embryo Development.

Chromosome instability (CIN) is an early step in carcinogenesis that promotes tumor cell progression and resistance to therapy. Using plasmids integrated adjacent to telomeres, we have previously demonstrated that the sensitivity of subtelomeric regions to DNA double-strand breaks (DSBs) contributes to telomere loss and CIN in cancer. A high-throughput screen was created to identify compounds that affect telomere loss due to subtelomeric DSBs introduced by I-SceI endonuclease, as detected by cells expressing green fluorescent protein (GFP). A screen of a library of 1832 biologically-active compounds identified a variety of compounds that increase or decrease the number of GFP-positive cells following activation of I-SceI. A curated screen done in triplicate at various concentrations found that inhibition of classical nonhomologous end joining (C-NHEJ) increased DSB-induced telomere loss, demonstrating that C-NHEJ is functional in subtelomeric regions. Compounds that decreased DSB-induced telomere loss included inhibitors of mTOR, p38 and tankyrase, consistent with our earlier hypothesis that the sensitivity of subtelomeric regions to DSBs is a result of inappropriate resection during repair. Although this assay was also designed to identify compounds that selectively target cells experiencing telomere loss and/or chromosome instability, no compounds of this type were identified in the current screen. 

High-throughput screen to identify compounds that prevent or target telomere loss in human cancer cells

Ovarian cancer (OC) shows the highest mortality rate among gynecological malignancies and, because of the absence of specific symptoms, it is frequently diagnosed at an advanced stage, mainly due to the lack of specific and early biomarkers, such as those based on cancer molecular signature identification. Indeed, although significant progress has been made toward improving the clinical outcome of other cancers, rates of mortality for OC are essentially unchanged since 1980, suggesting the need of new approaches to identify and characterize the molecular mechanisms underlying pathogenesis and progression of these malignancies. In addition, due to the low response rate and the high frequency of resistance to current treatments, emerging therapeutic strategies against OC focus on targeting single factors and pathways specifically involved in tumor growth and metastasis. To date, loss-of-function screenings are extensively applied to identify key drug targets in cancer, seeking for more effective, disease-tailored treatments to overcome lack of response or resistance to current therapies. We review here the information relative to essential genes and functional pathways recently discovered in OC, often strictly interconnected with each other and representing promising biomarkers and molecular targets to treat these malignancies.

An Overview of Candidate Therapeutic Target Genes in Ovarian Cancer.

Modified hTERT promoters-driven purine nucleoside phosphorylase-gene therapy in association with chemo- and targeted therapy in the context of ovarian cancer

Telomere Length as a Predictor of Therapy Response and Survival in Patients Diagnosed with Ovarian Carcinoma

Telomere dysfunction has been strongly implicated in the initiation of genomic instability and is suspected to be an early event in the carcinogenesis of human solid tumors. Recent findings have established the presence of telomere fusions in human breast and prostate malignancies; however, the onset of this genomic instability mechanism during progression of other solid cancers is not well understood. Herein, we explored telomere dynamics in patient-derived epithelial ovarian cancers (OC), a malignancy characterized by multiple distinct subtypes, extensive molecular heterogeneity, and widespread genomic instability. We discovered a high frequency of telomere fusions in ovarian tumor tissues; however, limited telomere fusions were detected in normal adjacent tissues or benign ovarian samples. In addition, we found relatively high levels of both telomerase activity and hTERT expression, along with anaphase bridges in tumor tissues, which were notably absent in adjacent normal ovarian tissues and benign lesions. These results suggest that telomere dysfunction may occur early in ovarian carcinogenesis and, importantly, that it may play a critical role in the initiation and progression of the disease. Recognizing telomere dysfunction as a pervasive feature of this heterogeneous malignancy may facilitate the future development of novel diagnostic tools and improved methods of disease monitoring and treatment.

Onset of Telomere Dysfunction and Fusions in Human Ovarian Carcinoma

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Onset of Telomere Dysfunction and Fusions in Human Ovarian Carcinoma

Onset of Telomere Dysfunction and Fusions in Human Ovarian Carcinoma