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Gene-expression BM1/BM2 classifications offer mechanistic insights but require high-throughput sequencing. This study develops an immunohistochemistry (IHC)-based system for practical subtype stratification and prognostic/therapeutic evaluation using two independent cohorts. Fourteen markers were screened and CD8 and ARHGEF17 selected to define iBM1 and iBM2, which matched transcriptomic subtypes and related immune and survival differences.",{"@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/a-robust-immunohistochemistry-based-classification-for-braf-v600e-mutant-colorectal-cancer-with-clinical-implications/448102/",{"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/a-robust-immunohistochemistry-based-classification-for-braf-v600e-mutant-colorectal-cancer-with-clinical-implications/448102.png","ImageObject",300,407,{"name":92,"@type":93},"Aria","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-04","2026-09-29",true,{"@type":102,"interactionType":103,"userInteractionCount":81},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"Why is BRAF V600E-mutant colorectal cancer considered heterogeneous?","Question",{"text":112,"@type":113},"Significant heterogeneity exists in biological behavior, the tumor microenvironment, and molecular characteristics, which influences systemic therapy efficacy.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How does the study define the two IHC-based subtypes?",{"text":117,"@type":113},"A decision tree selected CD8 and ARHGEF17 as key markers, defining iBM1 (CD8+/ARHGEF17−) and iBM2 (CD8− with any ARHGEF17 expression or CD8+/ARHGEF17+).",{"name":119,"@type":110,"acceptedAnswer":120},"How well do the IHC subtypes agree with transcriptomic BM subtypes?",{"text":121,"@type":113},"Concordance was reported as 82.69% (κ=0.55) in training, 72.22% (κ=0.44) in validation, and 83.33% (κ=0.57) in prospective evaluation.","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},448102,1790955465,{"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":81,"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},2336464648322,"https://ap-avatar.wpscdn.com/avatar/2200025388227c56fec?_k=1778556882303663488","Cancer Science  \nORIGINAL ARTICLE  OPEN ACCESS   \nA Robust Immunohistochemistry-Based Classification for BRAFV600E-Mutant Colorectal Cancer With Clinical Implications  \nChao Liu1,2,3,4  | Yuli Ruan1,2,3 | Tong Wu1,2 | Xindi Luan1,2,3 | Yue Ma1,2,3 | Hong Wang1,2 | Tianjiao Dang1,3 | Yiwen Ou1,3 | Bojun Wang1,2 | Chunhui Zhang1,2,3 | Hongxue Meng5 | Yanqiao Zhang1,2,3,4   \n1Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China | 2Clinical Research Center for Colorectal Cancer in Heilongjiang, Harbin Medical University Cancer Hospital, Harbin, China | 3Key Laboratory of Tumor Immunology in Heilongjiang, Harbin Medical University Cancer Hospital, Harbin, China | 4Key Laboratory of Preservation of Human Genetic Resources and Disease Control, Harbin Medical University, Harbin, China | 5Department of Pathology, Harbin Medical University Cancer Hospital, Harbin, China  \nCorrespondence: Hongxue Meng ([menghongxue@hrbmu.edu.cn](menghongxue@hrbmu.edu.cn)) | Yanqiao Zhang ([yanqiaozhang@ems.hrbmu.edu.cn](yanqiaozhang@ems.hrbmu.edu.cn))  \nReceived: 12 April 2025 | Revised: 25 August 2025 | Accepted: 10 October 2025  \nFunding: This work was supported by Noncommunicable Chronic Diseases-National Science and Technology Major Project (2023ZD0501600) the Key Project of Research and Development Plan in Heilongjiang Province (2022ZX06C01, JD2023SJ40) the National Natural Science Foundation of China (82373372, U22A20330) .  \nKeywords: BM subtypes | BRAF V600E-mutant colorectal cancer | ICIs therapy | immunohistochemistry | prognostic  \nABSTRACT  \nBRAF V600E-mutant colorectal cancer (CRC) represents a distinct molecular subtype with considerable heterogeneity in tumor biology and therapeutic response. Although gene expression-based classifications (BM1/BM2 subtypes) provide valuable insights into underlying molecular and immune features, their clinical application is limited by the need for high-throughput sequencing. This study aims to establish an immunohistochemistry (IHC)-based classification system to enable practical subtype stratification and aid prognostic and therapeutic evaluation. Using two independent cohorts (public dataset, n = 218; institutional cohort, n = 122), we performed differential expression analysis, machine learning modeling, and clinical feasibility evaluation. Fourteen candidate markers were identified, and a decision tree algorithm selected CD8 and ARHGEF17 as optimal classifiers. Based on these markers, two IHC-based subtypes were established: iBM1 (CD8+/ARHGEF17−) and iBM2 (CD8 − with any ARHGEF17 expression or CD8+/ARHGEF17+) . The IHC-based subtypes showed concordance with transcriptomic BM subtypes (training: 82.69%, κ = 0.55; validation: 72.22%, κ = 0.44; prospective: 83.33%, κ = 0.57). Transcriptomic profiling revealed enrichment of immune activation and epithelial–mesenchymal transition in iBM1, and cell cycle-related pathways in iBM2. In clinical validation, iBM1 was associated with poorer survival but greater sensitivity to immune checkpoint inhibitors. This IHC-based classification provides a practical and accessible approach for BM subtype stratification, reflecting underlying molecular and immune characteristics, and may support prognostic assessment and therapeutic decision-making in BRAF V600E-mutant CRC.  \n\n| Abbreviations: AUC, area under the curve; BRAF, B-Raf Proto-Oncogene, Serine/Threonine Kinase; CMS, consensus molecular subtypes; CRC, colorectal cancer; CT, tumor center; DAB, diaminobenzidine; DC, dendritic cells; DEGs, differentially expressed genes; EDTA, ethylenediaminetetraacetic acid; EMT, epithelial– mesenchymal transition; FFPE, formalin-fixed paraffin-embedded; GSEA, gene set enrichment analysis; HMUCH, Harbin Medical University Cancer Hospital; ICIs, immune checkpoint inhibitors; IHC, immunohistochemistry; IM, invasive margin; KEGG, Kyoto Encyclopedia of Genes and Genomes; LASSO, least absolute shrinkage and selection operator; MSigDB, M","cbCait7Dgyn8vk2K","https://ap.wps.com/l/cbCait7Dgyn8vk2K","pdf",6216811,11,"English","# Introduction\n## Clinical context of BRAF V600E-mutant CRC\n## Rationale for IHC-based classification\n## Study aims and approach","[{\"question\":\"Why is BRAF V600E-mutant colorectal cancer considered heterogeneous?\",\"answer\":\"Significant heterogeneity exists in biological behavior, the tumor microenvironment, and molecular characteristics, which influences systemic therapy efficacy.\"},{\"question\":\"How does the study define the two IHC-based subtypes?\",\"answer\":\"A decision tree selected CD8 and ARHGEF17 as key markers, defining iBM1 (CD8+/ARHGEF17−) and iBM2 (CD8− with any ARHGEF17 expression or CD8+/ARHGEF17+).\"},{\"question\":\"How well do the IHC subtypes agree with transcriptomic BM subtypes?\",\"answer\":\"Concordance was reported as 82.69% (κ=0.55) in training, 72.22% (κ=0.44) in validation, and 83.33% (κ=0.57) in prospective evaluation.\"}]","A Robust Immunohistochemistry-Based Classification for BRAF V600E-Mutant Colorectal Cancer With Clinical Implications | PDF",1790725296,28]