Department of Clinical Laboratory, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
Department of Clinical Laboratory, Lishui Central Hospital, Lishui, Zhejiang, China.
Clin Exp Med. 2024 Sep 9;24(1):212. doi: 10.1007/s10238-024-01465-2.
Emerging 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 of ccRCC characterization and guide clinical treatment. Targeting APOBEC3B may be regarded as a new therapeutic target for ccRCC.
新兴证据表明，APOBEC 家族与多种癌症有关，可能被用作癌症检测和治疗的新靶点。然而，APOBEC 家族在透明细胞肾细胞癌（ccRCC）中的失调和临床意义仍不清楚。TCGA 多组学数据促进了对癌症中 APOBEC 家族的全面研究，包括 ccRCC。重构分析将 ccRCC 患者分为两个不同的亚组：APOBEC 家族模式癌症亚型 1（APCS1）和亚型 2（APCS2）。本研究调查了这两个亚型之间临床参数、肿瘤免疫微环境、治疗反应和基因组突变景观的差异。开发并验证了一个基于 APOBEC 家族的风险模型，用于预测 ccRCC 患者的预后，该模型具有良好的敏感性和特异性。最后，研究了 APOBEC3B 功能在多种癌症中的概述，并在临床样本中进行了验证。APCS1 和 APCS2 在 ccRCC 中表现出明显不同的临床特征和生物学过程。APCS1 是一种侵袭性亚型，具有较晚期的临床阶段和较差的预后。APCS1 表现出致癌和代谢活跃的表型。APCS1 还表现出更高的肿瘤突变负荷和免疫抑制状态，导致免疫功能障碍和免疫检查点治疗耐药。APCS1 的基因组拷贝数变异，包括臂增益和损失，比 APCS2 多得多，这可能有助于解释疲惫的免疫系统。此外，这两种亚型在临床标本和匹配的细胞系中具有不同的药物敏感性模式。最后，我们基于亚型标志物开发了一个预测风险模型，该模型对 ccRCC 患者表现良好，并验证了 APOBEC3B 的临床影响。异常的 APOBEC 家族表达模式可能通过增加基因组突变频率来改变肿瘤免疫微环境，从而诱导免疫衰竭表型。基于 APOBEC 家族的分子亚型可以加强对 ccRCC 特征的理解，并指导临床治疗。靶向 APOBEC3B 可能被视为 ccRCC 的一种新的治疗靶点。
Zotero 插件
