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In a retrospective cohort study, researchers used the C-CAT database containing gene-panel sequencing from 60,056 solid-tumor cases to map somatic mutations in NRF2 and KEAP1 and link them to clinical outcomes. NRF2 variants clustered in exon 2, were common in esophageal and lung squamous cell carcinoma, and ETGE-motif variants predicted worse prognosis. KEAP1 variants appeared in 2.5% of cases, with poorer outcomes in lung and adenocarcinomas. TCGA expression analyses showed similar profiles for DLG/ETGE variant cancers but significant differences between KEAP1- and NRF2-variant tumors, supporting pathway genetic alterations as major prognostic determinants across cancer types.",{"@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/specific-cancer-types-and-prognosis-in-patients-with-variations-in-the-keap1-nrf2-system-a-retrospective-cohort-study/332828/",{"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/specific-cancer-types-and-prognosis-in-patients-with-variations-in-the-keap1-nrf2-system-a-retrospective-cohort-study/332828.png","ImageObject",300,407,{"name":92,"@type":93},"Evangeline","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-29","2026-09-21",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},"What did the study evaluate about KEAP1 and NRF2 in cancer patients?","Question",{"text":112,"@type":113},"The study assessed the distribution and frequency of somatic mutations in NRF2 and KEAP1 and analyzed how mutation status relates to patient prognosis across cancer types.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How were NRF2 variants distributed, and which variants predicted worse outcomes?",{"text":117,"@type":113},"NRF2 variants clustered in exon 2, and they were frequently observed in esophageal and lung squamous cell carcinoma. NRF2 variants within the ETGE motif were indicators of worse prognosis.",{"name":119,"@type":110,"acceptedAnswer":120},"How did the researchers compare gene expression between cancers with KEAP1 versus NRF2 variants?",{"text":121,"@type":113},"Gene expression analysis was conducted using TCGA data. Cancers with DLG and ETGE variants showed similar gene-expression profiles, while significant differences were observed between cancers with KEAP1 and NRF2 variants.","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},332828,1790172569,{"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":52,"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},13056703019662,"https://ap-avatar.wpscdn.com/avatar/be000253a8e92610077?_k=1778726343310543188","DOI: 10. 1111/cas.16355  \nOR I G I NAL ART I C L E  \nSpecific cancer types and prognosis in patients with variations in the KEAP1-NRF2 system: A retrospective cohort study  \nTomoyuki Iwasaki1 | Hidekazu Shirota1  | Keiju Sasaki1 | Kota Ouchi1  | Yuki Nakayama2 | Hiroyuki Oshikiri2 | Akihito Otsuki2 | Takafumi Suzuki2 | Masayuki Yamamoto2 | Chikashi Ishioka1   \n1Department of Medical Oncology, Tohoku University Hospital, Sendai, Japan 2Department of Biochemistry and Molecular Biology, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan  \nCorrespondence  \nHidekazu Shirota, Department of Medical Oncology, Tohoku University Hospital, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan.  \nEmail: [hidekazu.shirota.e1@tohoku.ac.jp](hidekazu.shirota.e1@tohoku.ac.jp)  \nAbstract  \nThe KEAP1–NRF2 system induces the expression of antioxidant genes in response to various types of oxidative stress. Some cancer cells activate this system, which increases their malignancy through genetic mutations. We performed a retrospective cohort study using the C-CAT database, which contains the gene-panel sequence data from 60,056 cases of diagnosed solid tumors. We analyzed somatic mutations in NRF2 and KEAP1 genes and their associations with clinical outcomes. Variants in the NRF2 gene were clustered in exon 2, which encodes the DLG and ETGE motifs essential for KEAP1 interaction. The NRF2 variants were frequently observed in esophageal and lung squamous cell carcinoma with frequencies of 35 .9% and 19. 6%, respectively. Among these mutations, the NRF2 variants in the ETGE motif were indicators of a worse prognosis. KEAP1 variants were found in 2. 5% of all cases. The variants were frequent in lung cancer and showed a worse prognosis in lung and other types of adenocarcinomas. We then conducted gene expression analysis using TCGA data. While cancers with DLG and ETGE variants were similar in terms of gene expression profiles, there were significant differences between cancers with KEAP1 and NRF2 variants. Our results indicate that genetic alteration of the KEAP1–NRF2 pathway is a major factor in patient prognosis for each cancer type and its genetic variant. Variants in NRF2 and KEAP1 genes can characterize the biological basis of each cancer type and are involved in carcinogenesis, resistance to therapy, and other biological differences.  \nK E Y WO R D S  \nC-CAT data, CGP test, KEAP1, NRF2, solid tumor  \nAbbreviations: C-CAT, Center for Cancer Genomics and Advanced Therapeutics; CGP, Comprehensive Genomic Profiling; DEG, differentially expressed genes; EGC, esophagogastric adenocarcinoma; ESCC, esophageal squamous cell carcinoma; F1 CDx, FoundationOne CDx; F1 liquid CDx, FoundationOne liquid CDx; KEAP1, Kelch ECH associating protein 1; LUAD, lung adenocarcinoma; LUSC, lung squamous cell carcinoma; NFE2L2, nuclear factor erythroid 2-related factor 2; NGS, next-generation sequencing; ROS, reactive oxygen species; TCGA, The Cancer Genome Atlas; VUS, variant of uncertain significance.  \nThis is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.  \n© 2024 The Author(s) . Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.  \n1 | INTRODUCTION  \nCancer is a multistep process, involving gene alterations and uncontrolled cell proliferation. During this process, cancer cells are exposed to a unique microenvironment evoked by the accumulation of ROS, hypoxia, and inflammation by the recruitment of immune cells.1,2 Excessive ROS accumulation results in growth arrest or cell death in cancer cells.3,4 In addition, cancer treatments, such as chemotherapy and radiotherapy provoke several types of oxidative stress in cancer cells. These conditions are inherently unfavorable for cell survival, but several gene","cbCaibitPuGzzNfF","https://ap.wps.com/l/cbCaibitPuGzzNfF","pdf",6992442,11,"English","# Introduction\n## KEAP1–NRF2 pathway and oxidative stress in cancer\n## Rationale for identifying gene mutations using CGP/NGS\n## Study aims and dataset description","[{\"question\":\"What did the study evaluate about KEAP1 and NRF2 in cancer patients?\",\"answer\":\"The study assessed the distribution and frequency of somatic mutations in NRF2 and KEAP1 and analyzed how mutation status relates to patient prognosis across cancer types.\"},{\"question\":\"How were NRF2 variants distributed, and which variants predicted worse outcomes?\",\"answer\":\"NRF2 variants clustered in exon 2, and they were frequently observed in esophageal and lung squamous cell carcinoma. NRF2 variants within the ETGE motif were indicators of worse prognosis.\"},{\"question\":\"How did the researchers compare gene expression between cancers with KEAP1 versus NRF2 variants?\",\"answer\":\"Gene expression analysis was conducted using TCGA data. Cancers with DLG and ETGE variants showed similar gene-expression profiles, while significant differences were observed between cancers with KEAP1 and NRF2 variants.\"}]","Specific cancer types and prognosis in patients with variations in the KEAP1-NRF2 system - A retrospective cohort study | PDF",1789999659,28]