[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"doc-seo-328213-105":3,"detail-sidebar-cat-0-en-105":81,"doc-detail-328213-en":130},{"code":4,"msg":5,"data":6},0,"ok",{"site_id":7,"language":8,"slug":9,"title":10,"keywords":11,"description":12,"schema_data":13,"social_meta":74,"head_meta":76,"extra_data":78,"updated_unix":80},105,"en","tumor-initiation-and-early-tumorigenesis-molecular-mechanisms-and-interventional-targets-review-article","Tumor initiation and early tumorigenesis: molecular mechanisms and interventional targets - Review article","","Tumorigenesis is presented as a multistep, low-probability transition from oncogenic mutations and early clonal expansion into irreversible, highly heterogeneous, invasive cancer. The review explains how environmental tumor-risk signals and epigenetic alterations shape early malignant evolution without directly driving mutations, and how tumor clonal evolution arises from intrinsic cellular identities under extrinsic selective pressures. It summarizes genetic, epigenetic, and external driver events that coordinate co-evolution with the tumor ecosystem, aiming to enable translational prediction and interception of malignant transformation.",{"@graph":14,"@context":73},[15,34,56],{"@type":16,"itemListElement":17},"BreadcrumbList",[18,23,27,31],{"item":19,"name":20,"@type":21,"position":22},"https://docshare.wps.com","Home","ListItem",1,{"item":24,"name":25,"@type":21,"position":26},"https://docshare.wps.com/document/","Document",2,{"item":28,"name":29,"@type":21,"position":30},"https://docshare.wps.com/document/research-report/","Research & Report",3,{"item":32,"name":10,"@type":21,"position":33},"https://docshare.wps.com/document/tumor-initiation-and-early-tumorigenesis-molecular-mechanisms-and-interventional-targets-review-article/328213/",4,{"url":32,"name":10,"@type":35,"image":36,"author":41,"headline":10,"publisher":44,"fileFormat":47,"inLanguage":8,"description":12,"dateModified":48,"datePublished":49,"encodingFormat":47,"isAccessibleForFree":50,"interactionStatistic":51},"DigitalDocument",{"url":37,"@type":38,"width":39,"height":40},"https://docshare.wps.com/thumbnails/tumor-initiation-and-early-tumorigenesis-molecular-mechanisms-and-interventional-targets-review-article/328213.png","ImageObject",300,407,{"name":42,"@type":43},"Maeve","Person",{"url":19,"name":45,"@type":46},"DocShare","Organization","application/pdf","2026-11-08","2026-09-21",true,{"@type":52,"interactionType":53,"userInteractionCount":55},"InteractionCounter",{"@type":54},"ViewAction",9,{"@type":57,"mainEntity":58},"FAQPage",[59,65,69],{"name":60,"@type":61,"acceptedAnswer":62},"Why is cancer transformation considered a rare event despite widespread somatic mutations and clonal expansion?","Question",{"text":63,"@type":64},"The review argues that oncogenic mutations and clonal advantage are insufficient by themselves; additional driver events are required for progression to irreversible, highly heterogeneous, invasive lesions.","Answer",{"name":66,"@type":61,"acceptedAnswer":67},"How do environmental tumor-risk factors and epigenetic alterations contribute to early tumorigenesis?",{"text":68,"@type":64},"They influence early clonal expansion and malignant evolution independently of inducing mutations, providing non-genetic and epigenetic drivers that release growth and survival potential.",{"name":70,"@type":61,"acceptedAnswer":71},"What determines the clonal evolution of transformed cells during tumor initiation?",{"text":72,"@type":64},"Clonal evolution reflects a balance between intrinsic cellular competency and extrinsic selective pressures, shaped by neighboring competitors, the microenvironment, and tissue architecture.","https://schema.org",{"og:url":32,"og:type":75,"og:title":10,"og:site_name":45,"og:description":12},"article",{"robots":77,"canonical":32},"index,follow",{"doc_id":79,"site_id":7},328213,1790196251,{"code":4,"msg":82,"data":83},"success",[84,88,92,96,101,106,111,115,119,122,126],{"id":22,"doc_module":4,"doc_module_name":25,"category_name":85,"show_sort_weight":86,"slug":87},"Story & Novel",90,"story-novel",{"id":26,"doc_module":4,"doc_module_name":25,"category_name":89,"show_sort_weight":90,"slug":91},"Literature",80,"literature",{"id":33,"doc_module":4,"doc_module_name":25,"category_name":93,"show_sort_weight":94,"slug":95},"Exam",70,"exam",{"id":97,"doc_module":4,"doc_module_name":25,"category_name":98,"show_sort_weight":99,"slug":100},5,"Comic",60,"comic",{"id":102,"doc_module":4,"doc_module_name":25,"category_name":103,"show_sort_weight":104,"slug":105},6,"Technology",50,"technology",{"id":107,"doc_module":4,"doc_module_name":25,"category_name":108,"show_sort_weight":109,"slug":110},7,"Healthcare",40,"healthcare",{"id":112,"doc_module":4,"doc_module_name":25,"category_name":29,"show_sort_weight":113,"slug":114},8,30,"research-report",{"id":55,"doc_module":4,"doc_module_name":25,"category_name":116,"show_sort_weight":117,"slug":118},"Religion & Spirituality",20,"religion-spirituality",{"id":117,"doc_module":4,"doc_module_name":25,"category_name":120,"show_sort_weight":117,"slug":121},"World Cup","world-cup",{"id":123,"doc_module":4,"doc_module_name":25,"category_name":124,"show_sort_weight":123,"slug":125},10,"Lifestyle","lifestyle",{"id":127,"doc_module":4,"doc_module_name":25,"category_name":128,"show_sort_weight":97,"slug":129},19,"General","general",{"code":4,"msg":82,"data":131},{"doc_id":79,"user_id":132,"nickname":42,"user_avatar":133,"doc_module":4,"category_id":112,"category_name":29,"doc_title":10,"doc_description":12,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":55,"is_deleted":4,"is_public":22,"is_downloadable":22,"audit_status":22,"page_count":139,"language":140,"language_code":8,"site_id":7,"html_lang":8,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":12,"update_tm":144,"read_time":145,"preview_page_count":4},5909877438554,"https://ap-avatar.wpscdn.com/avatar/5600025385ad2bf12a7?