[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-329486-105":59,"doc-detail-329486-en":130},{"code":4,"msg":5,"data":6},0,"success",[7,13,18,23,28,33,38,43,48,51,55],{"id":8,"doc_module":4,"doc_module_name":9,"category_name":10,"show_sort_weight":11,"slug":12},1,"Document","Story & Novel",90,"story-novel",{"id":14,"doc_module":4,"doc_module_name":9,"category_name":15,"show_sort_weight":16,"slug":17},2,"Literature",80,"literature",{"id":19,"doc_module":4,"doc_module_name":9,"category_name":20,"show_sort_weight":21,"slug":22},4,"Exam",70,"exam",{"id":24,"doc_module":4,"doc_module_name":9,"category_name":25,"show_sort_weight":26,"slug":27},5,"Comic",60,"comic",{"id":29,"doc_module":4,"doc_module_name":9,"category_name":30,"show_sort_weight":31,"slug":32},6,"Technology",50,"technology",{"id":34,"doc_module":4,"doc_module_name":9,"category_name":35,"show_sort_weight":36,"slug":37},7,"Healthcare",40,"healthcare",{"id":39,"doc_module":4,"doc_module_name":9,"category_name":40,"show_sort_weight":41,"slug":42},8,"Research & Report",30,"research-report",{"id":44,"doc_module":4,"doc_module_name":9,"category_name":45,"show_sort_weight":46,"slug":47},9,"Religion & Spirituality",20,"religion-spirituality",{"id":46,"doc_module":4,"doc_module_name":9,"category_name":49,"show_sort_weight":46,"slug":50},"World Cup","world-cup",{"id":52,"doc_module":4,"doc_module_name":9,"category_name":53,"show_sort_weight":52,"slug":54},10,"Lifestyle","lifestyle",{"id":56,"doc_module":4,"doc_module_name":9,"category_name":57,"show_sort_weight":24,"slug":58},19,"General","general",{"code":4,"msg":60,"data":61},"ok",{"site_id":62,"language":63,"slug":64,"title":65,"keywords":66,"description":67,"schema_data":68,"social_meta":123,"head_meta":125,"extra_data":127,"updated_unix":129},105,"en","developmental-mosaicism-underlying-egfr-mutant-lung-cancer-presenting-with-multiple-primary-tumors","Developmental mosaicism underlying EGFR-mutant lung cancer presenting with multiple primary tumors","","Study examines why some individuals with EGFR-mutant non-small cell lung cancer present with multiple anatomically distinct primary tumors despite lacking known environmental exposures. Ten early-stage resectable NSCLC patients were analyzed using whole-exome sequencing and hypermutable poly(G) repeat genotyping to trace tumor lineage. Four cases showed developmental mosaicism with a common non-germline origin, while two revealed germline EGFR variants with moderately enhanced in vitro signaling. Results define developmental mosaicism as a genetic predisposition mechanism shaping etiology and clinical management.",{"@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":40,"@type":76,"position":81},"https://docshare.wps.com/document/research-report/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/developmental-mosaicism-underlying-egfr-mutant-lung-cancer-presenting-with-multiple-primary-tumors/329486/",{"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/developmental-mosaicism-underlying-egfr-mutant-lung-cancer-presenting-with-multiple-primary-tumors/329486.png","ImageObject",300,407,{"name":92,"@type":93},"Seraphina","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-27","2026-09-21",true,{"@type":102,"interactionType":103,"userInteractionCount":24},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"Why does the study focus on multiple primary tumors in EGFR-mutant lung cancer without known exposures?","Question",{"text":112,"@type":113},"Multiple tumors at presentation cannot be fully explained by smoking-related field cancerization when EGFR-mutant cases lack known environmental exposures, so the study investigates alternative genetic mechanisms.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How were evolutionary relationships among tumors determined in each patient?",{"text":117,"@type":113},"The study used whole-exome sequencing and hypermutable poly(guanine)(poly(G)) repeat genotyping as orthogonal methods for lineage tracing.",{"name":119,"@type":110,"acceptedAnswer":120},"What did developmental mosaicism and germline EGFR variants contribute to the study’s conclusions?",{"text":121,"@type":113},"Developmental mosaicism indicated a common non-germline cell of origin in some patients, while other patients carried germline EGFR variants that showed moderately enhanced signaling when modeled in vitro; together these findings define distinct predisposition mechanisms.","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},329486,1790584912,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":39,"category_name":40,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":24,"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,"preview_page_count":4},962075114101,"https://ap-avatar.wpscdn.com/avatar/e000253a75eb197efd?x-image-process=image/resize,m_fixed,w_180,h_180&k=1780044092746381165","nature cancer  \nArticle [https://doi.org/10.1038/s43018-024-00840-y](https://doi.org/10.1038/s43018-024-00840-y)  \nDevelopmental mosaicism underlying EGFR-mutant lung cancer presenting with multiple primary tumors  \nReceived: 5 April 2023  \nAccepted: 10 September 2024  \n\n| Published online: 15 October 2024 |\n| --- |\n|  Check for updates |\n\nRisa Burr1,12, Ignaty Leshchiner  2,3,12, Christina L. Costantino1,4,12,  \nMartin Blohmer5,6, Tilak Sundaresan1, Justin Cha  2, Karsen Seeger1, Sara Guay1, Brian P. Danysh2, Ira Gore7, Raquel A. Jacobs2, Kara Slowik2, Filippo Utro  8, Kahn Rhrissorrakrai8, Chaya Levovitz  8, Jaimie L. Barth9, Taronish Dubash1, Brian Chirn1, Laxmi Parida  8, Lecia V. Sequist1,10, Jochen K. Lennerz9,  \nMari Mino-Kenudson9, Shyamala Maheswaran1,4, Kamila Naxerova  5,6, GadGetz  1,2,9  & DanielA. Haber  1,10,11   \nAlthough the development of multiple primary tumorsin smokers with lung cancer can be attributed to carcinogen-induced field cancerization, the occurrence of multiple tumorsat presentation in individuals with EGFR-mutant lung cancer who lack known environmental exposures remains unexplained. In the present study, we identified ten patients with early stage, resectable, non-small cell lung cancer who presented with multiple, anatomically distinct, EGFR-mutant tumors. We analyzed the phylogenetic relationships among multiple tumors from each patient using whole-exome sequencing (WES) and hypermutable poly(guanine)(poly(G)) repeat genotyping as orthogonal methods for lineage tracing. In four patients, developmental mosaicism, assessed by WESand poly(G) lineage tracing, indicates a common non-germline cell of origin. In two other patients, we identified germline EGFR variants, which confer moderately enhanced signaling when modeled in vitro. Thus, in addition to germline variants, developmental mosaicism defines a distinct mechanism of genetic predisposition to multiple EGFR-mutant primary tumors, with implications for their etiology and clinical management.  \nAs many as 10% of patients with non-small cell lung cancer (NSCLC) present with radiographic findings suggestive of two or more anatomically distinct synchronous lesions. This fraction is rising with the overall increased utilization of computed tomography (CT) imaging and specifically with improved utilization of low-doseCT screening in high-risk individuals with heavy smoking histories1–4. In such patients, multiple independent primary tumors are genetically unrelated, typically showing distinct genetic drivers, with mutational signatures of carcinogen-mediated DNA damage1,5,6. The concept of field cancerizationin lung and other tissues, such as ultraviolet-exposed skin, explains  \nthe lifelong risk of multiple primary tumorsand the need for regular cancer screening and monitoring in a subset of patients1,5–13.  \nNSCLC harboring activating mutations in theEGFR gene account for approximately 15% of all cases14. Specific, somatically acquired,‘canonical’ mutations (most commonly L858R and delE746–A750) strongly activate receptor signaling, driving tumorigenesis and leading to dramatic clinical responses to epidermal growth factor receptor (EGFR) kinase inhibitors15,16. Tumors with canonical EGFR mutations typically do not show smoking-associated mutational signaturesand the dramatic enrichment of cases among never smokers with NSCLC  \nA full list of affiliations appears at the end of the paper. [e-mail:](e-mail: gadgetz@broadinstitute.org)[ gadgetz@broadinstitute.org](e-mail: gadgetz@broadinstitute.org); [dhaber@mgh.harvard.edu](dhaber@mgh.harvard.edu)  \nTable 1 | Demographic and clinical characteristics of the patients  \n\n| Patient | Age decade (gender)a | Smoking | Genetic ancestry | Stage | No. of tumors | Contralateral/Multilobar | Classification |\n| --- | --- | --- | --- | --- | --- | --- | --- |\n| III-1 | 50s (M) | Moderate | European | 0 | >13 | Y/Y | Germline |\n| III-4 | 60s (F) | Never | European | 0 | 10 | Y/Y | Germline |\n| 1 | 60s (F) | F","cbCaiauf0b5bx9gL","https://ap.wps.com/l/cbCaiauf0b5bx9gL","pdf",5925466,23,"English","# Abstract-like summary\n## Patient cohort and selection\n## Methods for lineage tracing\n## Mosaicism versus germline variant findings\n## Clinical implications","[{\"question\":\"Why does the study focus on multiple primary tumors in EGFR-mutant lung cancer without known exposures?\",\"answer\":\"Multiple tumors at presentation cannot be fully explained by smoking-related field cancerization when EGFR-mutant cases lack known environmental exposures, so the study investigates alternative genetic mechanisms.\"},{\"question\":\"How were evolutionary relationships among tumors determined in each patient?\",\"answer\":\"The study used whole-exome sequencing and hypermutable poly(guanine)(poly(G)) repeat genotyping as orthogonal methods for lineage tracing.\"},{\"question\":\"What did developmental mosaicism and germline EGFR variants contribute to the study’s conclusions?\",\"answer\":\"Developmental mosaicism indicated a common non-germline cell of origin in some patients, while other patients carried germline EGFR variants that showed moderately enhanced signaling when modeled in vitro; together these findings define distinct predisposition mechanisms.\"}]","Developmental mosaicism underlying EGFR-mutant lung cancer presenting with multiple primary tumors | PDF",1789984299,58]