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Pathway based analysis of SNPs with relevance to 5-FU therapy: relation to intratumoral mRNA expression and survival

Silje H Nordgard1, Grethe I G Alnaes, Björn Hihn

  • 1Department of Genetics, Institute for Cancer Research, Rikshospitalet-Radiumhospitalet Medical Center, Montebello, Oslo, Norway.

International Journal of Cancer
|May 24, 2008
PubMed

Insights

Genetic variations influence chemotherapy response. Three copies of the TYMS 5'UTR repeat correlated with reduced survival in breast cancer patients receiving 5-fluorouracil (5-FU) and mitomycin therapy.

Area of Science:

  • Pharmacogenomics
  • Oncology
  • Molecular Biology

Background:

  • Genetic factors are implicated in patient resistance to chemotherapeutic agents like 5-fluorouracil (5-FU).
  • Numerous genes (approx. 30) are involved in 5-FU metabolism, and variations within them can impact anti-tumor efficacy.
  • Understanding these genetic influences is crucial for personalizing breast cancer treatment.

Purpose of the Study:

  • To investigate the association between genetic polymorphisms in 5-FU metabolism genes, tumoral gene expression, chemotherapy response, and survival in breast cancer patients.
  • To identify specific genetic variants that predict response or resistance to 5-FU-based chemotherapy.
  • To explore the role of TP53 and TYMS gene variations in 5-FU metabolism and patient outcomes.

Main Methods:

  • Analysis of 21 genetic variants in 35 breast cancer patients treated with 5-fluorouracil, mitomycin (FUMI), and in 90 patients treated with doxorubicin.
  • Comparison of genotype distributions with 109 healthy controls.
  • Correlation of genotypes with tumoral mRNA levels of 5-FU metabolizing genes, clinical response (tumor shrinkage), and patient survival.

Main Results:

  • No significant association was found between studied polymorphisms and chemotherapy response (tumor shrinkage).
  • Carriers of three copies of the TYMS 5'UTR repeat exhibited shorter survival in the FUMI group (p = .048) but not in the doxorubicin group.
  • Significant associations were observed between genotypes and the expression of 5-FU metabolizing genes, with a TP53 SNP at codon 72 acting as a key regulator.

Conclusions:

  • Three copies of the TYMS 5'UTR repeat may be associated with reduced survival in breast cancer patients undergoing specific chemotherapy regimens (FUMI).
  • The TP53 gene, specifically a SNP at codon 72, appears to play a direct, allele-specific role in 5-FU-mediated response.
  • These findings highlight the potential of pharmacogenomics in tailoring 5-FU chemotherapy for improved breast cancer treatment outcomes.

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