_k=1778553567797529272","Signal Transduction [and Targeted Therapy](and Targeted Therapy www.nature.com/sigtrans)[ www.nature.com/sigtrans](and Targeted Therapy www.nature.com/sigtrans)  \nREVIEW ARTICLE  \nOPEN  \nTumor initiation and early tumorigenesis: molecular mechanisms and interventional targets  \nShaosen Zhang 1,2, Xinyi Xiao1,2, Yonglin Yi1,2, Xinyu Wang 1,2, Lingxuan Zhu1,2,3, Yanrong Shen 1,2, Dongxin Lin 1,2,3,4,5 ✉ and Chen Wu1,2,3,4,6 ✉  \n\n|  | Tumorigenesis is a multistep process, with oncogenic mutations in a normal cell conferring clonal advantage as the initial event. However, despite pervasive somatic mutations and clonal expansion in normal tissues, their transformation into cancer remains a rare event, indicating the presence of additional driver events for progression to an irreversible, highly heterogeneous, and invasive lesion. Recently, researchers are emphasizing the mechanisms of environmental tumor risk factors and epigenetic alterations that are profoundly influencing early clonal expansion and malignant evolution, independently of inducing mutations. Additionally, clonal evolution in tumorigenesis reflects a multifaceted interplay between cell-intrinsic identities and various cell-extrinsic factors that exert selective pressures to either restrain uncontrolled proliferation or allow specific clones to progress into tumors. However, the mechanisms by which driver events induce both intrinsic cellular competency and remodel environmental stress to facilitate malignant transformation are not fully understood. In this review, we summarize the genetic, epigenetic, and external driver events, and their effects on the co-evolution of the transformed cells and their ecosystem during tumor initiation and early malignant evolution. A deeper understanding of the earliest molecular events holds promise for translational applications, predicting |  |\n| --- | --- | --- |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n| individuals at high-risk of tumor and developing strategies to intercept malignant transformation. |  |  |\n|  | Signal Transduction and Targeted Therapy (2024)9:149 ; [https://doi.org/10.1038/s41392-024-01848-7](https://doi.org/10.1038/s41392-024-01848-7) |  |\n|  |  |  |\n\nINTRODUCTION  \nIt is generally believed that tumorigenesis is a multi-stage process, wherein the initial step is the occurrence of an oncogenic mutation in a single somatic cell. The mutation endows cells with clonal advantages, allowing the mutant clone to expand and accumulate additional genetic and epigenetic alterations, ultimately resulting in an irreversible, highly heterogeneous, and invasive lesion1 (Fig. 1) . Mutations that confer growth competitiveness and promote cancer evolution are referred to as cancer driver mutations. Identifying driver mutations and revealing their roles in tumors represent key areas of focus in cancer genome research. Recent advancements in sampling and sequencing technologies facilitate the detection of somatic mutations and clonal expansion in normal tissues. It is surprising that eventhough driver mutations harbored by positively selected clones overlap to a great extent with cancer driver mutations and are pervasive in morphologically normal tissues, only a low annual incidence rate of cancer is diagnosed in populations. It is suggested that mutations alone are insufficient for tumor formation, and other prerequisite molecular events need to beidentified. Additionally, humans have evolved various strategies to maintain homeostasis and defend oncogenic transformation. However, environmental insults and aging often disrupt the balance and increase the risk of cancer formation.2,3 Although the  \nmechanisms of these risk factors contributing to cancer progression have been widely explored, how they are involved in early tumorigenesis and interact with specific oncogenic mutations are still not completely understood. The non-genetic effects of external si","cbCaiqnxwOiFo65W","https://ap.wps.com/l/cbCaiqnxwOiFo65W","pdf",4188514,36,"English","# INTRODUCTION\n## Tumorigenesis as a multistage process\n## Driver mutations and cancer genome research\n## Environmental and epigenetic contributions to early evolution\n## Transformed cells, clonal evolution, and microenvironment interactions\n# Significance for early intervention and targeted therapy","[{\"question\":\"Why is cancer transformation considered a rare event despite widespread somatic mutations and clonal expansion?\",\"answer\":\"The review argues that oncogenic mutations and clonal advantage are insufficient by themselves; additional driver events are required for progression to irreversible, highly heterogeneous, invasive lesions.\"},{\"question\":\"How do environmental tumor-risk factors and epigenetic alterations contribute to early tumorigenesis?\",\"answer\":\"They influence early clonal expansion and malignant evolution independently of inducing mutations, providing non-genetic and epigenetic drivers that release growth and survival potential.\"},{\"question\":\"What determines the clonal evolution of transformed cells during tumor initiation?\",\"answer\":\"Clonal evolution reflects a balance between intrinsic cellular competency and extrinsic selective pressures, shaped by neighboring competitors, the microenvironment, and tissue architecture.\"}]","Tumor initiation and early tumorigenesis: molecular mechanisms and interventional targets - Review article | PDF",1789978865,91]