TERT Promoter Mutations as Simple and Non-Invasive Urinary Biomarkers for the Detection of Urothelial Bladder Cancer in a High-Risk Region
Bladder cancer (BC) is the 10th most common cancer in the world. While there are FDA-approved urinary assays to detect BC, none have demonstrated sufficient sensitivity and specificity to be integrated into clinical practice. Telomerase Reverse Transcriptase (<i>TERT</i>) gene mutations...
| Main Authors: | , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-11-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/23/22/14319 |
| _version_ | 1797465036000591872 |
|---|---|
| author | Hamid Pakmanesh Omid Anvari Nathalie Forey Elisabete Weiderpass Reza Malekpourafshar Maryam Iranpour Armita Shahesmaeili Nahid Ahmadi Azam Bazrafshan Kazem Zendehdel Caroline Kannengiesser Ibrahima Ba James McKay Maria Zvereva Md Ismail Hosen Mahdi Sheikh Florence Le Calvez-Kelm |
| author_facet | Hamid Pakmanesh Omid Anvari Nathalie Forey Elisabete Weiderpass Reza Malekpourafshar Maryam Iranpour Armita Shahesmaeili Nahid Ahmadi Azam Bazrafshan Kazem Zendehdel Caroline Kannengiesser Ibrahima Ba James McKay Maria Zvereva Md Ismail Hosen Mahdi Sheikh Florence Le Calvez-Kelm |
| author_sort | Hamid Pakmanesh |
| collection | DOAJ |
| description | Bladder cancer (BC) is the 10th most common cancer in the world. While there are FDA-approved urinary assays to detect BC, none have demonstrated sufficient sensitivity and specificity to be integrated into clinical practice. Telomerase Reverse Transcriptase (<i>TERT</i>) gene mutations have been identified as the most common BC mutations that could potentially be used as non-invasive urinary biomarkers to detect BC. This study aims to evaluate the validity of these tests to detect BC in the Kerman province of Iran, where BC is the most common cancer in men. Urine samples of 31 patients with primary (<i>n</i> = 11) or recurrent (<i>n</i> = 20) bladder tumor and 50 controls were prospectively collected. Total urinary DNA was screened for the <i>TERT</i> promoter mutations (uTERTpm) by Droplet Digital PCR (ddPCR) assays. The performance characteristics of uTERTpm and the influence by disease stage and grade were compared to urine cytology results. The uTERTpm was 100% sensitive and 88% specific to detect primary BC, while it was 50% sensitive and 88% specific in detecting recurrent BC. The overall sensitivity and specificity of uTERTpm to detect bladder cancer were 67.7% and 88.0%, respectively, which were consistent across different tumor stages and grades. The most frequent uTERTpm mutations among BC cases were C228T (18/31), C250T (4/31), and C158A (1/31) with mutant allelic frequency (MAF) ranging from 0.2% to 63.3%. Urine cytology demonstrated a similar sensitivity (67.7%), but lower specificity (62.0%) than uTERTpm in detecting BC. Combined uTERTpm and urine cytology increased the sensitivity to 83.8%, but decreased the specificity to 52.0%. Our study demonstrated promising diagnostic accuracy for the uTERTpm as a non-invasive urinary biomarker to detect, in particular, primary BC in this population. |
| first_indexed | 2024-03-09T18:15:49Z |
| format | Article |
| id | doaj.art-802d339a5c2f4fa196ed389b56c0ad0e |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T18:15:49Z |
| publishDate | 2022-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-802d339a5c2f4fa196ed389b56c0ad0e2023-11-24T08:42:18ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-11-0123221431910.3390/ijms232214319TERT Promoter Mutations as Simple and Non-Invasive Urinary Biomarkers for the Detection of Urothelial Bladder Cancer in a High-Risk RegionHamid Pakmanesh0Omid Anvari1Nathalie Forey2Elisabete Weiderpass3Reza Malekpourafshar4Maryam Iranpour5Armita Shahesmaeili6Nahid Ahmadi7Azam Bazrafshan8Kazem Zendehdel9Caroline Kannengiesser10Ibrahima Ba11James McKay12Maria Zvereva13Md Ismail Hosen14Mahdi Sheikh15Florence Le Calvez-Kelm16Department of Urology, School of Medicine, Shahid Bahonar