title: Prostate stromal cell telomere shortening is associated with risk of prostate cancer in the placebo arm of the Prostate Cancer Prevention Trial.
abstract: 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.
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland.|Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Heaphy
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Gaurav
authors.initials: G
authors.lastname: Gaonkar
authors.affiliation: Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
authors.forename: Sarah B
authors.initials: SB
authors.lastname: Peskoe
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland.|Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
authors.forename: Corinne E
authors.initials: CE
authors.lastname: Joshu
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland.|Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland.|Department of Urology and the James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Angelo M
authors.initials: AM
authors.lastname: De Marzo
authors.affiliation: University of Colorado School of Medicine, Aurora, Colorado.
authors.forename: M Scott
authors.initials: MS
authors.lastname: Lucia
authors.affiliation: SWOG Statistical Center, and the Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Phyllis J
authors.initials: PJ
authors.lastname: Goodman
authors.affiliation: Moores Cancer Center, University of California, San Diego, California.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Lippman
authors.affiliation: UT Health Science Center at San Antonio, San Antonio, Texas.
authors.forename: Ian M
authors.initials: IM
authors.lastname: Thompson
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland.|Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.|Department of Urology and the James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Platz
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland.|Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland.|Department of Urology and the James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Alan K
authors.initials: AK
authors.lastname: Meeker
mesh_terms: D058891:5-alpha Reductase Inhibitors / Q000008:administration & dosage; D001706:Biopsy; D043171:Chromosomal Instability; D018450:Disease Progression; D018120:Finasteride / Q000008:administration & dosage*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011467:Prostate / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D012307:Risk Factors; D017154:Stromal Cells / Q000473:pathology*; D059505:Telomere Homeostasis; D059506:Telomere Shortening
chemical_list: D058891:5-alpha Reductase Inhibitors; D018120:Finasteride
keywords: Telomere; prostate cancer; stroma; tumor microenvironment