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

김예환,Chunri Yan,이일석,Xuan-Mei Piao,변영준,정필두,김원태,윤석중,김원재 대한비뇨의학회 2016 Investigative and Clinical Urology Vol.57 No.2

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.

[설비] 유니퀘스트(주)

김예환,조동진 한국조명·전기설비학회 2018 조명.전기설비 Vol.32 No.3

CDC6 mRNA Expression Is Associated with the Aggressiveness of Prostate Cancer

김예환,변영준,김원태,정필두,Chunri Yan,강호원,김용준,이상철,문성관,최영현,윤석중,김원재 대한의학회 2018 Journal of Korean medical science Vol.33 No.47

Background: Cell division cycle 6 (CDC6) is an essential regulator of DNA replication and plays important roles in the activation and maintenance of the checkpoint mechanisms in the cell cycle. CDC6 has been associated with oncogenic activities in human cancers; however, the clinical significance of CDC6 in prostate cancer (PCa) remains unclear. Therefore, we investigated whether the CDC6 mRNA expression level is a diagnostic and prognostic marker in PCa. Methods: The study subjects included 121 PCa patients and 66 age-matched benign prostatic hyperplasia (BPH) patients. CDC6 expression was evaluated using real-time polymerase chain reaction and immunohistochemical (IH) staining, and then compared according to the clinicopathological characteristics of PCa. Results: CDC6 mRNA expression was significantly higher in PCa tissues than in BPH control tissues (P = 0.005). In addition, CDC6 expression was significantly higher in patients with elevated prostate-specific antigen (PSA) levels (> 20 ng/mL), a high Gleason score, and advanced stage than in those with low PSA levels, a low Gleason score, and earlier stage, respectively. Multivariate logistic regression analysis showed that high expression of CDC6 was significantly associated with advanced stage (≥ T3b) (odds ratio [OR], 3.005; confidence interval [CI], 1.212–7.450; P = 0.018) and metastasis (OR, 4.192; CI, 1.079–16.286; P = 0.038). Intense IH staining for CDC6 was significantly associated with a high Gleason score and advanced tumor stage including lymph node metastasis stage (linear-by-linear association, P = 0.044 and P = 0.003, respectively). Conclusion: CDC6 expression is associated with aggressive clinicopathological characteristics in PCa. CDC6 may be a potential diagnostic and prognostic marker in PCa patients.

Novel Combination Markers for Predicting Survival in Patients with Muscle Invasive Bladder Cancer: USP18 and DGCR2

김예환,김원태,정필두,하윤석,강호원,윤석중,문성권,최영현,Isaac Yi Kim,김원재 대한의학회 2014 Journal of Korean medical science Vol.29 No.3

We performed gene expression profiling in bladder cancer patients to identify cancerspecificsurvival-related genes in muscle invasive bladder cancer (MIBC) patients. Sixty-twopatients with MIBC were selected as the original cohort and another 118 MIBC patientswere chosen as a validation cohort. The expression of USP18, DGCR2, and ZNF699 geneswere measured and we analyzed the association between gene signatures and survival. USP18 and DGCR2, were significantly correlated to cancer-specific death (P = 0.020,P = 0.007, respectively). Cancer-specific survival in the low USP18 or DGCR2 expressiongroup was significantly longer than the high expression group (P = 0.018, P = 0.006,respectively). In multivariate Cox regression analysis, a combination of USP18 and DGCR2mRNA expression levels were significant risk factors for cancer-specific death (HR, 2.106;CI, 1.043-4.254, P = 0.038). Overall survival and cancer-specific survival rates in the lowcombinationgroup were significantly longer than those in the high-expression group(P = 0.001, both). In conclusion, decreased expressions of USP18 and DGCR2 weresignificantly associated with longer cancer-specific survival, and also the combination oftwo genes was correlated to a longer survival for MIBC patients. Thus, the combination ofUSP18 and DGCR2 expression was shown to be a reliable prognostic marker for cancerspecificsurvival in MIBC.

Lower Levels of Human MOB3B Are Associated with Prostate Cancer Susceptibility and Aggressive Clinicopathological Characteristics

김은아,김예환,강호원,윤형윤,김원태,김용준,윤석중,문성권,최영현,Isaac Yi Kim,이상철,김원재 대한의학회 2015 Journal of Korean medical science Vol.30 No.7

Mps one binder (MOB) proteins are integral components of signaling pathways that control important cellular processes, such as mitotic exit, centrosome duplication, apoptosis, and cell proliferation. However, the biochemical and cellular functions of the human MOB (hMOB) protein family remain largely unknown. The present study investigated the association between hMOB3B expression and clinicopathological characteristics of prostate cancer (PCa).Study subjects included 137 PCa patients and 137 age-matched benign prostatic hyperplasia (BPH) patients. hMOB3B expression was estimated using real-time PCR and compared with clinicopathological parameters of PCa. hMOB3B mRNA expression was significantly lower in PCa tissues than in BPH control tissues (P < 0.001). According to receiver operating characteristics curve analysis, the sensitivity of hMOB3B expression for PCa diagnosis was 84.7%, with a specificity of 86% (AUC = 0.910; 95% CI = 0.869- 0.941; P < 0.001). hMOB3B expression was significantly lower in patients with elevated prostate specific antigen (PSA) levels (≥ 10 ng/mL), a Gleason score ≥ 8, and metastatic disease (any T, N+/M+) than in those with low PSA levels, a low Gleason score, and nonmetastatic disease (each P < 0.05). In conclusion, low levels of hMOB3B are closely associated with aggressive clinicopathologic features in patients with PCa. Our results suggest that hMOB3B may act as a tumor suppressor in human PCa.

Urinary Nucleic Acid TSPAN13-to-S100A9 Ratio as a Diagnostic Marker in Prostate Cancer

Chunri Yan,김예환,강호원,서성필,정필두,이일석,김동호,김정민,최영현,문성권,윤석중,김원재 대한의학회 2015 Journal of Korean medical science Vol.30 No.12

The potential use of urinary nucleic acids as diagnostic markers in prostate cancer (PCa) was evaluated. Ninety-five urine samples and 234 prostate tissue samples from patients with PCa and benign prostatic hyperplasia (BPH) were analyzed. Micro-array analysis was used to identify candidate genes, which were verified by the two-gene expression ratio and validated in tissue mRNA and urinary nucleic acid cohorts. Real-time quantitative polymerase chain reaction (qPCR) was used to measure urinary nucleic acid levels and tissue mRNA expression. The TSPAN13-to-S100A9 ratio was selected to determine the diagnostic value of urinary nucleic acids in PCa (P = 0.037) and shown to be significantly higher in PCa than in BPH in the mRNA and nucleic acid cohort analyses (P < 0.001 and P = 0.013, respectively). Receiver operating characteristic (ROC) analysis showed that the area under the ROC curve was 0.898 and 0.676 in tissue mRNA cohort and urinary nucleic acid cohort, respectively. The TSPAN13-to-S100A9 ratio showed a strong potential as a diagnostic marker for PCa. The present results suggest that the analysis of urine supernatant can be used as a simple diagnostic method for PCa that can be adapted to the clinical setting in the future.