Role of telomere length and chromosomal instability in prostatic carcinogenesis

Prostate cancer (CaP) is the most commonly diagnosed cancer in men in North America. To date, treatment and diagnosis of CaP is still problematic. Major challenges include reliable early detection of the disease, and identification of prognostic factors that accurately predict outcome. Studies of genetic alterations in early precursor lesions (atypical adenomatous hyperplasia and prostatic intraepithelial neoplasia (PIN)), suggest a multistep model of prostatic carcinogenesis, emphasizing accumulation of genetic hits, affecting key pathways. To account for the genotypic heterogeneity and multifocality evident in CaP, a model where one of the affected cell mechanisms is involved in maintenance of chromosomal stability has gained acceptance through numerous cytogenetic studies. Telomere related chromosomal instability (CIN) has generated attention in recent years due to its emerging role in carcinogenesis, and prostate cancer has been suggested as a likely target for telomere dysregulation. To improve our knowledge of telomere length erosion as the mechanism contributing to CIN generation during prostatic carcinogenesis, I have developed a quantitative FISH method of analysis of telomere length on the paraffin samples. A significant decrease in telomere length was observed in both high grade PIN and early invasive carcinoma in comparison with benign epithelium, and was paralleled by increased levels of numerical chromosomal aberrations and proliferation rate, suggesting telomere related chromosomal instability as a feature of CaP oncogenesis. To demonstrate the in vitro evidence of a CIN mechanism in karyotype evolution in CaP, I have used prostate cancer cell lines, derived from primary and metastatic tumors. The CIN mechanism, in the form of a Bridge-fusion-breakage (BFB) cycle, was shown to contribute to generation of complex structural abnormalities as evidenced by cytogenetic analysis of mitotic and chromosomal structures. Lastly, telomere erosion did not seem to be limited to early stages of CaP initiation and was further observed in hormone-refractory prostate cancer and in highly proliferative neuroendocrine form of prostate cancer arising after prolonged androgen deprivation treatment. Overall, these results emphasize the importance of telomere erosion in prostatic oncogenesis and implicate a telomere related chromosomal instability as a mechanism for generation of genotypic heterogeneity that characterizes both preneoplastic lesions and prostate cancer.