title: Incidence of additional genetic changes in the TEL and AML1 genes in DCOG and COALL-treated t(12;21)-positive pediatric ALL, and their relation with drug sensitivity and clinical outcome.
abstract: Clinical heterogeneity within t(12;21) or TEL/AML1-positive ALL (25% of childhood common/preB ALL) indicates that additional genetic changes might contribute to outcome. We studied the relation between additional genetic changes in TEL(ETV6) and AML1(RUNX1) (FISH), drug sensitivity (MTT assay) and clinical outcome in 143 DCOG and COALL-treated t(12;21)-positive ALL patients. Additional genetic changes in TEL and AML1 were present in 83% of the patients, and consisted of (partial) deletion of the second TEL gene (70%), an extra AML1 gene (23%) or an extra der(21)t(12;21) (10%). More than one additional change was observed in 20%. Disease-free survival (pDFS) of DCOG patients without additional genetic changes (4 years pDFS +/- s.e. 53 +/- 17%) and of those with an extra der(21)t(12;21) (60 +/- 22%) is poorer than that of compared to patients with other additional genetic changes in TEL or AML1 (79 +/- 6%; P-trend = 0.02). This was mainly due to the occurrence of early relapses within 2.5 years after the first diagnosis. Similar observations were found in the COALL cohort, albeit not significant owing to limited follow-up. Multivariate analysis including age, WBC and genetic abnormalities in TEL and/or AML1 showed that especially, in vitro resistance to prednisolone (hazard ratio 5.78, 95% CI 1.45-23.0; P=0.01) is an independent prognostic factor in DCOG- and COALL-treated t(12;21)-positive ALL.
authors.affiliation: Erasmus MC, Sophia Children's Hospital, Erasmus University Medical Center Rotterdam, Division of Pediatric Oncology/Hematology, Rotterdam, The Netherlands.
authors.forename: W A G
authors.initials: WA
authors.lastname: Stams
authors.forename: H B
authors.initials: HB
authors.lastname: Beverloo
authors.forename: M L
authors.initials: ML
authors.lastname: den Boer
authors.forename: R X
authors.initials: RX
authors.lastname: de Menezes
authors.forename: R L
authors.initials: RL
authors.lastname: Stigter
authors.forename: E
authors.initials: E
authors.lastname: van Drunen
authors.forename: N L
authors.initials: NL
authors.lastname: Ramakers-van-Woerden
authors.forename: A H
authors.initials: AH
authors.lastname: Loonen
authors.forename: E R
authors.initials: ER
authors.lastname: van Wering
authors.forename: G E
authors.initials: GE
authors.lastname: Janka-Schaub
authors.forename: R
authors.initials: R
authors.lastname: Pieters
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D002881:Chromosomes, Human, Pair 12; D002891:Chromosomes, Human, Pair 21; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics*; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics*; D014178:Translocation, Genetic; D016896:Treatment Outcome; D000097764:ETS Translocation Variant 6 Protein
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D015514:Oncogene Proteins, Fusion; C102421:TEL-AML1 fusion protein; D000097764:ETS Translocation Variant 6 Protein