Studies on the association of telomeres and cancer have sought to identify predictive and prognostic biomarkers for malignancy, targets for prevention and treatment, and a better understanding of the mechanisms underlying carcinogenesis. Telomeres are tandem repeated DNA sequences that cap linear chromosomes to maintain stability. Prolonged cell division after telomere depletion can be associated with diseases such as cancer. Malignant cells can also exploit one of two primary telomere maintenance mechanisms (TMM), which are normally dormant in somatic cells. The role of telomere length changes and differential engagement of TMM in colorectal cancer (CRC) survival remain unclear. With CRC being the second leading cause of cancer death in the United States, predicting survival for a CRC patient is crucial for individualizing care. Telomere length is a recognized biomarker in multiple cancers and is associated with cancer patient survival, but the comprehensive telomere profile of the individual has yet to be integrated into a clinically actionable survival prediction model for CRC patients. In fact, CRC survival has been linked to the host peripheral blood leukocyte (PBL) telomere length, where patients with shorter PBL telomeres have increased cancer mortality. However, cancer patients with genetically determined shorter telomeres actually have better survival rates. Additionally, inhibitors of a TMM component have shown promise for cancer treatment in vitro. Further characterization of telomere length stratified by genetic variation in telomere-related genes, as well as the TMM across CRC patients is necessary to understand the role of telomere dynamics in neoplastic transformation and further clarify the association between telomere length, genotype, TMM and CRC survival. The overall objective of this proposal is to identify novel relationships between telomere length, telomere-related genotype, TMM and features linked to CRC prognosis in the host PBL, normal colon, and tumor in order to establish a more accurate predictive model of disease-free survival for CRC. In the first two aims, we will measure telomere length, genotype of host PBL and TMM in PBL, normal colon and tumor in multiple CRC patients with accompanying survival data.
The final aim of our proposal is to develop a survival prediction tool incorporating the host PBL, normal colon and tumor telomere phenotype that will be pertinent to an individual with CRC rather than a model that evaluates survival trends at a population level. The work accomplished through this proposal will 1) provide a comprehensive profile of telomere length and TMM patterns in PBL, normal colon and tumor alone and the relationship of these telomere metrics across these three corresponding tissue compartments, 2) determine important prognostic telomere phenotypes in order to construct a biomarker panel that correlates with CRC survival; and 3) develop a survival prediction model incorporating the telomere phenotype (telomere length, telomere length-related genetic variants and TMM) with molecular and clinical features that will improve prediction for a patient's chance of survival fro CRC. This is an innovative approach that will move the fields of CRC and telomere research forward and produce the deliverable of a comprehensive telomere metrics biomarker panel for CRC prognostication and a survival prediction tool for clinical decision-making.
Telomeres and telomere maintenance mechanisms maintain genetic stability, and their disruption is associated with the development of many diseases including cancer. The results generated in this proposal will provide the first comprehensive profile of telomere dynamics across multiple colorectal cancer patient tissues. This information will be integrated into a survival prediction tool that will outperform existing clinical predictio models, which has the potential to improve detection, prevention and treatment of colorectal cancer.
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