Genetic Instability Persists in Non-Neoplastic Urothelial Cells from Patients with a History of Urothelial Cell Carcinoma

Abstract

Bladder cancer is one of the most common genitourinary neoplasms in industrialized countries. Multifocality and high recurrence rates are prominent clinical features of this disease and contribute to its high morbidity. Therefore, more sensitive and less invasive techniques could help identify individuals with asymptomatic disease. In this context, we used the micronucleus assay to evaluate whether cytogenetic alterations could be used as biomarkers for monitoring patients with a history of urothelial cell carcinoma (UCC). We determined the frequency of micronucleated urothelial cells (MNC) in exfoliated bladder cells from 105 patients with (n = 52) or without (n = 53) a history of UCC, all of whom tested negative for neoplasia by cytopathological and histopathological analyses. MNC frequencies were increased in patients with a history of UCC (non-smoker and smoker/ex-smoker patients vs non-smoker and smoker/ex-smoker controls; p<0.001), in non-smoker UCC patients (vs non-smoker controls; p<0.01), and in smoker/ex-smoker controls (vs non-smoker controls; p<0.001). Patients with a history of recurrent disease also demonstrated a higher MNC frequency compared to patients with non-recurrent neoplasia. However, logistic regression using smoking habits, age and gender as confounding factors did not confirm MNC frequency as a marker for UCC recurrence. Fluorescent in situ hybridization analysis (using a pan-centromeric probe) showed that micronuclei (MN) arose mainly from clastogenic events regardless of UCC and/or smoking histories. In conclusion, our results confirm previous indications that subjects with a history of UCC harbor genetically unstable cells in the bladder urothelium. Furthermore, these results support using the micronucleus assay as an important tool for monitoring patients with a history of UCC and tumor recurrence.

The frequencies of micronuclei, nucleoplasmic bridges and nuclear buds as biomarkers of genomic instability in patients with urothelial cell carcinoma

“…By contrast, slides from the control group did not contain MN 36 . Based on our findings and those of these aforementioned studies, it can be concluded that subjects who are at high risk for UCC, who have UCC, or who have a history of UCC harbour and accumulate genetically unstable cells in the bladder urothelium, which may represent early precursors of new UCC or subclones from previous UCC 35 . Lastly, it can be deduced that these changes can be readily detected via an MN assay performed on urine.…”

“…This result agrees with a previous study that phenotypically profiled urothelial cells in patients with a prior history of UCC 34 . Similarly, the results of a separate previous study indicated that the MN frequency in urothelial cells from bladder washings of patients with a history of UCC was higher than that of the control group 35 . Furthermore, in a retrospective study of urine samples, slides that had been identified as atypical urothelial cells and subsequently diagnosed as UCC positive were found to be positive for MN.…”

Increased micronucleus frequency in peripheral blood lymphocytes predicts the risk of bladder cancer

“…To our knowledge, only few studies investigated if the MN assay could be applied as a diagnostic tool to identify individuals who have BC (Arora et al , 2010; Sharma et al , 2012; de Castro Marcondes et al , 2014). The currently available data suggested that MN assays in UDC may be potentially a suitable diagnostic tool for detection of BC and for the surveillance of the patients (Nersesyan et al , 2014).…”

Acute crack cocaine exposure induces genetic damage in multiple organs of rats

“…Micronucleated cell indexes may reflect genetic damage (de Castro Marcondes et al 2014). The detection of an elevated frequency of micronuclei in a given population indicates increased risk of cancer.…”