title: Genetic variations in the glucocorticoid receptor gene are not related to glucocorticoid resistance in childhood acute lymphoblastic leukemia.
abstract: Glucocorticoid sensitivity is an important prognostic factor in pediatric acute lymphoblastic leukemia (ALL). For its antileukemic effect, glucocorticoid binds the intracellular glucocorticoid receptor (GR) subsequently regulating transcription of downstream genes. We analyzed whether genetic variations within the GR gene are related to differences in the cellular response to glucocorticoids.
  
  
  METHODS
  In leukemic samples of 57 children, the GR gene was screened for nucleotide variations using a PCR/single-strand conformational polymorphism sequencing strategy. Data were linked to in vivo and in vitro glucocorticoid resistance.
  
  
  RESULTS
  No somatic mutations were detected in the GR gene coding region, but six polymorphisms (i.e., ER22/23EK, N363S, BclI, intron mutation 16 bp upstream of exon 5, H588H, and N766N) were identified. In 67% of ALL cases, at least one minor allele of these polymorphisms was detected. Although only borderline significant, the incidence for the N363S polymorphism minor allele was higher (12% versus 6%, P = 0.06) and for the ER22/23EK minor allele lower (4% versus 7.6%, P = 0.1) than in a healthy, comparable population. The different genotypes of the polymorphisms were not related to prednisone resistance. In conclusion, polymorphisms but not somatic mutations in the GR gene coding region occur in leukemic blasts of children with ALL. Our data suggest that these genetic variations are not a major contributor for differences in cellular response to glucocorticoids in childhood ALL. The higher incidence of the N363S minor allele and the lower incidence of the ER22/23EK minor allele in our ALL population as compared with a normal population warrants further research.
authors.affiliation: Department of Pediatric Oncology/Hematology, Erasmus Medical Center/Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: Wim J E
authors.initials: WJ
authors.lastname: Tissing
authors.forename: Jules P P
authors.initials: JP
authors.lastname: Meijerink
authors.forename: Monique L
authors.initials: ML
authors.lastname: den Boer
authors.forename: Bas
authors.initials: B
authors.lastname: Brinkhof
authors.forename: Elisabeth F C
authors.initials: EF
authors.lastname: van Rossum
authors.forename: Elisabeth R
authors.initials: ER
authors.lastname: van Wering
authors.forename: Jan W
authors.initials: JW
authors.lastname: Koper
authors.forename: Pieter
authors.initials: P
authors.lastname: Sonneveld
authors.forename: Rob
authors.initials: R
authors.lastname: Pieters
mesh_terms: D001483:Base Sequence; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000737:chemistry / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D011110:Polymorphism, Genetic; D018807:Polymorphism, Single-Stranded Conformational; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D011239:Prednisolone / Q000494:pharmacology; D011965:Receptors, Glucocorticoid / Q000235:genetics*; D014407:Tumor Cells, Cultured
chemical_list: D004273:DNA, Neoplasm; D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D011239:Prednisolone