A genome-wide association study using HapMap cell lines reveals modulators of cellular response to cyclophosphamide.
Document Type
Article
Publication Date
6-2025
Identifier
DOI: 10.1080/14796694.2025.2501517; PMCID: PMC12150645
Abstract
AIMS: 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.
METHODS: 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 (p < 5 × 10-5) 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; N = 155) and without CTX.
RESULTS: Twenty SNPs were filtered out including rs12408401, which was associated with PM resistance (p = 3.89 × 10-5), potentially disrupted a CTCF-loop, and was associated with increased RFX5 expression (p = 0.036), which was associated with poor disease-free interval in ACT-BC patients (HR = 5.32; p = 0.028); and rs784562, which was associated with improved PM sensitivity (p = 6.41 × 10-6), potentially altered nearby enhancer functionality, and reduced expression of KRT72 which was associated with poor progression-free survival in ACT-BC patients (HR = 3.61; p = 0.040).
CONCLUSION: Our study identifies SNPs significantly associated with cellular CTX response with potential mechanistic and clinical relevance, thereby providing insights toward optimized CTX treatment strategies.
Journal Title
Future Oncol
Volume
21
Issue
14
First Page
1809
Last Page
1822
MeSH Keywords
Humans; Cyclophosphamide; Polymorphism, Single Nucleotide; Genome-Wide Association Study; Female; Breast Neoplasms; Cell Line, Tumor; Antineoplastic Agents, Alkylating; HapMap Project; Drug Resistance, Neoplasm; Phosphoramide Mustards; Gene Expression Regulation, Neoplastic
PubMed ID
40356407
Keywords
Cyclophosphamide; HapMap; SNPs; breast cancer; pharmacodynamics; pharmacogenomics
Recommended Citation
Gbadamosi MO, Bhise N, Ghosh TM, et al. A genome-wide association study using HapMap cell lines reveals modulators of cellular response to cyclophosphamide. Future Oncol. 2025;21(14):1809-1822. doi:10.1080/14796694.2025.2501517
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