Hospital, Kerman University of Medical Sciences, Kerman 7616913555, IranDepartment of Urology, School of Medicine, Shahid Bahonar Hospital, Kerman University of Medical Sciences, Kerman 7616913555, IranInternational Agency for Research on Cancer (IARC), Genomic Epidemiology Branch, 69008 Lyon, FranceInternational Agency for Research on Cancer (IARC), Genomic Epidemiology Branch, 69008 Lyon, FranceDepartment of Pathology, Pathology and Stem Cell Research Center, Kerman University of Medical Sciences, Kerman 7616913555, IranDepartment of Pathology, Pathology and Stem Cell Research Center, Kerman University of Medical Sciences, Kerman 7616913555, IranHIV/STI Surveillance Research Center, and WHO Collaborating Center for HIV Surveillance, Institute for Futures Studies in Health, Kerman University of Medical Sciences, Kerman 7616913555, IranDepartment of Pharmacology and Toxicology, Faculty of Pharmacy, Kerman University of Medical Sciences, Kerman 7616913555, IranHIV/STI Surveillance Research Center, and WHO Collaborating Center for HIV Surveillance, Institute for Futures Studies in Health, Kerman University of Medical Sciences, Kerman 7616913555, IranCancer Research Center, Cancer Institute, Tehran University of Medical Sciences, Tehran 1419733133, IranDepartment of Genetics, Bichat Claude Bernard Hospital, 75108 Paris, FranceDepartment of Genetics, Bichat Claude Bernard Hospital, 75108 Paris, FranceInternational Agency for Research on Cancer (IARC), Genomic Epidemiology Branch, 69008 Lyon, FranceChair of Chemistry of Natural Compounds, Department of Chemistry, Lomonosov Moscow State University, 119991 Moscow, RussiaDepartment of Biochemistry and Molecular Biology, Faculty of Biological Sciences, University of Dhaka, Dhaka 1000, BangladeshInternational Agency for Research on Cancer (IARC), Genomic Epidemiology Branch, 69008 Lyon, FranceInternational Agency for Research on Cancer (IARC), Genomic Epidemiology Branch, 69008 Lyon, FranceBladder cancer (BC) is the 10th most common cancer in the world. While there are FDA-approved urinary assays to detect BC, none have demonstrated sufficient sensitivity and specificity to be integrated into clinical practice. Telomerase Reverse Transcriptase (<i>TERT</i>) gene mutations have been identified as the most common BC mutations that could potentially be used as non-invasive urinary biomarkers to detect BC. This study aims to evaluate the validity of these tests to detect BC in the Kerman province of Iran, where BC is the most common cancer in men. Urine samples of 31 patients with primary (<i>n</i> = 11) or recurrent (<i>n</i> = 20) bladder tumor and 50 controls were prospectively collected. Total urinary DNA was screened for the <i>TERT</i> promoter mutations (uTERTpm) by Droplet Digital PCR (ddPCR) assays. The performance characteristics of uTERTpm and the influence by disease stage and grade were compared to urine cytology results. The uTERTpm was 100% sensitive and 88% specific to detect primary BC, while it was 50% sensitive and 88% specific in detecting recurrent BC. The overall sensitivity and specificity of uTERTpm to detect bladder cancer were 67.7% and 88.0%, respectively, which were consistent across different tumor stages and grades. The most frequent uTERTpm mutations among BC cases were C228T (18/31), C250T (4/31), and C158A (1/31) with mutant allelic frequency (MAF) ranging from 0.2% to 63.3%. Urine cytology demonstrated a similar sensitivity (67.7%), but lower specificity (62.0%) than uTERTpm in detecting BC. Combined uTERTpm and urine cytology increased the sensitivity to 83.8%, but decreased the specificity to 52.0%. Our study demonstrated promising diagnostic accuracy for the uTERTpm as a non-invasive urinary biomarker to detect, in particular, primary BC in this population.https://www.mdpi.com/1422-0067/23/22/14319bladder cancerurinary biomarkersnon-invasive detectiontelomerasesomatic mutationsTERT promoter mutations |
