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

Abstract

RRM1 is a gene crucial for determination of the tumor phenotype. It encodes the regulatory subunit of ribonucleotide reductase, and it is a molecular target of gemcitabine. In addition, RRM1 induces PTEN expression and inhibits cell migration, invasion, and metastasis formation. In patients with resected lung cancers, increased levels of RRM1 are highly associated with long survival. In contrast, patients on gemcitabine and cisplatin therapy for advanced disease have a poor survival if RRM1 expression is high presumably because of decreased efficacy of chemotherapy. We analyzed the RRM1 promoter for polymorphisms in an effort to develop a practical and inexpensive assay for RRM1 expression. Two single nucleotide polymorphisms, RR37 and RR524, were discovered. These polymorphisms impacted promoter activity in vitro and had different frequencies in various populations. Promoter allelotypes were highly associated with overall (P = 0.06) and disease-free (P = 0.03) patient survival. The allelotype with the highest predicted activity was associated with the best patient outcome. However, we did not find an association between allelotype and tumoral RRM1 expression. This is likely a result of the limited impact of the described promoter polymorphisms on overall in vivo gene expression. We conclude that clinical studies using RR37 and RR524 for decisions on chemotherapy are premature and that further functional studies on the RRM1 promoter are required to fully elucidate factors controlling RRM1 expression.