Urinary Nucleic Acid <i>TSPAN13</i> -to- <i>S100A9</i> Ratio as a Diagnostic Marker in Prostate Cancer

Yan, Chunri,Kim, Ye-Hwan,Kang, Ho Won,Seo, Sung Phil,Jeong, Pildu,Lee, Il-Seok,Kim, Dongho,Kim, Jung Min,Choi, Yung Hyun,Moon, Sung-Kwon,Yun, Seok Joong,Kim, Wun-Jae The Korean Academy of Medical Sciences 2015 JOURNAL OF KOREAN MEDICAL SCIENCE Vol.30 No.12

<P>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 <I>TSPAN13</I>-to-<I>S100A9</I> ratio was selected to determine the diagnostic value of urinary nucleic acids in PCa (<I>P</I> = 0.037) and shown to be significantly higher in PCa than in BPH in the mRNA and nucleic acid cohort analyses (<I>P</I> < 0.001 and <I>P</I> = 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 <I>TSPAN13</I>-to-<I>S100A9</I> 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.</P>

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.

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.

GSTM1 Tissue Genotype as a Recurrence Predictor in Nonmuscle Invasive Bladder Cancer

하윤석,Chunri Yan,정필두,김원태,윤석중,Isaac Yi Kim,문성권,김원재 대한의학회 2011 Journal of Korean medical science Vol.26 No.2

Tissue genotyping is more useful approach than using blood genomic DNA, which can reflect the effects of the somatic mutations in cancer. Although polymorphisms in glutathione S-transferase (GST ) have been associated with the risk of bladder cancer (BC)development, few reports provide information about the prognosis of BC. We investigated glutathione S-transferase mu (GSTM1) and glutathione S-transferase theta (GSTT1)genotypes using genomic DNA from primary 165 BC tissue samples to assess the association with disease prognosis. DNA samples from tumor were analyzed by multiplex polymerase chain reaction (PCR). The results were compared with clinicopathological parameters. The prognostic significance of the GSTs was evaluated by Kaplan-Meier and multivariate Cox regression model. Kaplan-Meier estimates revealed significant differences in time to tumor recurrence according to the GSTM1 tissue genotype (P = 0.038) in nonmuscle invasive bladder cancer (NMIBC). Multivariate Cox regression analysis also revealed that the tissue GSTM1 genotype (hazards ratio [HR]: 0.377, P = 0.031) was an independent predictor of bladder tumor recurrence in NMIBC. This identification of GSTM1tissue genotype as a prognosticator for determining recurrence in NMIBC should prove highly useful in a clinical setting.

<i>GSTT1</i> as a Prognosticator for Recurrence and Progression in Patients with Non-Muscle-Invasive Bladder Cancer

Ha, Yun-Sok,Yan, Chunri,Lym, Min Su,Jeong, Pildu,Kim, Won Tae,Kim, Yong-June,Yun, Seok-Joong,Lee, Sang-Cheol,Moon, Sung-Kwon,Choi, Yung Hyun,Kim, Wun-Jae IOS Press 2010 Disease markers Vol.29 No.2

<P>Although polymorphisms in glutathione S-transferase (GST) have been associated with the risk of bladder cancer (BC), few reports provide information about the development of BC. The aim of the present study was to investigate the effect of homozygous glutathione S-transferase-μ (GSTM1) and glutathione S-transferase-&phis; (GSTT1) deletions as prognostic markers in non-muscle-invasive bladder cancer (NMIBC). A total of 241 patients with primary NMIBC were enrolled in this study. GSTM1 and GSTT1 polymorphisms were analyzed by multiplex polymerase chain reaction (PCR) using blood genomic DNA. The results were compared with clinicopathological parameters. The prognostic significance of the GSTs was evaluated by Kaplan-Meier and multivariate Cox regression model. A statistically significant association between genotype and histopathological parameter was not observed. The patients with the GSTT1-positive genotype had significantly reduced recurrence- and progression-free survival than those with the GSTT1-null genotype (log-rank test, <I>p</I> < 0.05, respectively). Recurrenceand progressionfree survival were not related to the GSTM1 genotypes. In multivariate regression analysis, the GSTT1positive genotype was the independent predictor for recurrence [hazard ratio (HR), 1.631; <I>p</I> = 0.043] and progression (HR, 3.418; <I>p</I> = 0.006). These results suggested that the GSTT1 genotype could be a useful prognostic marker for recurrence and progression in NMIBC. </P>

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.

