[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-381657-105":59,"doc-detail-381657-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","fully-accessible-fitness-landscape-of-oncogene-negative-lung-adenocarcinoma","Fully accessible fitness landscape of oncogene-negative lung adenocarcinoma","","The cancer fitness landscape is explored for oncogene-negative lung adenocarcinoma, where no single dominant oncogene mutation exists. The study links tumor barcoding with combinatorial and multiplexed somatic genome editing to map how sequential genomic alterations shape tumor fitness. Fitness landscapes for NF1, RASA1, and PTEN inactivation are shown to be fully accessible, with each added mutation providing a growth advantage in any order. Accessibility persists even when additional tumor suppressor genes are inactivated, implying evolution constraints are reduced for mutational order.",{"@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/fully-accessible-fitness-landscape-of-oncogene-negative-lung-adenocarcinoma/381657/",{"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/fully-accessible-fitness-landscape-of-oncogene-negative-lung-adenocarcinoma/381657.png","ImageObject",300,407,{"name":92,"@type":93},"Cart","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-31","2026-09-24",true,{"@type":102,"interactionType":103,"userInteractionCount":52},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"Why are oncogene-negative lung tumors considered important for studying fitness landscapes?","Question",{"text":112,"@type":113},"They account for roughly 20% of lung adenocarcinoma cases and lack oncogene mutations, enabling analysis of how combinatorial inactivation of tumor suppressor genes drives initiation and growth.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How did the study quantify fitness landscapes in tumors?",{"text":117,"@type":113},"It coupled tumor barcoding with combinatorial and multiplexed somatic genome editing to characterize how different sequential genotypes affect tumor fitness.",{"name":119,"@type":110,"acceptedAnswer":120},"What does “fully accessible” mean in the context of the fitness landscape found here?",{"text":121,"@type":113},"It means that adding each additional mutation increases fitness in any order, keeping adaptive paths open despite the combinatorial complexity of genotypes.","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},381657,1790812848,{"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":52,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":44,"language":139,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":140,"faqs":141,"seo_title":142,"seo_description":67,"update_tm":143,"read_time":144},18829141979164,"https://eur-avatar.wpscdn.com/davatar_6f874abed73319feea01a86fa6f0fab8","Fully accessible fitness landscape of oncogene-negative lung adenocarcinoma  \nMaryam Yousefia, Laura Andrejkaa, Márton Szameczb , Monte M. Winslowa,c,d,1, Dmitri A. Petrovc,e,1, and Gábor Borosse,1  \nEdited by Anton Berns, Antoni van Leeuwenhoek Nederlands Kanker Instituut, Amsterdam, Netherlands; received March 6, 2023; accepted July 12, 2023  \nCancer genomes are almost invariably complex with genomic alterations cooperating during each step of carcinogenesis. In cancers that lack a single dominant oncogene mutation, cooperation between the inactivation of multiple tumor suppressor genes can drive tumor initiation and growth. Here, we shed light on how the sequential acquisition of genomic alterations generates oncogene-negative lung tumors. We couple tumor barcoding with combinatorial and multiplexed somatic genome editing to characterize the fitness landscapes of three tumor suppressor genes NF1, RASA1, and PTEN, the inactivation of which jointly drives oncogene-negative lung adenocarcinoma initiation and growth. The fitness landscape was surprisingly accessible, with each additional mutation leading to growth advantage. Furthermore, the fitness landscapes remained fully accessible across backgrounds with the inactivation of additional tumor suppressor genes. These results suggest that while predicting cancer evolution will be challenging, acquiring the multiple alterations that drive the growth of oncogene-negative tumors can be facilitated by the lack of constraints on mutational order.  \ncancer evolution | mouse models | quantitative | fitness landscapes  \nFitness landscapes are a helpful conceptual aid in understanding evolutionary processes (1). In a fitness landscape, genotypes are represented as nodes on a graph such that two genotypes are connected by an edge if they differ by a single allele and thus each genotype can be reached from the other by a single alteration (2) . Fitness values of each genotype are shown as an extra (height) dimension with adaptation represented as a hill-climbing adaptive walk. The key properties of evolutionary adaptation, such as its predictability and the ability of adaptation to reach the fittest genotype in a deterministic walk, are determined by the shape of the landscape, specifically by its ruggedness (3). The ruggedness of the fitness landscape is defined by the frequency of sign epistasis, a phenomenon where a mutation is advantageous in one genetic context but disadvantageous in another. Sign epistasis determines whether an adaptive walk can end up stalled on a local fitness peak and whether only some combinations of mutations are sequentially adaptive. Intriguingly, many previous studies found that rugged fitness landscapes are common across diverse evolutionary systems (3–7). This suggests that early adaptive mutations can strongly affect the direction of the adaptive process and limit the accessible adaptive paths (SI Appendix, Fig. S1) (8) .  \nCancers are driven by the sequential acquisition of genetic driver mutations and thus are canonical examples of adaptive walks on a fitness landscape. Nonetheless, full fitness landscapes for cancer remain poorly understood due to the difficulty of inferring the fitness of growing tumors, the combinatorially large numbers of intermediate genotypes for even moderately genetically complex tumors, and the fact that tumors are generally analyzed once they have accumulated a large number of mutations with the order of the early steps hidden from the study. Despite the importance of defining the properties of cancer fitness landscapes for understanding tumorigenesis, we currently lack experimental systems to quantify the fitness of nascent tumors of diverse sequential genotypes growing in vivo. Defining cancer fitness landscapes could help to determine cancer progression and its therapeutic vulnerabilities. Human cancer genomics has uncovered genomic alterations that are mutually exclusive with one another, and we and others have found sign","cbCaimZY7CcWTsI5","https://ap.wps.com/l/cbCaimZY7CcWTsI5","pdf",661764,"English","# Introduction\n## Fitness landscapes and adaptive walks\n## Why cancer fitness landscapes are hard to measure\n# Oncogene-negative lung adenocarcinoma\n## Clinical relevance and driving mechanisms\n## Study design and key findings\n# Significance","[{\"question\":\"Why are oncogene-negative lung tumors considered important for studying fitness landscapes?\",\"answer\":\"They account for roughly 20% of lung adenocarcinoma cases and lack oncogene mutations, enabling analysis of how combinatorial inactivation of tumor suppressor genes drives initiation and growth.\"},{\"question\":\"How did the study quantify fitness landscapes in tumors?\",\"answer\":\"It coupled tumor barcoding with combinatorial and multiplexed somatic genome editing to characterize how different sequential genotypes affect tumor fitness.\"},{\"question\":\"What does “fully accessible” mean in the context of the fitness landscape found here?\",\"answer\":\"It means that adding each additional mutation increases fitness in any order, keeping adaptive paths open despite the combinatorial complexity of genotypes.\"}]","Fully accessible fitness landscape of oncogene-negative lung adenocarcinoma | PDF",1790246301,23]