Telomere Attrition in Isolated High-Grade Prostatic Intraepithelial Neoplasia and Surrounding Stroma Is Predictive of Prostate Cancer

Abstract

The causes of early genomic events underlying the development of prostate cancer (CaP) remain unclear. The onset of chromosomal instability is likely to facilitate the formation of crucial genomic aberrations both in the precursor lesion high-grade prostatic intraepithelial neoplasia (HPIN) and in CaP. Instability generated by telomere attrition is one potential mechanism that could initiate chromosomal rearrangements. In this study, normalized telomere length variation was examined in a cohort of 68 men without CaP who had HPIN only on prostatic biopsies. Multiple significant associations between telomere attrition and eventual diagnosis of CaP in the HPIN and in the surrounding stroma were found. Kaplan-Meier analysis of telomere length demonstrated a significantly increased risk for the development of cancer with short telomeres in the surrounding stroma [P = .035; hazard ratio (HR) = 2.12; 95% confidence interval (95% CI) = 0.231-0.956], and a trend for HPIN itself (P = .126; HR = 1.72; 95% CI = 0.287-1.168). Cox regression analysis also demonstrated significance between the time from the original biopsy to the diagnosis of cancer and telomere length in HPIN and in the surrounding stroma. These analyses showed significance, both alone and in combination with baseline prostate-specific antigen, and lend support to the hypothesis that telomere attrition in prostatic preneoplasia may be fundamental to the generation of chromosomal instability and to the emergence of CaP.

DNA Damage Repair and Telomere Length in Normal Breast, Preneoplastic Lesions, and Invasive Cancer

“…Indeed, most cancer precursor lesions are known to accumulate genomic alterations; however, it remains unclear whether these alterations are the cause or consequence of carcinogenesis. [13][14][15][16][17] This increase in p-ATM also suggests that, despite the occurrence of DNA damage, the pathway leading to repair or apoptosis is functional in these lesions. Thus, the DDR pathway, including p-ATM, may prevent the development of breast cancer from preneoplastic lesions by DNA repair signaling.…”

Genomic Alterations in Tumor Stroma

“…LOH (Fig. 3), microsatellite instability, consistent cytogenetic abnormalities, and/or telomere attrition in stroma have been independently described by many different investigators for a broad variety of solid tumors and nonmalignant conditions, such as head and neck squamous cell carcinomas, colorectal adenomas and carcinomas, Barrett esophagus and esophageal adenocarcinomas, esophageal squamous cell carcinomas, and carcinomas of the cervix, ovary, bladder, and prostate, as well as inflammatory bowel disease (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22). However, do these genomic alterations in the stroma have any clinical implications for patients with cancers?…”

Molecular genetics of prostate cancer: new prospects for old challenges

“…Telomere length has been correlated with disease outcome (Fordyce et al 2005;Joshua et al 2007), while prostate carcinomas as well as many highgrade PINs display increased telomerase activity, which is not observed in benign prostate tissue (Sommerfeld et al 1996;Koeneman et al 1998). These observations suggest that telomere length is actively modulated during prostate cancer progression, but the mechanistic relationships between telomere shortening and cancer initiation, or to induction of cellular senescence (see below), are presently unclear.…”