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Ribonucleotide reductase M1 gene promoter activity, polymorphisms, population frequencies, and clinical relevance

Gerold Bepler1, Zhong Zheng, Ashish Gautam

  • 1Thoracic Oncology Program, Lee Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA. beplerg@moffitt.usf.edu

Lung Cancer (Amsterdam, Netherlands)
|January 11, 2005
PubMed

Insights

Investigating RRM1 gene promoter polymorphisms revealed associations with patient survival in lung cancer. However, these specific polymorphisms did not correlate with tumoral RRM1 expression levels.

Area of Science:

  • Genetics and Molecular Biology
  • Cancer Research
  • Oncology

Background:

  • The RRM1 gene encodes the regulatory subunit of ribonucleotide reductase, a key enzyme in DNA synthesis.
  • RRM1 influences tumor phenotype, PTEN expression, and inhibits cancer cell migration and metastasis.
  • High RRM1 expression correlates with poor survival in patients undergoing gemcitabine/cisplatin chemotherapy but good survival in resected lung cancer.

Purpose of the Study:

  • To identify RRM1 promoter polymorphisms for a potential RRM1 expression assay.
  • To investigate the impact of these polymorphisms on RRM1 promoter activity and patient survival.

Main Methods:

  • Analysis of the RRM1 promoter for single nucleotide polymorphisms (SNPs).
  • In vitro assessment of promoter activity for identified polymorphisms (RR37 and RR524).
  • Correlation analysis between promoter allelotypes and patient survival data (overall and disease-free).

Main Results:

  • Two SNPs, RR37 and RR524, were identified in the RRM1 promoter.
  • These polymorphisms demonstrated varying promoter activity in vitro and different population frequencies.
  • Promoter allelotypes showed a significant association with disease-free survival (P=0.03) and a trend with overall survival (P=0.06).
  • The allelotype with higher predicted activity was linked to better patient outcomes.
  • No significant association was found between allelotype and actual tumoral RRM1 expression.

Conclusions:

  • RRM1 promoter polymorphisms RR37 and RR524 are associated with lung cancer patient survival.
  • The identified polymorphisms have a limited impact on overall in vivo RRM1 gene expression.
  • Clinical application of these polymorphisms for chemotherapy decisions is premature; further research is needed.

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