Time Lapse to Cancer: Defining the Transition From Polyp to Colorectal Cancer Based on Telomere Metrics

Abstract

Introduction: Despite advances in prevention and early detection strategies, colorectal cancer (CRC) remains the second leading cause of cancer death in the United States. While the majority of CRC arises from adenomatous polyps, only 5% of colonoscopies result in a lesion determined to be at high risk for malignant transformation. It is essential to further understand the factors that lead only a small portion of polyps to progress to cancer. Telomere length is a recognized biomarker in multiple cancers, but the comprehensive role of telomeres in CRC progression has not been addressed. Telomere shortening and exploitation of telomere maintenance mechanisms (TMM) are implicated in carcinogenesis. Here we identify telomere metrics that distinguish polyps with aggressive features that remain benign from those that transform to cancer. Methods: We have measured telomere length and TMM in patient peripheral blood leukocytes (PBL), normal colon epithelium, polyp and adjacent CRC tumor trios and PBL, normal colon and cancer-free polyp pairs. Telomere length was determined using qPCR. TMM were determined through expression analysis of hTERT and hTR (TERC), and alternative lengthening of telomeres (ALT). Results: We found that extensive shortening occurs in the polyp and tumor of aggressive patients, while the non-aggressive patients show either lengthening in the tumor or only subtle changes in telomere length as compared to the normal colon. We also found that the telomere length of the normal colon exhibits lengthening compared to the PBL. This lengthening occurs more dramatically in the aggressive cases, suggesting early transformation events in the normal colon. We found that in the aggressive tumors that exhibited telomere shortening, expression of hTERT and hTR were increased compared to the non-aggressive tumors. In contrast, ALT was decreased in the aggressive tumors and highly elevated in the non-aggressive tumors. Conclusion: The finding that both telomere length and TMM are associated with aggressiveness of CRC is a novel finding for colorectal cancer research. Identifying changes in a patient's telomere profile between an individual's blood, normal and tumor cells may be used to characterize subtypes of disease based on telomere metrics for prognostication. We plan to examine additional telomere features to distinguish subtypes of disease and determine their potential for therapeutic targets.