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A risk model predicted prognosis with good sensitivity and specificity, and clinical validation supported APCS1 as more aggressive, genomically altered, immunologically dysfunctional, and resistant to immune checkpoint therapy, with distinct drug sensitivities. 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[https://doi.org/10.1007/s10238-024-01465-2](https://doi.org/10.1007/s10238-024-01465-2)  \nAPOBEC family reshapesthe immune microenvironment and therapy sensitivity in clear cell renal cell carcinoma  \nGuiying Huang1,2 · Xianlin Zhan3 · Lihong Shen1,5 · Luping Lou1,5 · Yuehong Dai1,5 · Aiming Jiang4 · Yuzhen Gao1,5 · Yanzhong Wang1,5 · Xinyou Xie1,5 · Jun Zhang1,5  \nReceived: 1 July 2024 / Accepted: 11 August 2024 / Published online: 9 September 2024 © The Author(s) 2024  \nAbstract  \nEmerging evidence suggests that the APOBEC family is implicated in multiple cancers and might be utilized as a new target for cancer detection and treatment. However, the dysregulation and clinical implication of the APOBEC family in clear cell renal cell cancer (ccRCC) remain elusive. TCGA multiomics data facilitated a comprehensive exploration of the APOBEC family across cancers, including ccRCC. Remodeling analysis classified ccRCC patients into two distinct subgroups: APOBEC family pattern cancer subtype 1 (APCS1) and subtype 2 (APCS2) . The study investigated differences in clinical parameters, tumor immune microenvironment, therapeutic responsiveness, and genomic mutation landscapes between these subtypes. An APOBEC family-related risk model was developed and validated for predicting ccRCC patient prognosis, demonstrating good sensitivity and specificity. Finally, the overview of APOBEC3B function was investigated in multiple cancers and verified in clinical samples. APCS1 and APCS2 demonstrated considerably distinct clinical features and biological processes in ccRCC. APCS1, an aggressive subtype, has advanced clinical stage and a poor prognosis. APCS1 exhibited an oncogenic and metabolically active phenotype. APCS1 also exhibited a greater tumor mutation load and immunocompromised condition, resulting in immunological dysfunction and immune checkpoint treatment resistance. The genomic copy number variation of APCS1, including arm gain and loss, was much more than that of APCS2, which may help explain the tired immune system. Furthermore, the two subtypes have distinct drug sensitivity patterns in clinical specimens and matching cell lines. Finally, we developed a predictive risk model based on subtype biomarkers that performed well for ccRCC patients and validated the clinical impact of APOBEC3B. Aberrant APOBEC family expression patterns might modify the tumor immune microenvironment by increasing the genome mutation frequency, thus inducing an immune-exhausted phenotype. APOBEC family-based molecular subtypes could strengthen the understanding ofccRCC characterization and guide clinical treatment. Targeting APOBEC3B may be regarded as a new therapeutic target for ccRCC.  \nKeywords Clear cell renal cell carcinoma · APOBEC family · Molecular subtypes · Tumor immunity · Multiomics · Machine learning  \nGuiying Huang and Xianlin Zhan contributed equally to this work.  \n* Xinyou Xie [srrshoffice@163.com](srrshoffice@163.com)  \n* Jun Zhang [jameszhang2000@zju.edu.cn](jameszhang2000@zju.edu.cn)  \n1 Department of Clinical Laboratory, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China  \n2 Department of Clinical Laboratory, Lishui Central Hospital, Lishui, Zhejiang, China  \n3 Department of Clinical Laboratory, PLA Navy Medical Center, Shanghai, China  \n4 Department of Urology, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai, China  \n5 Key Laboratory of Precision Medicine in Diagnosis and Monitoring Research of Zhejiang Province, Hangzhou, Zhejiang, China  \nIntroduction  \nRenal cell carcinoma (RCC) is one of the most common and lethal cancers in the urogenital system and originates from epithelial cells [1]. According to Global Cancer Statistics reports, more than 431,000 new cases and approximately 180,000 deaths are documented from RCC worldwide [2] . Clear cell renal cell carcinoma (ccRCC) is the most common type o","cbCaidlZwBWhhMAr","https://ap.wps.com/l/cbCaidlZwBWhhMAr","pdf",28873316,"English","# Abstract\n# Keywords\n# Introduction\n## Renal cell carcinoma and ccRCC background\n## Limits of current therapies and role of mutations\n## APOBEC family functions and prior cancer evidence","[{\"question\":\"What is the main question this study addresses about the APOBEC family in ccRCC?\",\"answer\":\"The study examines how APOBEC family dysregulation is linked to clinical implications in clear cell renal cell carcinoma and whether it can help explain immune microenvironment and therapy sensitivity.\"},{\"question\":\"How were ccRCC patients classified in this research?\",\"answer\":\"Using TCGA multiomics data, the analysis remodeled patients into two molecular subgroups: APCS1 and APCS2.\"},{\"question\":\"What clinical and biological differences were observed between APCS1 and APCS2?\",\"answer\":\"APCS1 showed more aggressive clinical features, advanced stage, poor prognosis, higher tumor mutation load, immune dysfunction, immune checkpoint treatment resistance, and distinct drug sensitivity patterns compared with APCS2.\"}]","APOBEC family reshapes the immune microenvironment and therapy sensitivity in clear cell renal cell carcinoma | PDF",1789998372]