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Genetic variations in the glucocorticoid receptor gene are not related to glucocorticoid resistance in childhood acute lymphoblastic leukemia

xre2004 添加于 2010-8-27 17:07 | 1467 次阅读 | 0 个评论

作者
Tissing WJE, Meijerink JPP, den Boer ML, Brinkhof B, van Rossum EFC, van Wering ER, Koper JW, Sonneveld P, Pieters R
摘要
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.
详细资料
- 关键词: Base Sequence; Cell Survival/drug effects/genetics; Child; Child, Preschool; DNA Mutational Analysis; DNA, Neoplasm/chemistry/genetics; Drug Resistance, Neoplasm/*genetics; Female; *Genetic Variation; Genotype; Glucocorticoids/*pharmacology; Humans; Infant; Infant, Newborn; Male; Mutation; Polymorphism, Genetic; Polymorphism, Single-Stranded Conformational; Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy/*genetics/pathology; Prednisolone/pharmacology; Receptors, Glucocorticoid/*genet
- 文献种类:期刊
- 期刊名称: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
- 期刊缩写: Clin Cancer Res
- 期卷页: 2005年第11卷第16期 6050-6056页
- 地址: Department of Pediatric Oncology/Hematology, Erasmus Medical Center/Sophia Children's Hospital, Rotterdam, The Netherlands
- ISBN: 1078-0432
- 备注:PMID:16115950
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附件
Genetic variations in the glucocorticoid receptor gene are not related to glucocorticoid resistance in childhood acute lymphoblastic leukemia