Onset of Telomere Dysfunction and Fusions in Human Ovarian Carcinoma.

Nazmul Huda,Nagarajan Kannan,Alison M Bates,Yan Xu,Deborah A Rankin,David Gilley

doi:10.3390/cells8050414

Abstract

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.

Highlights

The telomere, terminal chromosomal tandem DNA repeats and associated proteins, prevents the cellular DNA repair machinery from recognizing chromosome ends as double strand breaks [1].Telomerase is a special DNA polymerase with an integral RNA moiety that acts as a template for the synthesis of telomeric DNA [2]
Since degradation of the telomere has been implicated in the initiation of telomere fusions mRNA expression of the aforementioned catalytic subunit of the telomerase enzyme, known as andhTERT, subsequent breakage-fusion-bridge we examined telomere length in our samples
We determined the extent of telomere dysfunction in human epithelial ovarian carcinoma in order

Summary

Introduction

The telomere, terminal chromosomal tandem DNA repeats and associated proteins, prevents the cellular DNA repair machinery from recognizing chromosome ends as double strand breaks [1]. Telomerase is a special DNA polymerase with an integral RNA moiety that acts as a template for the synthesis of telomeric DNA [2]. Human mitotic somatic cells generally do not contain sufficient levels of telomerase to maintain telomere length, which causes telomere shortening with each cell cycle due to the “end replication problem” presented by conventional cellular DNA polymerases. Cells with potentially only one or a few critically shortened telomeres are likely eliminated via senescence and/or cell death. A very rare cell (or cells) may bypass these cellular elimination pathways resulting in telomere dysfunction-induced genomic instability via breakage-fusion-bridge cycles

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