GSTP1 and MDR1 Genotypes and Central Nervous System Relapse in Childhood Acute Lymphoblastic Leukemia

Abstract

The probability of event-free survival of childhood acute lymphoblastic leukemia (ALL) approaches 80% or more with the use of modern multiagent chemotherapeutic regimens. One major contribution to this success has been reduction of the rate of central nervous system (CNS) relapses to less than 5%. However, heterogeneity is observed with regard to the incidence of CNS relapse in homogenously treated patient populations. One potential explanation for this heterogeneity is variation in the genetic background of these populations. Glutathione S-transferase P1 and P-glycoprotein are implicated in resistance to a variety of chemotherapeutic agents and have been localized to the blood-brain barrier. In a matched case-control study, we investigated the associations between CNS relapse in childhood ALL and the presence of phenotypically relevant single nucleotide polymorphisms within the GSTP1 (codon 105 and 114) and MDR1 genes (ABCB1; coding for Pgp; exon 26, C3435T). Significant reductions in risk of CNS relapse were observed for patients homozygous for the GSTP1 Val105 allele as well as for patients with the MDR1 3435T/T or C/T genotype. For both genotypes, the effect was restricted to patients at intermediate or high risk of treatment failure. These results suggested a modulating role for host genetic variation in the development of CNS relapse in childhood ALL treated according to Berlin-Frankfurt-Münster protocols.

Genome-wide association study identifies germline polymorphisms associated with relapse of childhood acute lymphoblastic leukemia

“…Candidate SNPs in ABCB1 have been shown previously to be associated with outcome in ALL. 39,40 We conclude that germline SNPs were associated with risk of ALL relapse in this large cohort of newly diagnosed children with ALL, even among patients who were negative for MRD, so inherited SNP genotypes may be a useful additional feature for risk classification in this disease. institutions; Dr Jeannette Pullen from the University of Mississippi at Jackson and Dr Andrew Carroll from the University of Alabama at Birmingham for assistance in classification of patients with ALL; and Dr Mark Shriver at the Pennsylvania State University for sharing SNP genotype data of the 105 Native-American references.…”

Synergistic interaction of ABCB1 and ABCG2 polymorphisms predicts the prevalence of toxic encephalopathy during anticancer chemotherapy

“…In another study, the ABCB1 3435T allele was associated with higher occurrence of CNS relapse in children treated with the same chemotherapy protocol as our patients. 33 These findings warrant future chemotherapy individualization. For a large number of patients with good drug-transport properties, the current therapy is safe but insufficient.…”

MDR1 (C3435T) polymorphism: relation to the risk of breast cancer and therapeutic outcome

“…23 Furthermore, the C3435T genotype-related disease risk has been studied in several other cancers (renal cell carcinoma, colon cancer, lung cancer, acute lymphoblastic and myeloid leukemia, glioma) with mixed and inconsistent results. 14,[18][19][20][24][25][26] Several studies have considered the relationship between MDR1 expression and C3435T polymorphism examining clinical and pathological characteristics in patients with breast cancer. 11,22,23 However, the correlation was either nonsignificant or there was insufficient data.…”