Ji Jianghuai, Li Dongguo, Zhao Xiaoxiao, Wang Yajuan, Wang Binbing
Department of Radiation Physics, Zhejiang Key Laboratory of Radiation Oncology, Zhejiang Cancer Hospital, Hangzhou, 310022, Zhejiang, China.
Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310018, Zhejiang, China.
Sci Rep. 2025 Feb 15;15(1):5641. doi: 10.1038/s41598-025-90247-1.
Breast cancer (BC) is the most common malignancy with a poor prognosis. Radiotherapy is one of the leading traditional treatments for BC. However, radiotherapy-associated secondary diseases are severe issues for the treatment of BC. The present study integrated multi-omics data to investigate the molecular and epigenetic mechanisms involved in post-radiation BC. The differences in the expression of radiation-associated genes between post-radiation and pre-radiation BC samples were determined. Enrichment analysis revealed that these radiation-associated genes involved diverse biological functions and pathways in BC. Combining epigenetic data, we identified radiation-associated genes whose transcriptional changes might be associated with aberrant methylation. Then, we identified potential therapeutic targets and chemical drugs for post-radiation BC patient treatment by constructing a drug-target association network. Specifically, four radiation-associated genes (CD248, CCDC80, GADD45B, and MMP2) whose increased expression might be regulated by hypomethylation of the corresponding enhancer region were found to have excellent diagnostic effects and clinical prognostic value. Finally, we further used independent samples to verify CD248 expression and established a simple epigenetic regulatory model. In summary, this study provides novel insights for understanding the regulation of target genes mediated by DNA methylation and developing potential biomarkers for radiation-associated secondary diseases in BC.
乳腺癌（BC）是最常见的恶性肿瘤，预后较差。放射治疗是BC主要的传统治疗方法之一。然而，放疗相关的继发性疾病是BC治疗中的严重问题。本研究整合多组学数据，以探究放疗后BC所涉及的分子和表观遗传机制。确定了放疗后与放疗前BC样本中辐射相关基因表达的差异。富集分析表明，这些辐射相关基因在BC中涉及多种生物学功能和途径。结合表观遗传数据，我们鉴定出转录变化可能与异常甲基化相关的辐射相关基因。然后，通过构建药物-靶点关联网络，我们确定了放疗后BC患者治疗的潜在治疗靶点和化学药物。具体而言，发现四个辐射相关基因（CD248、CCDC80、GADD45B和MMP2），其表达增加可能受相应增强子区域低甲基化调控，具有良好的诊断效果和临床预后价值。最后，我们进一步使用独立样本验证CD248表达，并建立了一个简单的表观遗传调控模型。总之，本研究为理解DNA甲基化介导的靶基因调控以及开发BC放疗相关继发性疾病的潜在生物标志物提供了新的见解。
