Telomere length abnormalities occur early in the initiation of epithelial carcinogenesis.
OBJECTIVE
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.


METHODS
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.
Meeker
Alan K
AK
Brady Urological Institute, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
Hicks
Jessica L
JL
Iacobuzio-Donahue
Christine A
CA
Montgomery
Elizabeth A
EA
Westra
William H
WH
Chan
Theresa Y
TY
Ronnett
Brigitte M
BM
De Marzo
Angelo M
AM
D000328:Adult; D000368:Aged; D000818:Animals; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000473:pathology; D002869:Chromosome Aberrations; D002875:Chromosomes / Q000378:metabolism; D003110:Colonic Neoplasms / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism*; D004938:Esophageal Neoplasms / Q000378:metabolism; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D009062:Mouth Neoplasms / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics / Q000648:ultrastructure*; D009693:Nucleic Acid Hybridization; D011471:Prostatic Neoplasms / Q000378:metabolism; D016615:Telomere / Q000648:ultrastructure*; D001749:Urinary Bladder Neoplasms / Q000378:metabolism; D002583:Uterine Cervical Neoplasms / Q000378:metabolism
D014408:Biomarkers, Tumor