Leukocyte telomere length is associated with aggressive prostate cancer in localized prostate cancer patients

Abstract

Background: Telomeres play important roles in cancer initiation and progression. The aim of this study is to investigate whether leukocyte telomere length (LTL) is associated with aggressive prostate cancer (PCa). Methods: We measured relative LTL in a cohort of 1,889 white PCa patients who were treated and followed up at the University of Texas MD Anderson Cancer Center and assessed its associations with aggressive disease characteristics at diagnosis and biochemical recurrence (BCR) after active treatments (radical prostatectomy and radiotherapy). We further used a Mendelian randomization (MR) approach to compute a weighted genetic risk score (GRS) predictive of LTL using 10 established LTL-associated genetic variants and determined whether this GRS is associated with aggressive PCa. Findings: LTL was significantly shorter in patients with higher Gleason scores at diagnosis. Dichotomized at the median value of LTL, patients with short LTL exhibited a 2.74-fold (95% confidence interval, 1.79–4.18, P = 3.11 × 10−6) increased risk of presenting with GS≥8 disease than those with long LTL in multivariate logistic regression analysis. Moreover, shorter LTL was significantly associated with an increased risk of BCR (hazard ratio = 1.53, 95% confidence interval, 1.01–2.34) compared to longer LTL in localized patients receiving prostatectomy or radiotherapy with a significant dose-response association (P for trend = 0.017) in multivariate Cox proportional hazards regression analysis. In MR analysis, genetically predicted short LTL was also associated with an increased risk of BCR (HR=1.73, 95% CI, 1.08–2.78). Interpretation: Our results showed for the first time that LTL was shorter in PCa patients with high Gleason scores and that short LTL and genetically predicted short LTL are associated with worse prognosis in PCa patients receiving prostatectomy or radiotherapy. Funding: Cancer Prevention and Research Institute of Texas (CPRIT) grant (RP140556), National Cancer Institute Specialized Program of Research Excellence (SPORE) grant (CA140388), and MD Anderson Cancer Center start-up fund. Keywords: Leukocyte telomere length, Prostate cancer, Biochemical recurrence, Genetic risk score, Mendelian randomization