Gbadamosi Mohammed O, Bhise Neha, Ghosh Taraswi Mitra, Molchan Elizabeth K, Streeks Kathleen, Puglise Jason, Ohaegbulam Alyssa, Makarem Mariana, Olabige Oluwaseyi, Yang Changlin, Ricks-Santi Luisel, Mitchell Duane A, Fridley Brooke L, Lamba Jatinder K
Department of Pharmacotherapy and Translational Research, College of Pharmacy, Gainesville, FL, USA.
Department of Neurosurgery, Brain Tumor Immunotherapy Program, Preston A. Wells Jr. Center for Brain Tumor Therapy, University of Florida, Gainesville, FL, USA.
Future Oncol. 2025 Jun;21(14):1809-1822. doi: 10.1080/14796694.2025.2501517. Epub 2025 May 13.
This study identifies single-nucleotide polymorphisms (SNPs) associated with cellular response to cyclophosphamide (CTX) using phosphoramide mustard (PM), its primary cytotoxic metabolite, and explores the downstream consequences for breast cancer (BC) patients.
We analyzed 1,978,545 SNPs from EBV-transformed lymphoblastic cell lines (LCLs) derived from 53 unrelated European individuals, in a genome-wide association study using cellular PM sensitivity data. We filtered SNPs associated with PM sensitivity ( < 5 × 10) predicted to overlap with regulatory elements in breast tissue using a chromatin state prediction model. We then assessed the consequences using LCL transcriptomic data and data from BC patients treated with (ACT-BC; = 155) and without CTX.
Twenty SNPs were filtered out including rs12408401, which was associated with PM resistance ( = 3.89 × 10), potentially disrupted a CTCF-loop, and was associated with increased expression ( = 0.036), which was associated with poor disease-free interval in ACT-BC patients (HR = 5.32; = 0.028); and rs784562, which was associated with improved PM sensitivity ( = 6.41 × 10), potentially altered nearby enhancer functionality, and reduced expression of which was associated with poor progression-free survival in ACT-BC patients (HR = 3.61; = 0.040).
Our study identifies SNPs significantly associated with cellular CTX response with potential mechanistic and clinical relevance, thereby providing insights toward optimized CTX treatment strategies.
本研究使用环磷酰胺（CTX）的主要细胞毒性代谢产物磷酰胺氮芥（PM）来鉴定与细胞对CTX反应相关的单核苷酸多态性（SNP），并探讨其对乳腺癌（BC）患者的下游影响。
在一项全基因组关联研究中，我们使用细胞对PM的敏感性数据，分析了来自53名无关欧洲个体的EB病毒转化淋巴细胞系（LCL）中的1,978,545个SNP。我们使用染色质状态预测模型筛选出与PM敏感性相关（<5×10）且预计与乳腺组织中的调控元件重叠的SNP。然后，我们使用LCL转录组数据以及接受（ACT-BC；n = 155）和未接受CTX治疗的BC患者的数据来评估其后果。
筛选出了20个SNP，其中包括rs12408401，它与PM耐药相关（P = 3.89×10），可能破坏了一个CTCF环，并且与ACT-BC患者中较差的无病间期相关（HR = 5.32；P = 0.028）；以及rs784562，它与PM敏感性提高相关（P = 6.41×10），可能改变了附近增强子的功能，并降低了ACT-BC患者中与较差的无进展生存期相关的表达（HR = 3.61；P = 0.040）。
我们的研究鉴定出了与细胞对CTX反应显著相关的SNP，具有潜在的机制和临床相关性，从而为优化CTX治疗策略提供了见解。
