Yang Xu, Cai Geng-Xi, Han Bo-Wei, Guo Zhi-Wei, Wu Ying-Song, Lyu Xiaoming, Huang Li-Min, Zhang Yuan-Bin, Li Xin, Ye Guo-Lin, Yang Xue-Xi
Clinical Innovation and Research Center, Shenzhen Hospital, Southern Medical University, Shenzhen, China.
The Third School of Clinical Medicine, Southern Medical University, Guangzhou, China.
NPJ Breast Cancer. 2021 Mar 26;7(1):35. doi: 10.1038/s41523-021-00237-5.
Gene expression signatures have been used to predict the outcome of chemotherapy for breast cancer. The nucleosome footprint of cell-free DNA (cfDNA) carries gene expression information of the original tissues and thus may be used to predict the response to chemotherapy. Here we carried out the nucleosome positioning on cfDNA from 85 breast cancer patients and 85 healthy individuals and two cancer cell lines T-47D and MDA-MB-231 using low-coverage whole-genome sequencing (LCWGS) method. The patients showed distinct nucleosome footprints at Transcription Start Sites (TSSs) compared with normal donors. In order to identify the footprints of cfDNA corresponding with the responses to neoadjuvant chemotherapy in patients, we mapped on nucleosome positions on cfDNA of patients with different responses: responders (pretreatment, n = 28; post-1 cycle, post-3/4 cycles, and post-8 cycles of treatment, n = 12) and nonresponders (pretreatment, n = 10; post-1 cycle, post-3/4 cycles, and post-8 cycles of treatment, n = 10). The coverage depth near TSSs in plasma cfDNA differed significantly between responders and nonresponders at pretreatment, and also after neoadjuvant chemotherapy treatment cycles. We identified 232 TSSs with differential footprints at pretreatment and 321 after treatment and found enrichment in Gene Ontology terms such as cell growth inhibition, tumor suppressor, necrotic cell death, acute inflammatory response, T cell receptor signaling pathway, and positive regulation of vascular endothelial growth factor production. These results suggest that cfDNA nucleosome footprints may be used to predict the efficacy of neoadjuvant chemotherapy for breast cancer patients and thus may provide help in decision making for individual patients.
基因表达特征已被用于预测乳腺癌化疗的结果。游离DNA（cfDNA）的核小体足迹携带了原始组织的基因表达信息，因此可用于预测化疗反应。在此，我们使用低覆盖度全基因组测序（LCWGS）方法，对85例乳腺癌患者、85例健康个体以及两种癌细胞系T-47D和MDA-MB-231的cfDNA进行了核小体定位。与正常供体相比，患者在转录起始位点（TSS）处显示出明显不同的核小体足迹。为了确定与患者新辅助化疗反应相对应的cfDNA足迹，我们对不同反应患者（反应者：治疗前，n = 28；治疗1周期后、3/4周期后和8周期后，n = 12；无反应者：治疗前，n = 10；治疗1周期后、3/4周期后和8周期后，n = 10）的cfDNA上的核小体位置进行了定位。在治疗前以及新辅助化疗治疗周期后，反应者和无反应者血浆cfDNA中TSS附近的覆盖深度存在显著差异。我们在治疗前鉴定出232个具有差异足迹的TSS，治疗后鉴定出321个，并发现这些TSS在细胞生长抑制、肿瘤抑制、坏死性细胞死亡、急性炎症反应、T细胞受体信号通路以及血管内皮生长因子产生的正调控等基因本体术语中富集。这些结果表明，cfDNA核小体足迹可用于预测乳腺癌患者新辅助化疗的疗效，从而可能为个体患者的决策提供帮助。
