title: CYP3A genotypes and treatment response in paediatric acute lymphoblastic leukaemia.
abstract: Acute lymphoblastic leukaemia (ALL) is the most common paediatric cancer with a cure rate of approximately 80%. Relapse occurs despite treatment stratification based on clinical criteria. Relapse risk in ALL may be related to simple nucleotide polymorphisms (SNPs) of enzymes that metabolize chemotherapeutic agents. We evaluated whether SNPs in the cytochrome P450 3A family (CYP3A4*1B, CYP3A5*3 and CYP3A5*6) were associated with relapse risk on a national Children's Cancer Group (CCG) paediatric ALL trial (CCG-1891). CCG-1891 enrolled 1204 patients, and obtained both relapse and toxicity data prospectively. One hundred and twenty-four relapsed patients and 409 non-relapsed patients were assayed for each SNP. CYP3A variants were not associated with an increased risk of relapse. However, patients with the CYP3A4*1B and CYP3A5*3 genotypes had a decreased risk of peripheral neuropathy that was statistically significant on univariate analysis. After correction for multiple comparisons, the association between CYP3A*1B and CYP3A5*3 genotypes approached, but did not reach, statistical significance. CYP3 genotypes may not significantly modify the risk of relapse in childhood ALL, but may modify the risk of toxicity.
authors.affiliation: Children's Hospital of Philadelphia, Philadelphia, University of Pennsylvania, PA, Children's Cancer Study Group, Arcadia, CA, USA. replenc@cceb.upenn.edu
authors.forename: Richard
authors.initials: R
authors.lastname: Aplenc
authors.forename: Wendy
authors.initials: W
authors.lastname: Glatfelter
authors.forename: Peggy
authors.initials: P
authors.lastname: Han
authors.forename: Eric
authors.initials: E
authors.lastname: Rappaport
authors.forename: Mei
authors.initials: M
authors.lastname: La
authors.forename: Avital
authors.initials: A
authors.lastname: Cnaan
authors.forename: M Anne
authors.initials: MA
authors.lastname: Blackwood
authors.forename: Beverly
authors.initials: B
authors.lastname: Lange
authors.forename: Timothy
authors.initials: T
authors.lastname: Rebbeck
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D051544:Cytochrome P-450 CYP3A; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D008297:Male; D016017:Odds Ratio; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D012008:Recurrence; D012306:Risk; D016019:Survival Analysis
chemical_list: D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating