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.

中文翻译：

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白细胞端粒长度与局部前列腺癌患者的侵袭性前列腺癌有关。

背景技术端粒在癌症的发生和发展中起重要作用。这项研究的目的是调查白细胞端粒长度（LTL）是否与侵袭性前列腺癌（PCa）相关。方法我们测量了1889名白人PCa患者的相对LTL，这些患者在德克萨斯大学MD安德森癌症中心接受治疗和随访，并在积极治疗（根治性前列腺切除术）后评估其与诊断性疾病和生化复发（BCR）的相关性。和放疗）。我们进一步使用孟德尔随机（MR）方法，使用10个已建立的与LTL相关的遗传变异来计算LTL的加权遗传风险评分（GRS），并确定该GRS是否与侵袭性PCa相关。发现诊断时格里森评分较高的患者的LTL明显短。按照LTL的中值二分法，短LTL的患病率比长LTL的患病风险高2.74倍（95％置信区间，1.79-4.18，P = 3.11×10-6）。多元逻辑回归分析。此外，与接受前列腺切除术或放疗且具有明显剂量反应关系的局部患者较长的LTL相比，较短的LTL与BCR风险增加显着相关（危险比= 1.53，95％置信区间，1.01-2.34）（P为趋势） = 0.017）在多变量Cox比例风险回归分析中。在MR分析中，遗传预测的短LTL也与BCR风险增加相关（HR = 1.73，95％CI，1.08-2.78）。解释我们的结果首次显示，格里森评分较高的PCa患者的LTL较短，而接受前列腺切除或放疗的PCa患者的LTL短和遗传学预测的LTL短与预后差有关。得克萨斯州癌症预防与研究所（CPRIT）拨款（RP140556），美国国家癌症研究所卓越研究专业计划（SPORE）拨款（CA140388）和MD安德森癌症中心启动基金。