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Cancer-causing mutations emerge in urothelium before clinical signs. This work identifies mutation hotspots in cancer-driving genes from NMIBC and MIBC samples, quantifies hotspot mutation burden in normal urothelium, and links it to bladder-cancer hotspot tissue. Machine-learning models combining measured hotspot burden and personal risk factors predict high- versus low-risk normal urothelium, enabling earlier risk stratification.",{"@graph":69,"@context":123},[70,84,106],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/mutation-hotspots-found-in-bladder-cancer-aid-prediction-of-carcinogenic-risk-in-normal-urothelium/377848/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/mutation-hotspots-found-in-bladder-cancer-aid-prediction-of-carcinogenic-risk-in-normal-urothelium/377848.png","ImageObject",300,407,{"name":92,"@type":93},"Miles","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-11-03","2026-09-24",true,{"@type":102,"interactionType":103,"userInteractionCount":105},"InteractionCounter",{"@type":104},"ViewAction",12,{"@type":107,"mainEntity":108},"FAQPage",[109,115,119],{"name":110,"@type":111,"acceptedAnswer":112},"Why is early bladder cancer prevention important in this research?","Question",{"text":113,"@type":114},"The work highlights that although bladder cancer cases are estimated to be high, the 5-year survival rate has not changed for decades, so prevention and early risk assessment are urgently needed.","Answer",{"name":116,"@type":111,"acceptedAnswer":117},"How do the authors relate normal urothelium to bladder cancer risk?",{"text":118,"@type":114},"They measure mutation burden in normal urothelium within hotspot regions and find a significant correlation with mutation burden in bladder cancer tissue in the same hotspots.",{"name":120,"@type":111,"acceptedAnswer":121},"What role do machine-learning models play in the study?",{"text":122,"@type":114},"The study uses combinations of measured hotspot burden and personal risk factors to fit machine-learning classification models, evaluating how well they distinguish benign adjacent urothelium and normal urothelium from bladder cancer patients.","https://schema.org",{"og:url":83,"og:type":125,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":127,"canonical":83},"index,follow",{"doc_id":129,"site_id":62},377848,1790318622,{"code":4,"msg":5,"data":132},{"doc_id":129,"user_id":133,"nickname":92,"user_avatar":134,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":135,"file_id":136,"file_url":137,"file_type":138,"file_size":139,"view_count":105,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":140,"language":141,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":142,"faqs":143,"seo_title":144,"seo_description":67,"update_tm":145,"read_time":146},13056703019404,"https://ap-avatar.wpscdn.com/davatar_29158cc5080c5b710cf443261637dec0","Article  \nMutation Hotspots Found in Bladder Cancer Aid Prediction of Carcinogenic Risk in Normal Urothelium  \nSydney R. Grant 1,2, Li Tang 3, Lei Wei 4, Barbara A. Foster 5, Gyorgy Paragh 1,2, * and Wendy J. Huss 1,2, *  \nCitation: Grant, S.R.; Tang, L.; Wei, L.; Foster, B.A.; Paragh, G.; Huss, W.J. Mutation Hotspots Found in Bladder Cancer Aid Prediction of Carcinogenic Risk in Normal Urothelium. Int. J. Mol. Sci. 2023, 24, 7852. [https://doi.org/](https://doi.org/)[ ](https://doi.org/)[10.3390/ijms24097852](10.3390/ijms24097852)  \nAcademic Editor: Ahmad R. Safa  \nReceived: 8 March 2023  \nRevised: 11 April 2023  \nAccepted: 22 April 2023  \nPublished: 25 April 2023  \nCopyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) .  \n1 Department of Dermatology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA  \n2 Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA  \n3 Department of Cancer Prevention & Control, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA  \n4 Department of Biostatistics & Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA  \n5 Department of Pharmacology & Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA  \n* Correspondence: gyorgy.paragh@roswellpark.org (G.P.); [wendy.huss@roswellpark.org](wendy.huss@roswellpark.org) (W.J.H.)  \nAbstract: More than 80,000 new cases of bladder cancer are estimated to be diagnosed in 2023 . However, the 5-year survival rate for bladder cancer has not changed in decades, highlighting the need for prevention. Numerous cancer-causing mutations are present in the urothelium long before signs of cancer arise. Mutation hotspots in cancer-driving genes were identified in nonmuscle-invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC) tumor samples. Mutation burden within the hotspot regions was measured in normal urothelium with a low and high risk of cancer. A significant correlation was found between the mutation burden in normal urothelium and bladder cancer tissue within the hotspot regions. A combination of measured hotspot burden and personal risk factors was used to fit machine learning classification models. The efficacy of each model to differentiate between adjacent benign urothelium from bladder cancer patients and normal urothelium from healthy donors was measured. A random forest model using a combination of personal risk factors and mutations within MIBC hotspots yielded the highest AUC of 0.9286 for the prediction of high-vs. low-risk normal urothelium. Currently, there are no effective biomarkers to assess subclinical field disease and early carcinogenic progression in the bladder. Our findings demonstrate novel differences in mutation hotspots in NMIBC and MIBC and provide the first evidence for mutation hotspots to aid in the assessment of cancer risk in the normal urothelium. Early risk assessment and identification of patients at high risk of bladder cancer before the clinical presentation of the disease can pave the way for targeted personalized preventative therapy.  \nKeywords: urothelium; mutation hotspot; clonal mutations; carcinogenesis; bladder cancer; machine learning  \n1. Introduction  \nIn 2023, there will be an estimated 82,290 new cases of bladder cancer, with an estimated 16,0 deaths, in the United States [1] . The most common clinical presentation of bladder cancer at the time of diagnosis is visible hematuria [2] . At diagnosis, cancers are classified as non-muscle-invasive bladder cancer (NMIBC) or muscle-invasive bladder cancer (MIBC) . Most bladder cancers are NMIBC and are treated by resection with cystoscopy, with","cbCaibKONKveIBX1","https://ap.wps.com/l/cbCaibKONKveIBX1","pdf",1951045,15,"English","# Abstract\n# Keywords\n# Introduction","[{\"question\":\"Why is early bladder cancer prevention important in this research?\",\"answer\":\"The work highlights that although bladder cancer cases are estimated to be high, the 5-year survival rate has not changed for decades, so prevention and early risk assessment are urgently needed.\"},{\"question\":\"How do the authors relate normal urothelium to bladder cancer risk?\",\"answer\":\"They measure mutation burden in normal urothelium within hotspot regions and find a significant correlation with mutation burden in bladder cancer tissue in the same hotspots.\"},{\"question\":\"What role do machine-learning models play in the study?\",\"answer\":\"The study uses combinations of measured hotspot burden and personal risk factors to fit machine-learning classification models, evaluating how well they distinguish benign adjacent urothelium and normal urothelium from bladder cancer patients.\"}]","Mutation Hotspots Found in Bladder Cancer - Aid Prediction of Carcinogenic Risk in Normal Urothelium | PDF",1790227367,38]