A genome-wide association study using HapMap cell lines reveals modulators of cellular response to cyclophosphamide

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.