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Prostate stromal cell telomere shortening is associated with risk of prostate cancer in the placebo arm of the Prostate Cancer Prevention Trial
Author(s) -
Heaphy Christopher M.,
Gaonkar Gaurav,
Peskoe Sarah B.,
Joshu Corinne E.,
De Marzo Angelo M.,
Lucia M. Scott,
Goodman Phyllis J.,
Lippman Scott M.,
Thompson Ian M.,
Platz Elizabeth A.,
Meeker Alan K.
Publication year - 2015
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/pros.22997
Subject(s) - prostate cancer , telomere , medicine , prostate , cancer , stromal cell , biopsy , oncology , prostate biopsy , telomerase , pathology , biology , genetics , dna , gene
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. Prostate 75: 1160–1166, 2015 . © 2015 Wiley Periodicals, Inc.