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High-risk HPV (hr-HPV) integrates more readily, driving a dynamic multi-stage oncogenic cascade. The process links viral entry, immune evasion, persistent infection, and genomic integration into vulnerable host sites, followed by sustained oncogene expression, genomic rearrangements, epigenetic dysregulation, and immune microenvironment remodeling. The review highlights HPV integration as a specific molecular biomarker with potential for precision screening and targeted therapy.",{"@graph":69,"@context":122},[70,84,105],{"@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/from-viral-infection-to-genome-reshaping-the-triggering-role-of-hpv-integration-in-cervical-cancer/372695/",{"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/from-viral-infection-to-genome-reshaping-the-triggering-role-of-hpv-integration-in-cervical-cancer/372695.png","ImageObject",300,407,{"name":92,"@type":93},"Franzy","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-30","2026-09-23",true,{"@type":102,"interactionType":103,"userInteractionCount":34},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"Why is HPV integration considered a hallmark event in cervical cancer development?","Question",{"text":112,"@type":113},"HPV integration is closely linked to cervical carcinogenesis and genomic transformation. It drives downstream events such as viral oncogene persistence, host rearrangements, and epigenetic and immune microenvironment changes that collectively promote cancer progression.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How does HPV progress from infection to genomic integration?",{"text":117,"@type":113},"The progression is described as a dynamic multi-step process involving viral entry, immune evasion, persistent infection, and then integration into vulnerable host genomic sites. Integration occurs through pathways such as microhomology-mediated end joining (MMEJ) and other alternative mechanisms.",{"name":119,"@type":110,"acceptedAnswer":120},"What is the clinical value of detecting HPV integration?",{"text":121,"@type":113},"The review states that HPV integration can serve as a highly specific molecular biomarker. This supports precision screening and can inform targeted therapeutic strategies for hr-HPV-positive individuals.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},372695,1790906610,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":34,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":145},2336478945519,"https://ap-avatar.wpscdn.com/davatar_085a072bc5b1113ac321206ff7593b45","Review  \nFrom Viral Infection to Genome Reshaping: The Triggering Role of HPV Integration in Cervical Cancer  \nJunlan Li  and Shuang Li *  \nAcademic Editor: Marco Ciotti  \nReceived: 15 August 2025  \nRevised: 11 September 2025  \nAccepted: 15 September 2025  \nPublished: 21 September 2025  \nCitation: Li, J.; Li, S. From Viral  \nInfection to Genome Reshaping: The Triggering Role of HPV Integration in Cervical Cancer. Int. J. Mol. Sci. 2025, 26, 9214. [https://doi.org/10.3390/](https://doi.org/10.3390/)[ ](https://doi.org/10.3390/)ijms26189214  \nCopyright: © 2025 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://creativecommons.org/](https://creativecommons.org/)[ ](https://creativecommons.org/)[licenses/by/4.0/](licenses/by/4.0/)) .  \nDepartment of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; [m202376483@hust.edu.cn](m202376483@hust.edu.cn)  \n* Correspondence: [shuangli@hust.edu.cn](shuangli@hust.edu.cn)  \nAbstract  \nHuman papillomavirus (HPV) integration is recognized as a hallmark event in cervical carcinogenesis. However, it does not represent a routine phase of the viral life cycle but rather a stochastic occurrence, often constituting a dead-end pathway for the virus. Highrisk human papillomavirus (hr-HPV) exhibits a greater propensity for integration. The progression from initial infection to genomic integration constitutes a dynamic multi-step oncogenic process in the development of cervical cancer (CC) . This process involves viral entry, immune evasion, persistent infection, and ultimately integration. This article innovatively provides a comprehensive overview of this multi-stage mechanism: HPV, via the L1/L2 proteins, mediates internalization and establishes infection. Subsequently, under the influence of factors such as the host’s genetic background, vaginal microbiota imbalance, and immune evasion, the host’s DNA damage response (DDR) pathways are activated. Viral DNA integrates into host genome vulnerable sites (e.g., 3q28 and 8q24) through microhomology-mediated end joining (MMEJ) or other alternative pathways. Following integration, the expression of viral oncogenes persists, triggering host genomic rearrangements, aberrant epigenetic modifications, and immune microenvironment remodeling, all of which collectively drive cervical cancer progression. The study further reveals the clinical potential of HPV integration as a highly specific molecular biomarker, offering new perspectives for precision screening and targeted therapy. This dynamic model deepensour understanding of the HPV carcinogenic mechanism and provides a theoretical basis for intervention strategies.  \nKeywords: HPV integration; cervical carcinogenesis; genomic instability; microhomologymediated repair; viral–host interaction  \n1. Background  \nGlobally, cervical cancer (CC) ranks as the fourth most common cancer in women, after breast, colorectal, and lung cancers. According to 2022 global cancer statistics, approximately 661,021 new cases and 348,189 deaths occur annually [1] . The incidence and mortality rates vary significantly due to disparities in socioeconomic levels and healthcare services, ranging from 2.2 (1.9–2.4) in Iraq to 84.6 (74.8–94.3) in Eswatini for incidence and from 1.0 (0.8–1.2) in Switzerland to 55.7 (47.7–63.7) in Eswatini for mortality [2] . The World Health Organization (WHO)’s global strategy to eliminate CC aims to reduce its incidence to less than 4 cases per 100,000 women annually within this century [3] . While advancements in prevention and screening technologies have substantially decreased CC rates in high-income countries, low-and middle-income countries (LMICs) still face incidence  \nand mortality rates far exceeding the WHO’s elimination threshold [2] . In most nations, CC is still a ","cbCaiarNyrqb8M1U","https://ap.wps.com/l/cbCaiarNyrqb8M1U","pdf",1278360,22,"English","# Abstract\n# Background\n## Global burden and WHO elimination strategy\n## Persistent hr-HPV infection and screening limitations\n## Rationale for HPV integration testing","[{\"question\":\"Why is HPV integration considered a hallmark event in cervical cancer development?\",\"answer\":\"HPV integration is closely linked to cervical carcinogenesis and genomic transformation. It drives downstream events such as viral oncogene persistence, host rearrangements, and epigenetic and immune microenvironment changes that collectively promote cancer progression.\"},{\"question\":\"How does HPV progress from infection to genomic integration?\",\"answer\":\"The progression is described as a dynamic multi-step process involving viral entry, immune evasion, persistent infection, and then integration into vulnerable host genomic sites. Integration occurs through pathways such as microhomology-mediated end joining (MMEJ) and other alternative mechanisms.\"},{\"question\":\"What is the clinical value of detecting HPV integration?\",\"answer\":\"The review states that HPV integration can serve as a highly specific molecular biomarker. This supports precision screening and can inform targeted therapeutic strategies for hr-HPV-positive individuals.\"}]","From Viral Infection to Genome Reshaping - The Triggering Role of HPV Integration in Cervical Cancer | PDF",1790195145,55]