Extensive Telomere Erosion in the Initiation of Colorectal Adenomas and Its Association With Chromosomal Instability
Abstract
BACKGROUND: Telomere shortening, dysfunction, and fusion may facilitate the acquisition of large-scale genomic rearrangements, driving clonal evolution and tumor progression. The relative contribution that telomere dysfunction and/or APC mutation play in the chromosome instability that occurs during colorectal tumorigenesis is not clear. METHODS: We used high-resolution telomere length and fusion analysis to analyze 85 adenomatous colorectal polyps obtained from 10 patients with familial adenomatous polyposis and a panel of 50 colorectal carcinomas with patient-matched normal colonic mucosa. Telomerase activity was determined using the telomeric repeat amplification protocol. Array-CGH was used to detect large-scale genomic rearrangements. Pearson correlation and Student t test were used, and all statistical tests were two-sided. RESULTS: Despite the presence of telomerase activity, we observed apparent telomere shortening in colorectal polyps that correlated with large-scale genomic rearrangements (P < .0001) but was independent of polyp size and indistinguishable from that observed in colorectal carcinomas (P = .82). We also observed apparent lengthening of telomeres in both polyps and carcinomas. The extensive differences in mean telomere length of up to 4.6kb between patient-matched normal mucosa and polyps were too large to be accounted for by replicative telomere erosion alone. Telomere fusion events were detected in both polyps and carcinomas; the mutational spectrum accompanying fusion was consistent with alternative nonhomologous end joining. CONCLUSIONS: Telomere length distributions observed in colorectal polyps reflect the telomere length composition of the normal originating cells from which clonal growth was initiated. Originating cells containing both short telomeres and APC mutations may give rise to polyps that exhibit short telomeres and are prone to telomere dysfunction, driving genomic instability and progression to malignancy. J Natl Cancer Inst;2013;105:1202-1211.
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When telomeres are compromised by loss of TRF2, their repair is carried out by c-NHEJ.
“By contrast, when telomeres are compromised through the loss of TRF2, their repair is carried out by c-NHEJ80–82.”
From Telomeres in cancer: tumour suppression and genome instability (2017) · cites this paper as [80]
Genome instability in cells undergoing telomere crisis was initially found to cause aneuploidy, translocations, loss of heterozygosity, and regional amplification through breakage-fusion-bridge cycles.
“Genome instability in cells undergoing telomere crisis was initially found to give rise to chromosome gains and losses (aneuploidy), translocations, gene loss (manifested as loss of heterozygosity (LOH)) and regional amplification through breakage–fusion–bridge (BFB) cycles1,80,83.”
From Telomeres in cancer: tumour suppression and genome instability (2017) · cites this paper as [80]
Critically shortened telomeres are frequently observed in early neoplastic lesions.
“Critically shortened telomeres are frequently observed in early neoplastic lesions [86,346,347]”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [347]
Studies on telomere dynamics and karyotype analysis in many human tumor types revealed telomeric fusions indicative of telomere crisis.
“studies on telomere dynamics and karyotype analysis in many human tumor types revealed telomeric fusions, indicative of telomere crisis [347,352,354,355].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [347]
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Telomeres in cancer: tumour suppression and genome instability
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- Authors
- Roger, L., Jones, R. E., Heppel, N. H., Williams, G. T., Sampson, J. R., & Baird, D. M.
- Affiliations
- Cardiff University (GB)
- Venue
- JNCI: Journal of the National Cancer Institute
- Publisher
- Oxford University Press (OUP)
- Published
- 2013-08-13
- Volume
- 105
- Issue
- 16
- Pages
- 1202-1211
- ISSN
- 0027-8874 (ISSN-L)
- 1460-2105
- OpenAlex
- W2034615025
- Cited by
- 97
- References
- 8
- Citations by year
- 2025: 2 · 2024: 8 · 2023: 6 · 2022: 4 · 2021: 9 · 2020: 4 · 2019: 4 · 2018: 13 · 2017: 18 · 2016: 7 · 2015: 12 · 2014: 8 · 2013: 2
- FWCI
- 6.71
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- JNCI Journal of the National Cancer Institute (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- Cancer Research UK (C17199/A13490)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- telomere shortening, telomere fusion, telomere length, colorectal adenoma, colorectal cancer, familial adenomatous polyposis, chromosomal instability, telomerase activity, APC mutation, clonal evolution, colorectal carcinogenesis
- MeSH terms
- Aneuploidy, Cell Transformation, Neoplastic, DNA, Neoplasm, Humans, Adenomatous Polyposis Coli, Colorectal Neoplasms, Disease Progression, Chromosomal Instability, Comparative Genomic Hybridization, Telomere Shortening, Wnt Signaling Pathway
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