| spellingShingle | Hamid Pakmanesh Omid Anvari Nathalie Forey Elisabete Weiderpass Reza Malekpourafshar Maryam Iranpour Armita Shahesmaeili Nahid Ahmadi Azam Bazrafshan Kazem Zendehdel Caroline Kannengiesser Ibrahima Ba James McKay Maria Zvereva Md Ismail Hosen Mahdi Sheikh Florence Le Calvez-Kelm TERT Promoter Mutations as Simple and Non-Invasive Urinary Biomarkers for the Detection of Urothelial Bladder Cancer in a High-Risk Region International Journal of Molecular Sciences bladder cancer urinary biomarkers non-invasive detection telomerase somatic mutations TERT promoter mutations |
| title | TERT Promoter Mutations as Simple and Non-Invasive Urinary Biomarkers for the Detection of Urothelial Bladder Cancer in a High-Risk Region |
| title_full | TERT Promoter Mutations as Simple and Non-Invasive Urinary Biomarkers for the Detection of Urothelial Bladder Cancer in a High-Risk Region |
| title_fullStr | TERT Promoter Mutations as Simple and Non-Invasive Urinary Biomarkers for the Detection of Urothelial Bladder Cancer in a High-Risk Region |
| title_full_unstemmed | TERT Promoter Mutations as Simple and Non-Invasive Urinary Biomarkers for the Detection of Urothelial Bladder Cancer in a High-Risk Region |
| title_short | TERT Promoter Mutations as Simple and Non-Invasive Urinary Biomarkers for the Detection of Urothelial Bladder Cancer in a High-Risk Region |
| title_sort | tert promoter mutations as simple and non invasive urinary biomarkers for the detection of urothelial bladder cancer in a high risk region |
| topic | bladder cancer urinary biomarkers non-invasive detection telomerase somatic mutations TERT promoter mutations |
| url | https://www.mdpi.com/1422-0067/23/22/14319 |
| work_keys_str_mv | AT hamidpakmanesh tertpromotermutationsassimpleandnoninvasiveurinarybiomarkersforthedetectionofurothelialbladdercancerinahighriskregion AT omidanvari tertpromotermutationsassimpleandnoninvasiveurinarybiomarkersforthedetectionofurothelialbladdercancerinahighriskregion AT nathalieforey tertpromotermutationsassimpleandnoninvasiveurinarybiomarkersforthedetectionofurothelialbladdercancerinahighriskregion AT elisabeteweiderpass tertpromotermutationsassimpleandnoninvasiveurinarybiomarkersforthedetectionofurothelialbladdercancerinahighriskregion AT rezamalekpourafshar tertpromotermutationsassimpleandnoninvasiveurinarybiomarkersforthedetectionofurothelialbladdercancerinahighriskregion AT maryamiranpour tertpromotermutationsassimpleandnoninvasiveurinarybiomarkersforthedetectionofurothelialbladdercancerinahighriskregion AT armitashahesmaeili tertpromotermutationsassimpleandnoninvasiveurinarybiomarkersforthedetectionofurothelialbladdercancerinahighriskregion AT nahidahmadi tertpromotermutationsassimpleandnoninvasiveurinarybiomarkersforthedetectionofurothelialbladdercancerinahighriskregion AT azambazrafshan tertpromotermutationsassimpleandnoninvasiveurinarybiomarkersforthedetectionofurothelialbladdercancerinahighriskregion AT kazemzendehdel tertpromotermutationsassimpleandnoninvasiveurinarybiomarkersforthedetectionofurothelialbladdercancerinahighriskregion AT carolinekannengiesser tertpromotermutationsassimpleandnoninvasiveurinarybiomarkersforthedetectionofurothelialbladdercancerinahighriskregion AT ibrahimaba tertpromotermutationsassimpleandnoninvasiveurinarybiomarkersforthedetectionofurothelialbladdercancerinahighriskregion AT jamesmckay tertpromotermutationsassimpleandnoninvasiveurinarybiomarkersforthedetectionofurothelialbladdercancerinahighriskregion AT mariazvereva tertpromotermutationsassimpleandnoninvasiveurinarybiomarkersforthedetectionofurothelialbladdercancerinahighriskregion AT mdismailhosen tertpromotermutationsassimpleandnoninvasiveurinarybiomarkersforthedetectionofurothelialbladdercancerinahighriskregion AT mahdisheikh tertpromotermutationsassimpleandnoninvasiveurinarybiomarkersforthedetectionofurothelialbladdercancerinahighriskregion AT florencelecalvezkelm tertpromotermutationsassimpleandnoninvasiveurinarybiomarkersforthedetectionofurothelialbladdercancerinahighriskregion |