Urine Cellular DNA Point Mutation and Methylation for Identifying Upper Tract Urinary Carcinoma

Background: To improve the selection of patients for ureteroscopy, avoid excessive testing and reduce costs, we aimed to develop and validate a diagnostic urine assay for upper tract urinary carcinoma (UTUC). Methods: In this cohort study we recruited 402 patients from six Hunan hospitals who underw...

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Main Authors: Wei Ouyang, Lufeng Luo, Junjie Zhang, Ran Xu, Qiang Lu, Zhenzhou Xu, Jianye Liu, Pei Li, Yaqun Zhang, Chuanchi Zhou, Wei Tang, Zhenting Wang, Manman Cao, Genming Xu, Long Wang
Format: Article
Language:English
Published: MDPI AG 2022-07-01
Series:Cancers
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Online Access:https://www.mdpi.com/2072-6694/14/14/3537
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author Wei Ouyang
Lufeng Luo
Junjie Zhang
Ran Xu
Qiang Lu
Zhenzhou Xu
Jianye Liu
Pei Li
Yaqun Zhang
Chuanchi Zhou
Wei Tang
Zhenting Wang
Manman Cao
Genming Xu
Long Wang
author_facet Wei Ouyang
Lufeng Luo
Junjie Zhang
Ran Xu
Qiang Lu
Zhenzhou Xu
Jianye Liu
Pei Li
Yaqun Zhang
Chuanchi Zhou
Wei Tang
Zhenting Wang
Manman Cao
Genming Xu
Long Wang
author_sort Wei Ouyang
collection DOAJ
description Background: To improve the selection of patients for ureteroscopy, avoid excessive testing and reduce costs, we aimed to develop and validate a diagnostic urine assay for upper tract urinary carcinoma (UTUC). Methods: In this cohort study we recruited 402 patients from six Hunan hospitals who underwent ureteroscopy for hematuria, including 95 patients with UTUC and 307 patients with non-UTUC findings. Midstream morning urine samples were collected before ureteroscopy and surgery. DNA was extracted and qPCR was used to analyze mutations in <i>TERT</i> and <i>FGFR3</i> and the methylation of <i>NRN1</i>. In the training set, the random forest algorithm was used to build an optimal panel. Lastly, the Beijing cohort (<i>n</i> = 76) was used to validate the panel. Results: The panel combining the methylation with mutation markers led to an AUC of 0.958 (95% CI: 0.933–0.975) with a sensitivity of 91.58% and a specificity of 94.79%. The panel presented a favorable diagnostic value for UTUC vs. other malignant tumors (AUC = 0.920) and UTUC vs. benign disease (AUC = 0.975). Furthermore, combining the panel with age revealed satisfactory results, with 93.68% sensitivity, 94.44% specificity, AUC = 0.970 and NPV = 98.6%. In the external validation process, the model showed an AUC of 0.971, a sensitivity of 95.83% and a specificity of 92.31, respectively. Conclusions: A novel diagnostic model for analyzing hematuria patients for the risk of UTUC was developed, which could lead to a reduction in the need for invasive examinations. Combining <i>NRN1</i> methylation and gene mutation (<i>FGFR3</i> and <i>TERT</i>) with age resulted in a validated accurate prediction model.
