Polymorphisms in Genes Involved in the Corticosteroid Response and the Outcome of Childhood Acute Lymphoblastic Leukemia

Abstract

A reduction in survival probability in children with ALL was associated with homozygosity for G allele of the NR3C1BclI RFLP polymorphism, particularly in certain patient subgroups. Further analysis is required to replicate this finding and to understand the mechanism underlying the observed association.

Pharmacogenetics of minimal residual disease response in children with B-precursor acute lymphoblastic leukemia: a report from the Children's Oncology Group

“…by guest www.bloodjournal.org From ALL treated with uniform therapy. [4][5][6][7][8][19][20][21][22] The potential involvement of multiple genes in modifying response to chemotherapy must be interpreted in the context of clinical and blast characteristics known to affect treatment response. CART analysis has a number of advantages over other classification methods, including multivariate logistic regression.…”

“…[4][5][6] However, multiple drugs are used to treat children with ALL, and more recent studies have identified additional loci that may modify response to therapy, including genes participating in folate metabolism, steroid response and drug transport, metabolism, and detoxification. [7][8][9] In addition, analysis of the numerous "nongenetic" characteristics, such as age, white cell count, and race that influence treatment response in addition to polymorphic genotypes is necessary to adequately assess the importance of germ line variation on antileukemic response.…”

NR3C1 (nuclear receptor subfamily 3, group C, member 1/glucocorticoid receptor)

“…In two key models of acute lymphoblastic leukemia the GCs resistance was associated with mutations at the level of the glucocorticoid receptor (some of which were newly identified; previously not associated with GC resistance, such as: A484D, P515H, L756N, Y663H, L680P, and R714W0 (Schmidt et al, 2006). The survival probabilities in children with ALL were associated with homozygocity of G allele of the NR3C1 BcII polymorphism, presenting a worse progression and prognosis of the disease (Fleury et al, 2004), and also three other NR3C1 SNPs polymorphism; ?627A/G, intron2 +646)C/T and 9bT/C were associated with dismal childhood cALL outcome with reduced event-free and overall survival (Labuda et al, 2010) …”

Diagnostics of Molecular Markers in Childhood Acute Leukaemia Using Biochips

“…Numerous studies have investigated an association of polymorphisms in different genes coding drug-metabolizing enzymes with patient responses to chemotherapy. The cytochrome P450 enzymes are involved in the Phase I metabolism of many antileukemic agents including cyclophosphamide, etoposide, doxorubicin and vincristine, and might influence on ALL therapy outcomes (Fleury et al, 2004;Rocha et al, 2005). A number of Phase II metabolism enzymes are involved in inactivation of antileukemic agents.…”