Telomere Length Abnormalities Occur Early in the Initiation of Epithelial Carcinogenesis
Abstract
Purpose: Telomeres help maintain chromosomal integrity. Dysfunctional telomeres can cause genetic instability in vitro and an increased cancer incidence in telomerase knock out mouse models. We recently reported that telomere shortening was a prevalent alteration in human prostate, pancreas, and breast cancer precursor lesions. In the present study, we address whether the previous findings are broadly applicable to human epithelial cancer precursors in general. Experimental Design: Surgical specimens of epithelial cancer precursor lesions from the urinary bladder, esophagus, large intestine, oral cavity, and uterine cervix were examined using a recently developed technique for direct in situ telomere length assessment in formalin-fixed human tissue specimens. Results: Widespread telomere length abnormalities were nearly universal (97.1% of cases) in the preinvasive stages of human epithelial carcinogenesis in all sites examined in this series, with telomere shortening the predominant abnormality (88.6% of cases). Conclusions: Telomere length abnormalities appear to be one of the earliest and most prevalent genetic alterations acquired in the multistep process of malignant transformation. These findings support a model whereby telomere dysfunction induces chromosomal instability as an initiating event in many, perhaps most, human epithelial cancers. Together with previous findings from the prostate and pancreas, the percentage of intraepithelial neoplasia lesions showing telomere length abnormalities is 95.6%. The implications of these findings include the potential that telomere length assessment in situ may be a widely useful biomarker for monitoring disease prevention strategies and for improved early diagnosis.
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Shorter telomeres are frequently observed in cancer relative to adjacent normal tissue.
“Shorter telomeres are frequently observed in cancer relative to their adjacent normal tissue135–142.”
From Telomeres in cancer: tumour suppression and genome instability (2017) · cites this paper as [142]
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 [346]
Telomeres were shorter in invasive breast, prostate and pancreatic cancers and in their pre-invasive counterparts.
“telomeres were shown to be shorter in invasive cancers Telomeres and telomerase in cancer of the breast, prostate and pancreas, as well as in their pre-invasive counterparts (123-126).”
From Telomeres and telomerase in cancer (2010) · cites this paper as [125]
Both telomere dysfunction and the DDR are activated at the earliest stages in many human carcinomas.
“Recent observations indicate that both telomere dysfunction73, 74 and the DDR75, 76 are activated at the earliest stages in many human carcinomas.”
From Telomere dysfunction and tumour suppression: the senescence connection (2008) · cites this paper as [74]
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- Authors
- Meeker, A. K., Hicks, J. L., Iacobuzio-Donahue, C. A., Montgomery, E. A., Westra, W. H., Chan, T. Y., Ronnett, B. M., & De Marzo, A. M.
- Affiliations
- Johns Hopkins University (US)
- 2Pathology and
- 1Brady Urological Institute, and Departments of
- Venue
- Clinical Cancer Research
- Published
- 2004-05-15
- Volume
- 10
- Issue
- 10
- Pages
- 3317-3326
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- OpenAlex
- W2122672345
- Cited by
- 306
- References
- 8
- Citations by year
- 2025: 3 · 2024: 2 · 2023: 9 · 2022: 3 · 2021: 12 · 2020: 11 · 2019: 11 · 2018: 13 · 2017: 12 · 2016: 17 · 2015: 16 · 2014: 9 · 2013: 23 · 2012: 15
- FWCI
- 12.74
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Johns Hopkins University
- National Institutes of Health (5k08ca078588-02)
- National Cancer Institute (P50CA058236, K08CA78588, P50-CA58236)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK07552)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- telomere length, telomere shortening, epithelial carcinogenesis, precancerous lesions, chromosomal instability, telomere dysfunction, malignant transformation, biomarkers, early diagnosis, bladder cancer, esophageal cancer, colorectal cancer, oral cancer, cervical cancer
- MeSH terms
- Adult, Aged, Animals, Urinary Bladder Neoplasms, Breast Neoplasms, Uterine Cervical Neoplasms, Chromosome Aberrations, Chromosomes, Colonic Neoplasms, Epithelial Cells, Esophageal Neoplasms, Female, Humans, Image Processing, Computer-Assisted, Male, Middle Aged, Mouth Neoplasms, Neoplasms, Neoplasms, Glandular and Epithelial, Nucleic Acid Hybridization, Prostatic Neoplasms, Biomarkers, Tumor, Telomere, In Situ Hybridization, Fluorescence, Mice, Knockout, Mice
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