title: 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.
authors.affiliation: Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany. Stanulla.Martin@MH-Hannover.de
authors.forename: Martin
authors.initials: M
authors.lastname: Stanulla
authors.forename: Elke
authors.initials: E
authors.lastname: Schäffeler
authors.forename: Stefan
authors.initials: S
authors.lastname: Arens
authors.forename: Anke
authors.initials: A
authors.lastname: Rathmann
authors.forename: André
authors.initials: A
authors.lastname: Schrauder
authors.forename: Karl
authors.initials: K
authors.lastname: Welte
authors.forename: Michel
authors.initials: M
authors.lastname: Eichelbaum
authors.forename: Ulrich M
authors.initials: UM
authors.lastname: Zanger
authors.forename: Martin
authors.initials: M
authors.lastname: Schrappe
authors.forename: Matthias
authors.initials: M
authors.lastname: Schwab
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000293:Adolescent; D016543:Central Nervous System Neoplasms / Q000453:epidemiology / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005260:Female; D005838:Genotype; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D007223:Infant; D007527:Isoenzymes / Q000235:genetics*; D008297:Male; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000453:epidemiology / Q000235:genetics*; D012008:Recurrence; D012307:Risk Factors
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D007527:Isoenzymes; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase
references.citation: Leukemia. 2000 Dec;14(12):2286-94
references.pmid: 11187920
references.citation: Leukemia. 2000 Dec;14(12):2223-33
references.pmid: 11187913
references.citation: J Clin Invest. 1996 Jun 1;97(11):2517-24
references.pmid: 8647944
references.citation: Blood. 1994 Nov 1;84(9):3122-33
references.pmid: 7949185
references.citation: Pharmacol Ther. 1990;48(3):357-69
references.pmid: 2084706
references.citation: Pharmacogenetics. 1998 Feb;8(1):27-31
references.pmid: 9511178
references.citation: Biochem Biophys Res Commun. 1997 Sep 18;238(2):397-402
references.pmid: 9299520
references.citation: Blood. 1994 Jul 15;84(2):355-66
references.pmid: 8025264
references.citation: Annu Rev Pharmacol Toxicol. 1996;36:161-83
references.pmid: 8725386
references.citation: Gastroenterology. 2000 Feb;118(2):279-88
references.pmid: 10648456
references.citation: J Am Soc Nephrol. 2002 Jul;13(7):1847-54
references.pmid: 12089380
references.citation: N Engl J Med. 2003 Apr 10;348(15):1442-8
references.pmid: 12686700
references.citation: Proc Natl Acad Sci U S A. 2000 Mar 28;97(7):3473-8
references.pmid: 10716719
references.citation: Carcinogenesis. 1997 Apr;18(4):641-4
references.pmid: 9111193
references.citation: Neuropathol Appl Neurobiol. 1990 Aug;16(4):293-303
references.pmid: 2234311
references.citation: Eur J Haematol. 2004 May;72(5):314-21
references.pmid: 15059065
references.citation: Adv Drug Deliv Rev. 2003 Jan 21;55(1):83-105
references.pmid: 12535575
references.citation: Joint Bone Spine. 2000 Jan;67(1):30-9
references.pmid: 10773966
references.citation: Ann Hum Genet. 1989 Jul;53(Pt 3):205-13
references.pmid: 2596826
references.citation: Leukemia. 2000 Dec;14(12):2205-22
references.pmid: 11187912
references.citation: Pharmacogenetics. 2001 Jun;11(4):293-8
references.pmid: 11434506
references.citation: Nat Rev Cancer. 2002 Jan;2(1):48-58
references.pmid: 11902585
references.citation: Pharmacogenetics. 2000 Nov;10(8):715-26
references.pmid: 11186134
references.citation: Eur J Biochem. 1994 Sep 15;224(3):893-9
references.pmid: 7925413
references.citation: Annu Rev Pharmacol Toxicol. 2003;43:285-307
references.pmid: 12359865
references.citation: Blood. 2000 Jun 1;95(11):3310-22
references.pmid: 10828010