Telomeres are nucleoprotein structures that function to cap the ends of linear chromosomes, preventing them from being recognised as DNA double strand breaks. In normal somatic cells, telomeres shorten with each round of cell division, eventually resulting in cell cycle arrest. The replicative immortality of human cancer cells is achieved by activation of a telomere maintenance mechanism (TMM) to extend telomeric DNA and counteract telomere attrition. To achieve this, cancer cells utilise either the enzyme telomerase, or the Alternative Lengthening of Telomeres (ALT) pathway. These distinct molecular pathways are incompletely understood with respect to activation and propagation, as well as their associations with clinical outcomes. We have identified significant differences in the telomere repeat composition of tumours that use ALT compared to tumours that do not. We have used these differences to stratify the TMM of tumours using telomere reads extracted from whole genome sequencing datasets. This has enabled us to investigate the genetic signatures associated with telomerase and ALT activation in cancers. Importantly, this classification approach is applicable across all tumour types. Analysis of pathway mutations that were under-represented in ALT tumours, across 1,075 tumour samples, revealed that the autophagy, cell cycle control of chromosomal replication, and transcriptional regulatory network in embryonic stem cells pathways are involved in the survival of ALT tumours. We are currently conducting functional studies to determine how these pathways contribute to ALT activation and propagation. Overall, our approach demonstrates that telomere sequence content can be used to stratify TMM in cancers, and has identified novel molecular mechanisms involved in these pathways.
Telomeres are nucleoprotein structures that function to cap the ends of linear chromosomes, preventing them from being recognised as DNA double strand breaks. In normal somatic cells, telomeres shorten with each round of cell division, eventually resulting in cell cycle arrest. The replicative immortality of human cancer cells is achieved by activation of a telomere maintenance mechanism (TMM) to extend telomeric DNA and counteract telomere attrition. To achieve this, cancer cells utilise either the enzyme telomerase, or the Alternative Lengthening of Telomeres (ALT) pathway. These distinct molecular pathways are incompletely understood with respect to activation and propagation, as well as their associations with clinical outcomes. We have identified significant differences in the telomere repeat composition of tumours that use ALT compared to tumours that do not. We have used these differences to stratify the TMM of tumours using telomere reads extracted from whole genome sequencing datasets. This has enabled us to investigate the genetic signatures associated with telomerase and ALT activation in cancers. Importantly, this classification approach is applicable across all tumour types. Analysis of pathway mutations that were under-represented in ALT tumours, across 1,075 tumour samples, revealed that the autophagy, cell cycle control of chromosomal replication, and transcriptional regulatory network in embryonic stem cells pathways are involved in the survival of ALT tumours. We are currently conducting functional studies to determine how these pathways contribute to ALT activation and propagation. Overall, our approach demonstrates that telomere sequence content can be used to stratify TMM in cancers, and has identified novel molecular mechanisms involved in these ...
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