title: RRM1 and RRM2 pharmacogenetics: association with phenotypes in HapMap cell lines and acute myeloid leukemia patients.
abstract: BACKGROUND
  Ribonucleotide reductase catalyzes an essential step in the cellular production of deoxyribonucleotide triphosphates and has been associated with clinical outcome in cancer patients receiving nucleoside analog-based chemotherapy.
  
  
  METHODS
  In the current study, we sequenced the genes RRM1 and RRM2 in genomic DNA from HapMap cell lines with European (Utah residents with northern and western European ancestry [CEU]; n = 90) or African (Yoruba people in Ibadan, Nigeria [YRI]; n = 90) ancestry.
  
  
  RESULTS
  We identified 44 genetic variants including eight coding SNPs in RRM1 and 15 SNPs including one coding SNP in RRM2. RRM1 and RRM2 mRNA expression levels were significantly correlated with each other in both CEU and YRI lymphoblast cell lines, and in leukemic blasts from acute myeloid leukemia (AML) patients (AML97, n = 89; AML02, n = 187). Additionally, RRM1 expression was higher among patient features indicative of a high relapse hazard. We evaluated SNPs within the RRM1 and RRM2 genes in the HapMap lymphoblast cell lines from CEU and YRI panels for association with expression and cytarabine chemosensitivity. SNPs of potential significance were further evaluated in AML patients. RRM1 SNPs rs1042919 (which occurs in linkage disequilbrium with multiple other SNPs) and promoter SNP rs1561876 were associated with intracellular 1-β-D-arabinofuranosyl-CTP levels, response after remission induction therapy, risk of relapse and overall survival in AML patients receiving cytarabine and cladribine.
  
  
  CONCLUSIONS
  These results suggest that SNPs within ribonucleotide reductase might be helpful predictive markers of response to nucleoside analogs and should be further validated in larger cohorts.
authors.affiliation: Department of Biostatistics, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Xueyuan
authors.initials: X
authors.lastname: Cao
authors.forename: Amit K
authors.initials: AK
authors.lastname: Mitra
authors.forename: Stanley
authors.initials: S
authors.lastname: Pounds
authors.forename: Kristine R
authors.initials: KR
authors.lastname: Crews
authors.forename: Varsha
authors.initials: V
authors.lastname: Gandhi
authors.forename: William
authors.initials: W
authors.lastname: Plunkett
authors.forename: M Eileen
authors.initials: ME
authors.lastname: Dolan
authors.forename: Christine
authors.initials: C
authors.lastname: Hartford
authors.forename: Susana
authors.initials: S
authors.lastname: Raimondi
authors.forename: Dario
authors.initials: D
authors.lastname: Campana
authors.forename: James
authors.initials: J
authors.lastname: Downing
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Rubnitz
authors.forename: Raul C
authors.initials: RC
authors.lastname: Ribeiro
authors.forename: Jatinder K
authors.initials: JK
authors.lastname: Lamba
mesh_terms: D045744:Cell Line, Tumor; D017338:Cladribine / Q000008:administration & dosage / Q000009:adverse effects; D003561:Cytarabine / Q000008:administration & dosage / Q000009:adverse effects; D056726:Genetic Association Studies; D060148:HapMap Project; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D015810:Linkage Disequilibrium; D010597:Pharmacogenetics / Q000379:methods; D020641:Polymorphism, Single Nucleotide; D012262:Ribonucleoside Diphosphate Reductase / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D025521:Tumor Suppressor Proteins; D003561:Cytarabine; D017338:Cladribine; C093713:ribonucleotide reductase M2; C475286:RRM1 protein, human; D012262:Ribonucleoside Diphosphate Reductase
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