[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"doc-seo-332433-105":3,"detail-sidebar-cat-0-en-105":73,"doc-detail-332433-en":122},{"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":66,"head_meta":68,"extra_data":70,"updated_unix":72},105,"en","impaired-tgf-signaling-via-ahnak-family-mutations-elicits-an-esophageal-cancer-subtype-with-sensitivities-to-genotoxic-therapy-and-immunotherapy","Impaired TGF-β signaling via AHNAK family mutations elicits an esophageal cancer subtype with sensitivities to genotoxic therapy and immunotherapy","","Genome instability is a hallmark of esophageal squamous cell carcinoma, yet the mechanisms that shape it remain unclear. This study analyzed 201 ESCC samples and used multi-omics validation across patient material, single-cell data, and cancer cell lines. It identifies an AHNAK/AHNAK2 mutation signature defining a TGF-β–impaired subtype with enhanced neoantigens, active antigen presentation, and proficient CD8+ T-cell infiltration. The signature also predicts improved responses to DNA-damaging therapy and immunotherapy-associated neoadjuvant treatment, supporting molecular classification for prognosis stratification.",{"@graph":14,"@context":65},[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/impaired-tgf-signaling-via-ahnak-family-mutations-elicits-an-esophageal-cancer-subtype-with-sensitivities-to-genotoxic-therapy-and-immunotherapy/332433/",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/impaired-tgf-signaling-via-ahnak-family-mutations-elicits-an-esophageal-cancer-subtype-with-sensitivities-to-genotoxic-therapy-and-immunotherapy/332433.png","ImageObject",300,407,{"name":42,"@type":43},"Theodore","Person",{"url":19,"name":45,"@type":46},"DocShare","Organization","application/pdf","2026-11-05","2026-09-21",true,{"@type":52,"interactionType":53,"userInteractionCount":55},"InteractionCounter",{"@type":54},"ViewAction",7,{"@type":57,"mainEntity":58},"FAQPage",[59],{"name":60,"@type":61,"acceptedAnswer":62},"How can the two-gene signature guide treatment selection?","Question",{"text":63,"@type":64},"The signature predicts better responses to DNA-damaging therapy in multiple clinical contexts and associates with higher pCR rates in ESCCs receiving neoadjuvant immunotherapy-involved treatment, supporting prognosis stratification via a molecular classification scheme.","Answer","https://schema.org",{"og:url":32,"og:type":67,"og:title":10,"og:site_name":45,"og:description":12},"article",{"robots":69,"canonical":32},"index,follow",{"doc_id":71,"site_id":7},332433,1790921853,{"code":4,"msg":74,"data":75},"success",[76,80,84,88,93,98,102,106,111,114,118],{"id":22,"doc_module":4,"doc_module_name":25,"category_name":77,"show_sort_weight":78,"slug":79},"Story & Novel",90,"story-novel",{"id":26,"doc_module":4,"doc_module_name":25,"category_name":81,"show_sort_weight":82,"slug":83},"Literature",80,"literature",{"id":33,"doc_module":4,"doc_module_name":25,"category_name":85,"show_sort_weight":86,"slug":87},"Exam",70,"exam",{"id":89,"doc_module":4,"doc_module_name":25,"category_name":90,"show_sort_weight":91,"slug":92},5,"Comic",60,"comic",{"id":94,"doc_module":4,"doc_module_name":25,"category_name":95,"show_sort_weight":96,"slug":97},6,"Technology",50,"technology",{"id":55,"doc_module":4,"doc_module_name":25,"category_name":99,"show_sort_weight":100,"slug":101},"Healthcare",40,"healthcare",{"id":103,"doc_module":4,"doc_module_name":25,"category_name":29,"show_sort_weight":104,"slug":105},8,30,"research-report",{"id":107,"doc_module":4,"doc_module_name":25,"category_name":108,"show_sort_weight":109,"slug":110},9,"Religion & Spirituality",20,"religion-spirituality",{"id":109,"doc_module":4,"doc_module_name":25,"category_name":112,"show_sort_weight":109,"slug":113},"World Cup","world-cup",{"id":115,"doc_module":4,"doc_module_name":25,"category_name":116,"show_sort_weight":115,"slug":117},10,"Lifestyle","lifestyle",{"id":119,"doc_module":4,"doc_module_name":25,"category_name":120,"show_sort_weight":89,"slug":121},19,"General","general",{"code":4,"msg":74,"data":123},{"doc_id":71,"user_id":124,"nickname":42,"user_avatar":125,"doc_module":4,"category_id":103,"category_name":29,"doc_title":10,"doc_description":12,"doc_content":126,"file_id":127,"file_url":128,"file_type":129,"file_size":130,"view_count":55,"is_deleted":4,"is_public":22,"is_downloadable":22,"audit_status":22,"page_count":131,"language":132,"language_code":8,"site_id":7,"html_lang":8,"table_of_contents":133,"faqs":134,"seo_title":135,"seo_description":12,"update_tm":136,"read_time":137,"preview_page_count":4},7971461740886,"https://ap-avatar.wpscdn.com/davatar_3d24733baf745e90a7e4bdd5f77d97b2","Cancer Immunology, Immunotherapy (2024) 73:225 [https://doi.org/10.1007/s00262-024-03798-z](https://doi.org/10.1007/s00262-024-03798-z)  \nImpaired TGF‑β signaling via AHNAK family mutations elicitsan esophageal cancer subtype with sensitivities to genotoxic therapy and immunotherapy  \nZihang Mai1,2,3 · Kongjia Luo1,2,3 · Xinye Wang1,2,3 · Xiuying Xie1,2,3 · Lanlan Pang2 · Hong Yang1,2,3 · JingWen2,3 · Jianhua Fu1,2,3  \nReceived: 22 March 2024 / Accepted: 1 August 2024 / Published online: 5 September 2024 © The Author(s) 2024  \nAbstract  \nBackground Genome instability (GI) is a hallmark of esophageal squamous cell carcinoma (ESCC) while factors affecting GI remain unclear.  \nMethods Here, we aimed to characterize genomic events representing specific mechanisms of GI based on 201 ESCC samples and validated our findings at the patient, single-cell and cancer cell-line levels, including a newly generated multi-omics dataset of the trial NCT04006041 .  \nResults A two-gene (AHNAK and AHNAK2) mutation signature was identified to define the “AHNAK1/2-mutant” cancer subtype. Single-cell-assisted multi-omics analysis showed that this subtype had a higher neoantigen load, active antigen presentation, and proficient CD8 + T cell infiltrations, which were validated at pan-cancer levels. Mechanistically, AHNAK1/2-mutant ESCC was characterized by impaired response of TGF-β and the inefficient alternative end-join repair (Alt-EJ) that might promote GI. Knockdown of AHNAK in ESCC cell lines resulted in more Alt-EJ events and increased sensitivities tocisplatin. Furthermore, this two-gene signature accurately predicted better responses to DNA-damaging therapy in various clinical settings (HR ≈ 0.25) . The two-gene signature predicted higher pCR rates in ESCCs receiving neoadjuvant immunotherapy-involved treatment. Finally, a molecular classification scheme was built and outperformed established molecular typing models in the prognosis stratification of ESCC patients.  \nConclusion Our study extended our understanding of the AHNAK family in promoting GI and selecting treatment responders of ESCC.  \nKeywords Esophageal cancer · Multi-omics · Molecular classification · Chemoradiotherapy · Immunotherapy  \nZihang Mai, Kongjia Luo and Xinye Wang have contributed equally to this work.  \n* Hong Yang [yanghong@sysucc.org.cn](yanghong@sysucc.org.cn)  \n* Jing Wen [wenjing@sysucc.org.cn](wenjing@sysucc.org.cn)  \n* Jianhua Fu [fujh@mail.sysu.edu.cn](fujh@mail.sysu.edu.cn)  \n1 Department of Thoracic Surgery, Sun Yat-Sen University Cancer Center, Guangzhou 510060, Guangdong Province, China  \n2 State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, Guangdong Province, China  \n3 Guangdong Esophageal Cancer Institute, Guangzhou 510060, Guangdong Province, China  \nAbbreviations  \nAUC  \nDFS  \nESCC  \nGI  \nICI  \nLN  \nOR  \nOS  \npN  \npT  \nROC curvescRNA SNV  \nTCGA  \nTMB  \nArea under curve Disease-free survival  \nEsophageal squamous cell carcinoma Genome instability  \nImmune checkpoint inhibitors Lymph node  \nOdd ratio  \nOverall survival Pathological lymph node stage  \nPathological tumor stage  \nReceiver operation characteristic curve Single-cell RNA  \nSingle nucleotide variation The Cancer Genome Atlas Tumor mutation burden  \nTME Tumor microenvironment  \nTNM Tumor-lymph node-metastasis stage  \nIntroduction  \nEsophageal cancer, the sixth leading cause of cancer-related deaths, is a major health threat worldwide, with approximately 500,000 cases diagnosed in China annually. Esophageal squamous cell carcinoma (ESCC), the predominant pathological subtype in China, is a heterogeneous disease with various prognosis and treatment responses [1] . Recent studies have elucidated the molecular determinants behind clinical phenomenon across various cancer types [2], such as genome instability, but progress in ESCC is scarce [3] . This malignancy type also had an unstable gen","cbCaimWhl1L9Mnqh","https://ap.wps.com/l/cbCaimWhl1L9Mnqh","pdf",2201153,13,"English","# Abstract\n# Background\n# Methods and Validation\n# Results\n## Mutation signature and subtype definition\n## Mechanistic links to TGF-β and Alt-EJ\n## Treatment response prediction and classification\n# Conclusion\n# Keywords","[{\"question\":\"How can the two-gene signature guide treatment selection?\",\"answer\":\"The signature predicts better responses to DNA-damaging therapy in multiple clinical contexts and associates with higher pCR rates in ESCCs receiving neoadjuvant immunotherapy-involved treatment, supporting prognosis stratification via a molecular classification scheme.\"}]","Impaired TGF-β signaling via AHNAK family mutations elicits an esophageal cancer subtype with sensitivities to genotoxic therapy and immunotherapy | PDF",1789998175,33]