The Relationship between Telomere Length and Nucleoplasmic Bridges and Severity of Disease in Prostate Cancer Patients

Abstract

Telomeres are repetitive nucleotide (TTAGGG) sequences that stabilize the chromosome ends and play an important role in the prevention of cancer initiation and progression. Nucleoplasmic bridges (NPBs) are formed when chromatids remain joined together during mitotic anaphase either due to mis-repair of DNA breaks or due to chromatid end fusion as a result of telomere loss or telomere dysfunction. We tested the hypotheses that (i) telomere length (TL) is shorter in prostate cancer (PC) patients relative to healthy age-matched individuals, (ii) TL differs in different stages of PC and (iii) shorter TL is significantly correlated with NPBs formation in PC cases. TL was measured in whole blood by well-established quantitative PCR method and the frequency of NPBs was measured in lymphocytes using cytokinesis-block micronucleus cytome (CBMNcyt) assay. Our results indicate that TL is shorter and NPBs are increased in PC patients relative to age-matched healthy controls. Furthermore, TL was significantly shorter (p = 0.03) in patients with a Gleason score more than 7 and there was also a significant trend of decreasing TL across all three stages (p trend = 0.01; Gleason score <7, 7 and >7). Furthermore, TL was significantly inversely correlated with NPB frequency in PC patients (r = -0.316; p = 0.001) but not in controls (r = 0.163; p = 0.06) and their relationships became stronger with higher Gleason scores. More studies are required that can confirm our observations and explore mechanistic differences in the role of telomeres in NPB formation in PC cases relative to non-cancer cases.

Keywords: Gleason score; nucleoplasmic bridges; prostate cancer (PC); telomere length (TL).

Figure 1

The correlation of baseline and radiation-induced DNA damage biomarkers MN (A,B), NPBs (C,D) and NBuds (E,F), respectively, with telomere length. MN, micronuclei; NPBs, nucleoplasmic bridges; NBuds, nuclear buds; BN cells, binucleated cells; bp, base pairs.

Figure 2

(A) Telomere length (TL) in healthy controls and PC cases (left panel), and TL in three different stages of cancer based on the Gleason score (right panel). (B,C) frequency of baseline and radiation-induced NPBs in different stages of disease stratified based on Gleason score. MN, micronuclei; NPBs, nucleoplasmic bridges; NBuds, nuclear buds; BN cells, binucleated cells; GS, Gleason score.

Figure 3

The correlation of baseline and radiation-induced NPBs with telomere length in different stages of PC stratified as per Gleason score: <7 (A,B), 7 (C,D) and >7 (E,F), respectively. MN, micronuclei; NPBs, nucleoplasmic bridges; NBuds, nuclear buds; BN cells, binucleated cells; bp, base pairs.

Figure 4

The correlation in PC cases of (A) PSA with TL and (B) PSA with NPBs. The correlation in controls of (C) PSA with TL and (D) PSA with NPBs. PSA, prostate-specific antigen; PC, prostate cancer; TL, telomere length; NPBs, nucleoplasmic bridges.

Figure 5

Proposed mechanisms by which telomere loss or telomere shortening induces nucleoplasmic bridge (NBP) formation, which leads to chromosomal instability (CIN) and an ultimately higher cancer risk.