Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
Prostate. 2011 May 15;71(7):778-90. doi: 10.1002/pros.21294. Epub 2010 Oct 28.
Many critical events in prostatic carcinogenesis appear to relate to the emergence of genomic instability. Characteristic genomic abnormalities such as 8p loss, 8q gain, trisomy 7, and PTEN microdeletions may provide selective advantages to increase neoplastic transformation. Evidence suggests that telomere dysfunction is a plausible mechanism for some of these abnormalities on the basis of the break-fusion-bridge cycle that can lead to manifestations of genomic instability.
In this study, we correlate telomere length measured by quantitative FISH in various prostatic histologies with markers of genomic instability and immunohistochemical measures of proliferation and oxidative stress.
We find that telomere shortening is correlated with abnormalities on chromosome 8, but not with trisomy 7 or abnormalities of the PTEN locus. There are associations with C-MYC aberrations in stroma with greater proximity to cancer and a correlation between telomere length in a number of prostatic histologies and the adjacent stroma, suggesting the importance of microenvironmental effects on telomere maintenance in the prostate. This finding was also supported by the finding of the correlation between telomere attrition and the levels of oxidative stress as measured by malondialdehyde staining in HPIN lesions close to cancer.
Telomere attrition in the prostate gland is associated with particular genomic aberrations that contribute to the genomic instability characteristic of prostatic carcinogenesis. Correlations between various histologies and adjacent stroma telomere length suggest it is also may reveal microenvironmental effects within the prostate gland. Oxidative stress may contribute to telomere attrition in HPIN close to cancer.
许多前列腺癌发生过程中的关键性事件似乎都与基因组不稳定性的出现有关。特征性的基因组异常，如 8p 缺失、8q 获得、7 号染色体三体和 PTEN 微缺失，可能为增加肿瘤转化提供选择优势。有证据表明，端粒功能障碍是这些异常的一种合理机制，其基础是可以导致基因组不稳定性表现的断裂-融合-桥循环。
在这项研究中，我们将通过定量 FISH 测量的各种前列腺组织学中的端粒长度与基因组不稳定性的标志物以及增殖和氧化应激的免疫组织化学测量进行关联。
我们发现端粒缩短与 8 号染色体异常相关，但与 7 号染色体三体或 PTEN 基因座异常无关。在靠近癌症的基质中存在与 C-MYC 异常的关联，并且在许多前列腺组织学中存在端粒长度与相邻基质之间的相关性，这表明微环境对前列腺中端粒维持的重要性。这一发现也得到了以下发现的支持：在靠近癌症的 HPIN 病变中，通过丙二醛染色测量的氧化应激水平与端粒损耗之间存在相关性。
前列腺中端粒的损耗与导致前列腺癌发生过程中特征性基因组不稳定性的特定基因组异常有关。各种组织学与相邻基质端粒长度之间的相关性表明，它也可能揭示前列腺内的微环境效应。氧化应激可能导致靠近癌症的 HPIN 中端粒损耗。