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spelling doaj.art-978a7775c1de4ec682a369782345709c2023-11-30T22:57:14ZengMDPI AGCancers2072-66942022-07-011414353710.3390/cancers14143537Urine Cellular DNA Point Mutation and Methylation for Identifying Upper Tract Urinary CarcinomaWei Ouyang0Lufeng Luo1Junjie Zhang2Ran Xu3Qiang Lu4Zhenzhou Xu5Jianye Liu6Pei Li7Yaqun Zhang8Chuanchi Zhou9Wei Tang10Zhenting Wang11Manman Cao12Genming Xu13Long Wang14Department of Urology, The Third Xiangya Hospital, Central South University, Changsha 410008, ChinaDepartment of Urology, The Third Xiangya Hospital, Central South University, Changsha 410008, ChinaDepartment of Urology, The Third Xiangya Hospital, Central South University, Changsha 410008, ChinaDepartment of Urology, The Second Xiangya Hospital, Central South University, Changsha 410028, ChinaDepartment of Urology, Hunan Provincial People’s Hospital, First Affiliated Hospital of Hunan Normal University, Changsha 410002, ChinaDepartment of Urology, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medical, Central South University, Changsha 410013, ChinaDepartment of Urology, The Third Xiangya Hospital, Central South University, Changsha 410008, ChinaYearth Biotechnology Co., Ltd., Changsha 410205, ChinaDepartment of Urology, Beijing Hospital, Beijing 100000, ChinaDepartment of Urology, The Third Xiangya Hospital, Central South University, Changsha 410008, ChinaYearth Biotechnology Co., Ltd., Changsha 410205, ChinaAffiliated Haikou Hospital of Xiangya Medical College, Central South University, Haikou 570100, ChinaYearth Biotechnology Co., Ltd., Changsha 410205, ChinaYearth Biotechnology Co., Ltd., Changsha 410205, ChinaDepartment of Urology, The Third Xiangya Hospital, Central South University, Changsha 410008, ChinaBackground: To improve the selection of patients for ureteroscopy, avoid excessive testing and reduce costs, we aimed to develop and validate a diagnostic urine assay for upper tract urinary carcinoma (UTUC). Methods: In this cohort study we recruited 402 patients from six Hunan hospitals who underwent ureteroscopy for hematuria, including 95 patients with UTUC and 307 patients with non-UTUC findings. Midstream morning urine samples were collected before ureteroscopy and surgery. DNA was extracted and qPCR was used to analyze mutations in <i>TERT</i> and <i>FGFR3</i> and the methylation of <i>NRN1</i>. In the training set, the random forest algorithm was used to build an optimal panel. Lastly, the Beijing cohort (<i>n</i> = 76) was used to validate the panel. Results: The panel combining the methylation with mutation markers led to an AUC of 0.958 (95% CI: 0.933–0.975) with a sensitivity of 91.58% and a specificity of 94.79%. The panel presented a favorable diagnostic value for UTUC vs. other malignant tumors (AUC = 0.920) and UTUC vs. benign disease (AUC = 0.975). Furthermore, combining the panel with age revealed satisfactory results, with 93.68% sensitivity, 94.44% specificity, AUC = 0.970 and NPV = 98.6%. In the external validation process, the model showed an AUC of 0.971, a sensitivity of 95.83% and a specificity of 92.31, respectively. Conclusions: A novel diagnostic model for analyzing hematuria patients for the risk of UTUC was developed, which could lead to a reduction in the need for invasive examinations. Combining <i>NRN1</i> methylation and gene mutation (<i>FGFR3</i> and <i>TERT</i>) with age resulted in a validated accurate prediction model.https://www.mdpi.com/2072-6694/14/14/3537upper tract urinary carcinomaliquid biopsyDNA methylationgene mutation
spellingShingle Wei Ouyang
Lufeng Luo
Junjie Zhang
Ran Xu
Qiang Lu
Zhenzhou Xu
Jianye Liu
Pei Li
Yaqun Zhang
Chuanchi Zhou
Wei Tang
Zhenting Wang
Manman Cao
Genming Xu
Long Wang
Urine Cellular DNA Point Mutation and Methylation for Identifying Upper Tract Urinary Carcinoma
Cancers
upper tract urinary carcinoma
liquid biopsy
DNA methylation
gene mutation
title Urine Cellular DNA Point Mutation and Methylation for Identifying Upper Tract Urinary Carcinoma
title_full Urine Cellular DNA Point Mutation and Methylation for Identifying Upper Tract Urinary Carcinoma
title_fullStr Urine Cellular DNA Point Mutation and Methylation for Identifying Upper Tract Urinary Carcinoma
title_full_unstemmed Urine Cellular DNA Point Mutation and Methylation for Identifying Upper Tract Urinary Carcinoma
title_short Urine Cellular DNA Point Mutation and Methylation for Identifying Upper Tract Urinary Carcinoma
title_sort urine cellular dna point mutation and methylation for identifying upper tract urinary carcinoma
topic upper tract urinary carcinoma
liquid biopsy
DNA methylation
gene mutation
url https://www.mdpi.com/2072-6694/14/14/3537
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