Somatic Mutations and Polymorphisms of the Glucocorticoid Receptor Gene Are Not Related to Glucocorticoid Resistance in Childhood ALL.

In vivo and in vitro response to glucocorticoids (GC) are important prognostic factors in childhood ALL. To induce apoptosis, GC bind to the intracellular GC receptor (GR), which subsequently triggers transactivation and repression of downstream genes. As somatic mutations and polymorphisms have been linked to both increased and decreased GC sensitivity in healthy individuals, we studied the relationship between these gene alterations and GC sensitivity in childhood ALL.

Methods: We analysed leukemic cells taken at diagnosis and normal lymphocytes at time of complete remission (CR) from 57 children. DNA mutations were screened for using a PCR - SSCP technique. PCR products with abnormal SSCP patterns were sequenced. In vivo response to prednisone was determined according to BFM criteria as prednisone good response (PGR) or prednisone poor response (PPR). The in vitro prednisolone sensitivity was determined by MTT assay.

Results: The polymorphism ER22/23EK was found in 4% of cases, N363S in 12%, Bcl1 in 55%, intron mutation 16 basepairs upstream of exon 5 in 40%, H588H in 2% and N766N in 21%. They were proven to be polymorphisms as they were found in normal lymphocytes of the same patients at CR as well. The incidence of the polymorphisms was comparable to reports in the literature in the healthy population, except for N363S, which was found at a 2–4 fold higher incidence in ALL patients. Using the Chi-square test and the Mann-Whitney U test, no relation could be found between the occurrence of polymorphisms and in vivo prednisone response or in vitro sensitivity to prednisolone.

Conclusion: GC resistance in childhood ALL can not be attributed to polymorphisms of the hGR. The association between a higher incidence of the N363S polymorphism in childhood ALL as compared to the normal population needs further investigation.