Investig Clin Urol.  2016 Mar;57(2):106-112. 10.4111/icu.2016.57.2.106.

Value of urinary topoisomerase-IIA cell-free DNA for diagnosis of bladder cancer

• Kim YH
• Yan C
• Lee IS
• Piao XM
• Byun YJ
• Jeong P
• Kim WT
• Yun SJ
• Kim WJ

• KMID: 2363132
• DOI: http://doi.org/10.4111/icu.2016.57.2.106

Abstract

PURPOSE
Topoisomerase-II alpha (TopoIIA ), a DNA gyrase isoform that plays an important role in the cell cycle, is present in normal tissues and various human cancers, and can show altered expression in both. The aim of the current study was to examine the value of urinary TopoIIA cell-free DNA as a noninvasive diagnosis of bladder cancer (BC).
MATERIALS AND METHODS
Two patient cohorts were examined. Cohort 1 (73 BC patients and seven controls) provided bladder tissue samples, whereas cohort 2 (83 BC patients, 54 nonmalignant hematuric patients, and 61 normal controls) provided urine samples. Real-time quantitative polymerase chain reaction was used to measure expression of TopoIIA mRNA in tissues and TopoIIA cell-free DNA in urine samples.
RESULTS
The results showed that expression of TopoIIA mRNA in BC tissues was significantly higher than that in noncancer control tissues (p<0.001). The expression of urinary TopoIIA cell-free DNA in BC patients was also significantly higher than that in noncancer patient controls and hematuria patients (p < 0.001 and p < 0.001, respectively). High expression of urinary TopoIIA cell-free DNA was also detected in muscle invasive bladder cancer (MIBC) when compared with nonmuscle invasive bladder cancer (NMIBC) (p=0.002). Receiver operating characteristics (ROC) curve analysis was performed to examine the sensitivity/specificity of urinary TopoIIA cell-free DNA for diagnosing BC, NMIBC, and MIBC. The areas under the ROC curve for BC, NMIBC, and MIBC were 0.741, 0.701, and 0.838, respectively.
CONCLUSIONS
In summary, the results of this study provide evidence that cell-free TopoIIA DNA may be a potential biomarker for BC.

Keyword

Biomarkers; DNA topoisomerase II alpha; Hematuria; Urinary bladder neoplasms; Urine

MeSH Terms

Adult
Aged
Antigens, Neoplasm/genetics/*urine
Biomarkers, Tumor/genetics/*urine
Case-Control Studies
Cell-Free System
Cohort Studies
DNA Topoisomerases, Type II/genetics/*urine
DNA, Neoplasm/genetics
DNA-Binding Proteins/genetics/*urine
Female
Gene Expression
Hematuria/urine
Humans
Male
Middle Aged
Neoplasm Grading
Neoplasm Staging
RNA, Messenger/genetics
RNA, Neoplasm/genetics
Sensitivity and Specificity
Urinary Bladder Neoplasms/complications/*diagnosis/pathology
Antigens, Neoplasm
Biomarkers, Tumor
DNA Topoisomerases, Type II
DNA, Neoplasm
DNA-Binding Proteins
RNA, Messenger
RNA, Neoplasm

Figure

• 

  Fig. 1 Box-plot showing TopoIIA mRNA expression levels in normal controls and bladder cancer (BC) tissues.

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  Fig. 2 Box-plots showing TopoIIA urinary cell-free DNA expression in bladder cancer (BC) patients (A), normal controls, and hematuria patients, and in nonmuscle invasive bladder cancer (NMIBC) and muscle invasive bladder cancer (MIBC) patients (B).

• 

  Fig. 3 Receiver operating characteristics (ROC) curve generated to calculate the sensitivity and specificity of the TopoIIA urinary cell-free DNA assay. (A) Bladder cancer, (B) nonmuscle invasive bladder cancer (NMIBC), and (C) muscle invasive bladder cancer (MIBC). AUC, area under the ROC curve.

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