Widespread telomere instability in prostatic lesions.
A critical function of the telomere is to disguise chromosome ends from cellular recognition as double strand breaks, thereby preventing aberrant chromosome fusion events. Such chromosome end-to-end fusions are known to initiate genomic instability via breakage-fusion-bridge cycles. Telomere dysfunction and other forms of genomic assault likely result in misregulation of genes involved in growth control, cell death, and senescence pathways, lowering the threshold to malignancy and likely drive disease progression. Shortened telomeres and anaphase bridges have been reported in a wide variety of early precursor and malignant cancer lesions including those of the prostate. These findings are being extended using methods for the analysis of telomere fusions (decisive genetic markers for telomere dysfunction) specifically within human tissue DNA. Here we report that benign prostatic hyperplasia (BPH), high-grade prostatic intraepithelial neoplasia (PIN), and prostate cancer (PCa) prostate lesions all contain similarly high frequencies of telomere fusions and anaphase bridges. Tumor-adjacent, histologically normal prostate tissue generally did not contain telomere fusions or anaphase bridges as compared to matched PCa tissues. However, we found relatively high levels of telomerase activity in this histologically normal tumor-adjacent tissue that was reduced but closely correlated with telomerase levels in corresponding PCa samples. Thus, we present evidence of high levels of telomere dysfunction in BPH, an established early precursor (PIN) and prostate cancer lesions but not generally in tumor adjacent normal tissue. Our results suggest that telomere dysfunction may be a common gateway event leading to genomic instability in prostate tumorigenesis. .
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana.
LiRen
L
Tu
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana.
Nazmul
N
Huda
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana.
Brenda R
BR
Grimes
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana.
Roger B
RB
Slee
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana.
Alison M
AM
Bates
Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
Liang
L
Cheng
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana.
David
D
Gilley
D000368:Aged; D000369:Aged, 80 and over; D045744:Cell Line, Tumor; D043171:Chromosomal Instability; D006367:HeLa Cells; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D011470:Prostatic Hyperplasia / Q000235:genetics*; D019048:Prostatic Intraepithelial Neoplasia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016615:Telomere / Q000378:metabolism*
benign prostatic hyperplasia; genomic instability; prostate cancer; prostatic intraepithelial neoplasia; telomere dysfunction