Vukovic Bisera, Park Paul C, Al-Maghrabi Jaudah, Beheshti Ben, Sweet Joan, Evans Andy, Trachtenberg John, Squire Jeremy
Ontario Cancer Institute/Princess Margaret Hospital, The University Health Network, Toronto, Canada.
Oncogene. 2003 Apr 3;22(13):1978-87. doi: 10.1038/sj.onc.1206227.
Mechanisms underlying prostate cancer (CaP) initiation and progression are poorly understood. A chromosomal instability mechanism leading to the generation of numerical and structural chromosomal changes has been implicated in the preneoplastic and neoplastic stages of CaP. Telomere dysfunction is one potential mechanism associated with the onset of such instability. To determine whether there was alteration in telomere length and chromosome number, 15 paraffin-embedded prostatectomy specimens were investigated using quantitative peptide nucleic acid (PNA) FISH analysis of representative foci of carcinoma, putative precancerous lesions (high-grade prostatic intraepithelial neoplasia, HPIN) and nondysplastic prostate epithelium. A significant decrease in telomere length was shown in both HPIN and CaP in comparison with normal epithelium. In addition, elevated rates of aneusomy suggested that increased levels of chromosomal aberrations were associated with decreased telomere length. Moreover, multiple foci of HPIN were shown to have a heterogeneous overall reduction of telomere length. This reduction was more evident in the histologic regions of the prostate containing CaP. Such observations lend support to the hypothesis that telomere erosion may be a consistent feature of CaP oncogenesis and may also be associated with the generation of chromosomal instability that characterizes this malignancy.
前列腺癌（CaP）起始和进展的潜在机制目前仍知之甚少。一种导致染色体数目和结构变化的染色体不稳定机制已被认为与CaP的癌前和肿瘤阶段有关。端粒功能障碍是与此类不稳定性发生相关的一种潜在机制。为了确定端粒长度和染色体数目是否发生改变，我们使用定量肽核酸（PNA）荧光原位杂交（FISH）分析，对15例石蜡包埋的前列腺切除标本中具有代表性的癌灶、假定的癌前病变（高级别前列腺上皮内瘤变，HPIN）和无发育异常的前列腺上皮进行了研究。与正常上皮相比，HPIN和CaP中的端粒长度均显著缩短。此外，非整倍体率升高表明，染色体畸变水平的增加与端粒长度的缩短有关。而且，多个HPIN病灶显示出端粒长度整体存在异质性降低。这种降低在前列腺中含有CaP的组织学区域更为明显。这些观察结果支持了这样一种假说，即端粒侵蚀可能是CaP肿瘤发生的一个持续特征，并且可能还与这种恶性肿瘤所特有的染色体不稳定性的产生有关。
