PMID- 25893825 OWN - NLM STAT- MEDLINE DCOM- 20150828 LR - 20220223 IS - 1097-0045 (Electronic) IS - 0270-4137 (Print) IS - 0270-4137 (Linking) VI - 75 IP - 11 DP - 2015 Aug 1 TI - Prostate stromal cell telomere shortening is associated with risk of prostate cancer in the placebo arm of the Prostate Cancer Prevention Trial. PG - 1160-6 LID - 10.1002/pros.22997 [doi] AB - BACKGROUND: Telomeres are repetitive nucleoproteins that help maintain chromosomal stability by inhibiting exonucleolytic degradation, prohibiting inappropriate homologous recombination, and preventing chromosomal fusions by suppressing double-strand break signals. We recently observed that men treated for clinically localized prostate cancer with shorter telomeres in their cancer-associated stromal cells, in combination with greater variation in cancer cell telomere lengths, were significantly more likely to progress to distant metastases, and die from their disease. Here, we hypothesized that shorter stromal cell telomere length would be associated with prostate cancer risk at time of biopsy. METHODS: Telomere-specific fluorescence in situ hybridization (FISH) analysis was performed in normal-appearing stromal, basal epithelial, and luminal epithelial cells in biopsies from men randomized to the placebo arm of the Prostate Cancer Prevention Trial. Prostate cancer cases (N = 32) were either detected on a biopsy performed for cause or at the end of the study per trial protocol, and controls (N = 50), defined as negative for cancer on an end-of-study biopsy performed per trial protocol (e.g., irrespective of indication), were sampled. Logistic regression was used to estimate the association between mean telomere length of the particular cell populations, cell-to-cell telomere length variability, and risk of prostate cancer. RESULTS: Men with short stromal cell telomere lengths (below median) had 2.66 (95% CI 1.04-3.06; P = 0.04) times the odds of prostate cancer compared with men who had longer lengths (at or above median). Conversely, we did not observe statistically significant associations for short telomere lengths in normal-appearing basal (OR = 2.15, 95% CI 0.86-5.39; P= 0 .10) or luminal (OR = 1.15, 95% CI 0.47-2.80; P = 0.77) cells. CONCLUSIONS: These findings suggest that telomere shortening in normal stromal cells is associated with prostate cancer risk. It is essential to extend and validate these findings, while also identifying the cellular milieu that comprises the subset of cells with short telomeres within the prostate tumor microenvironment. CI - (c) 2015 Wiley Periodicals, Inc. FAU - Heaphy, Christopher M AU - Heaphy CM AD - Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland. AD - Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland. FAU - Gaonkar, Gaurav AU - Gaonkar G AD - Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland. FAU - Peskoe, Sarah B AU - Peskoe SB AD - Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland. FAU - Joshu, Corinne E AU - Joshu CE AD - Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland. AD - Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland. FAU - De Marzo, Angelo M AU - De Marzo AM AD - Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland. AD - Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland. AD - Department of Urology and the James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland. FAU - Lucia, M Scott AU - Lucia MS AD - University of Colorado School of Medicine, Aurora, Colorado. FAU - Goodman, Phyllis J AU - Goodman PJ AD - SWOG Statistical Center, and the Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington. FAU - Lippman, Scott M AU - Lippman SM AD - Moores Cancer Center, University of California, San Diego, California. FAU - Thompson, Ian M Jr AU - Thompson IM Jr AD - UT Health Science Center at San Antonio, San Antonio, Texas. FAU - Platz, Elizabeth A AU - Platz EA AD - Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland. AD - Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland. AD - Department of Urology and the James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland. FAU - Meeker, Alan K AU - Meeker AK AD - Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland. AD - Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland. AD - Department of Urology and the James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland. LA - eng GR - U10 CA037429/CA/NCI NIH HHS/United States GR - P50 CA058236/CA/NCI NIH HHS/United States GR - P01 CA108964/CA/NCI NIH HHS/United States GR - U10 CA37429/CA/NCI NIH HHS/United States GR - UG1 CA189974/CA/NCI NIH HHS/United States GR - P50 CA58236/CA/NCI NIH HHS/United States GR - UM1 CA182883/CA/NCI NIH HHS/United States PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20150420 PL - United States TA - Prostate JT - The Prostate JID - 8101368 RN - 0 (5-alpha Reductase Inhibitors) RN - 57GNO57U7G (Finasteride) SB - IM MH - 5-alpha Reductase Inhibitors/administration & dosage MH - Biopsy MH - Chromosomal Instability MH - Disease Progression MH - Finasteride/*administration & dosage MH - Humans MH - Male MH - Middle Aged MH - Prostate/*pathology MH - *Prostatic Neoplasms/drug therapy/genetics/pathology/physiopathology MH - Risk Factors MH - Stromal Cells/*pathology MH - Telomere Homeostasis MH - *Telomere Shortening PMC - PMC4475463 MID - NIHMS673417 OTO - NOTNLM OT - Telomere OT - prostate cancer OT - stroma OT - tumor microenvironment EDAT- 2015/04/22 06:00 MHDA- 2015/09/01 06:00 PMCR- 2016/08/01 CRDT- 2015/04/21 06:00 PHST- 2015/01/09 00:00 [received] PHST- 2015/03/09 00:00 [accepted] PHST- 2015/04/21 06:00 [entrez] PHST- 2015/04/22 06:00 [pubmed] PHST- 2015/09/01 06:00 [medline] PHST- 2016/08/01 00:00 [pmc-release] AID - 10.1002/pros.22997 [doi] PST - ppublish SO - Prostate. 2015 Aug 1;75(11):1160-6. doi: 10.1002/pros.22997. Epub 2015 Apr 20.