title: 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.
authors.affiliation: Thoracic Oncology Program, Lee Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA. beplerg@moffitt.usf.edu
authors.forename: Gerold
authors.initials: G
authors.lastname: Bepler
authors.forename: Zhong
authors.initials: Z
authors.lastname: Zheng
authors.forename: Ashish
authors.initials: A
authors.lastname: Gautam
authors.forename: Swati
authors.initials: S
authors.lastname: Sharma
authors.forename: Alan
authors.initials: A
authors.lastname: Cantor
authors.forename: Anupama
authors.initials: A
authors.lastname: Sharma
authors.forename: W Douglas
authors.initials: WD
authors.lastname: Cress
authors.forename: Young-Chul
authors.initials: YC
authors.lastname: Kim
authors.forename: Rafael
authors.initials: R
authors.lastname: Rosell
authors.forename: Colleen
authors.initials: C
authors.lastname: McBride
authors.forename: Lary
authors.initials: L
authors.lastname: Robinson
authors.forename: Eric
authors.initials: E
authors.lastname: Sommers
authors.forename: Eric
authors.initials: E
authors.lastname: Haura
mesh_terms: D001681:Biological Assay / Q000379:methods; D044383:Black People; D005006:Ethnicity; D020869:Gene Expression Profiling; D005787:Gene Frequency; D005819:Genetic Markers; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D012262:Ribonucleoside Diphosphate Reductase; D016019:Survival Analysis; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis* / Q000235:genetics*; D044465:White People
chemical_list: D005819:Genetic Markers; D025521:Tumor Suppressor Proteins; C475286:RRM1 protein, human; D012262:Ribonucleoside Diphosphate Reductase