A genome-wide association study using HapMap cell lines reveals modulators of cellular response to cyclophosphamide
Mohammed O Gbadamosi1,2,3, Neha Bhise4, Taraswi Mitra Ghosh4,5
1Department of Pharmacotherapy and Translational Research, College of Pharmacy, Gainesville, FL, USA.
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.
Insights
This study identifies single-nucleotide polymorphisms (SNPs) linked to cyclophosphamide (CTX) cellular response. These findings offer insights into optimizing CTX treatment strategies for breast cancer patients.
Area of Science:
- Genomics
- Cancer Biology
- Pharmacogenomics
Background:
- Cyclophosphamide (CTX) is a cornerstone chemotherapy for breast cancer (BC).
- Individual response to CTX varies significantly, impacting treatment efficacy and patient outcomes.
- Understanding the genetic basis of CTX response is crucial for personalized medicine.
Purpose of the Study:
- To identify single-nucleotide polymorphisms (SNPs) associated with cellular sensitivity to phosphoramide mustard (PM), the active metabolite of CTX.
- To explore the downstream functional and clinical implications of these identified SNPs in breast cancer patients.
Main Methods:
- Genome-wide association study (GWAS) on 1,978,545 SNPs in lymphoblastic cell lines (LCLs) from 53 European individuals.
- Filtering SNPs associated with PM sensitivity (p < 5x10^-5) and predicted to overlap with regulatory elements in breast tissue.
- Assessing consequences using LCL transcriptomic data and clinical data from 155 breast cancer patients treated with CTX (ACT-BC).
Main Results:
- Identified 20 significant SNPs, including rs12408401 (associated with PM resistance and increased RFX5 expression, linked to poor disease-free interval) and rs784562 (associated with improved PM sensitivity and reduced KRT72 expression, linked to poor progression-free survival).
- rs12408401 potentially disrupted a CTCF-loop, while rs784562 may have altered enhancer functionality.
- Demonstrated associations between specific SNPs, gene expression, and clinical outcomes in ACT-BC patients.
Conclusions:
- The study successfully identified SNPs with significant associations to cellular CTX response.
- These findings highlight potential mechanistic links and clinical relevance for optimizing CTX-based therapies.
- The identified SNPs provide valuable targets for future research in personalized breast cancer treatment.