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

Kim, Ye-Hwan,Yan, Chunri,Lee, Il-Seok,Piao, Xuan-Mei,Byun, Young Joon,Jeong, Pildu,Kim, Won Tae,Yun, Seok-Joong,Kim, Wun-Jae The Korean Urological Association 2016 Investigative and Clinical Urology Vol.48 No.3

<P><B>Purpose</B></P><P>Topoisomerase-II alpha (<I>TopoIIA</I> ), 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 <I>TopoIIA</I> cell-free DNA as a noninvasive diagnosis of bladder cancer (BC).</P><P><B>Materials and Methods</B></P><P>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 <I>TopoIIA</I> mRNA in tissues and <I>TopoIIA</I> cell-free DNA in urine samples.</P><P><B>Results</B></P><P>The results showed that expression of <I>TopoIIA</I> mRNA in BC tissues was significantly higher than that in noncancer control tissues (p<0.001). The expression of urinary <I>TopoIIA</I> 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 <I>TopoIIA</I> 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 <I>TopoIIA</I> 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.</P><P><B>Conclusions</B></P><P>In summary, the results of this study provide evidence that cell-free <I>TopoIIA</I> DNA may be a potential biomarker for BC.</P>

<i>GSTM1</i> Tissue Genotype as a Recurrence Predictor in Non-muscle Invasive Bladder Cancer

Ha, Yun-Sok,Yan, Chunri,Jeong, Pildu,Kim, Won Tae,Yun, Seok-Joong,Kim, Isaac Yi,Moon, Sung-Kwon,Kim, Wun-Jae The Korean Academy of Medical Sciences 2011 JOURNAL OF KOREAN MEDICAL SCIENCE Vol.26 No.2

<P>Tissue genotyping is more useful approach than using blood genomic DNA, which can reflect the effects of the somatic mutations in cancer. Although polymorphisms in glutathione S-transferase (<I>GST</I>) have been associated with the risk of bladder cancer (BC) development, few reports provide information about the prognosis of BC. We investigated glutathione S-transferase mu (<I>GSTM1</I>) and glutathione S-transferase theta (<I>GSTT1</I>) genotypes using genomic DNA from primary 165 BC tissue samples to assess the association with disease prognosis. DNA samples from tumor were analyzed by multiplex polymerase chain reaction (PCR). The results were compared with clinicopathological parameters. The prognostic significance of the <I>GST</I>s was evaluated by Kaplan-Meier and multivariate Cox regression model. Kaplan-Meier estimates revealed significant differences in time to tumor recurrence according to the <I>GSTM1</I> tissue genotype (<I>P</I> = 0.038) in non-muscle invasive bladder cancer (NMIBC). Multivariate Cox regression analysis also revealed that the tissue <I>GSTM1</I> genotype (hazards ratio [HR]: 0.377, <I>P</I> = 0.031) was an independent predictor of bladder tumor recurrence in NMIBC. This identification of <I>GSTM1</I> tissue genotype as a prognosticator for determining recurrence in NMIBC should prove highly useful in a clinical setting.</P>

Tissue hOGG1 Genotype Predicts Bladder Cancer Prognosis: A Novel Approach Using a Peptide Nucleic Acid Clamping Method

Ha, Yun-Sok,Yan, Chunri,Kim, Isaac Yi,Yun, Seok-Joong,Moon, Sung-Kwon,Kim, Wun-Jae Springer - Society of Surgical Oncology 2011 Annals of surgical oncology Vol.18 No.6

Metabolic Pathway Signatures Associated with Urinary Metabolite Biomarkers Differentiate Bladder Cancer Patients from Healthy Controls

Kim, Won Tae,Yun, Seok Joong,Yan, Chunri,Jeong, Pildu,Kim, Ye Hwan,Lee, Il-Seok,Kang, Ho-Won,Park, Sunghyouk,Moon, Sung-Kwon,Choi, Yung-Hyun,Choi, Young Deuk,Kim, Isaac Yi,Kim, Jayoung,Kim, Wun-Jae Yonsei University College of Medicine 2016 Yonsei medical journal Vol.57 No.4

<P><B>Purpose</B></P><P>Our previous high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry study identified bladder cancer (BCA)-specific urine metabolites, including carnitine, acylcarnitines, and melatonin. The objective of the current study was to determine which metabolic pathways are perturbed in BCA, based on our previously identified urinary metabolome.</P><P><B>Materials and Methods</B></P><P>A total of 135 primary BCA samples and 26 control tissue samples from healthy volunteers were analyzed. The association between specific urinary metabolites and their related encoding genes was analyzed.</P><P><B>Results</B></P><P>Significant alterations in the carnitine-acylcarnitine and tryptophan metabolic pathways were detected in urine specimens from BCA patients compared to those of healthy controls. The expression of eight genes involved in the carnitine-acylcarnitine metabolic pathway (<I>CPT1A, CPT1B, CPT1C, CPT2, SLC25A20</I>, and <I>CRAT</I>) or tryptophan metabolism (<I>TPH1</I> and <I>IDO1</I>) was assessed by RT-PCR in our BCA cohort (n=135). C<I>PT1B, CPT1C, SLC25A20, CRAT, TPH1</I>, and <I>IOD1</I> were significantly downregulated in tumor tissues compared to normal bladder tissues (<I>p</I><0.05 all) of patients with non-muscle invasive BCA, whereas <I>CPT1B, CPT1C, CRAT</I>, and <I>TPH1</I> were downregulated in those with muscle invasive BCA (<I>p</I><0.05), with no changes in <I>IDO1</I> expression.</P><P><B>Conclusion</B></P><P>Alterations in the expression of genes associated with the carnitine-acylcarnitine and tryptophan metabolic pathways, which were the most perturbed pathways in BCA, were determined.</P>