title: A novel integrated cytogenetic and genomic classification refines risk stratification in pediatric acute lymphoblastic leukemia.
abstract: Recent genomic studies have provided a refined genetic map of acute lymphoblastic leukemia (ALL) and increased the number of potential prognostic markers. Therefore, we integrated copy-number alteration data from the 8 most commonly deleted genes, subordinately, with established chromosomal abnormalities to derive a 2-tier genetic classification. The classification was developed using 809 ALL97/99 patients and validated using 742 United Kingdom (UK)ALL2003 patients. Good-risk (GR) genetic features included ETV6-RUNX1, high hyperdiploidy, normal copy-number status for all 8 genes, isolated deletions affecting ETV6/PAX5/BTG1, and ETV6 deletions with a single additional deletion of BTG1/PAX5/CDKN2A/B. All other genetic features were classified as poor risk (PR). Three-quarters of UKALL2003 patients had a GR genetic profile and a significantly improved event-free survival (EFS) (94%) compared with patients with a PR genetic profile (79%). This difference was driven by a lower relapse rate (4% vs 17%), was seen across all patient subgroups, and was independent of other risk factors. Even genetic GR patients with minimal residual disease (>0.01%) at day 29 had an EFS in excess of 90%. In conclusion, the integration of genomic and cytogenetic data defines 2 subgroups with distinct responses to treatment and identifies a large subset of children suitable for treatment deintensification.
authors: Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom;
authors: Anthony V
authors: AV
authors: Moorman
authors: Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom;
authors: Amir
authors: A
authors: Enshaei
authors: Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom;
authors: Claire
authors: C
authors: Schwab
authors: Clinical Trial Service Unit, University of Oxford, Oxford, United Kingdom;
authors: Rachel
authors: R
authors: Wade
authors: Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom;
authors: Lucy
authors: L
authors: Chilton
authors: Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom;
authors: Alannah
authors: A
authors: Elliott
authors: Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom;
authors: Stacey
authors: S
authors: Richardson
authors: Bristol Genetics Laboratory, North Bristol National Health Service Trust, Bristol, United Kingdom;
authors: Jeremy
authors: J
authors: Hancock
authors: Leeds Institute of Molecular Medicine, University of Leeds, Leeds, United Kingdom; Department of Paediatric Haematology and Oncology, Leeds General Infirmary, Leeds, United Kingdom;
authors: Sally E
authors: SE
authors: Kinsey
authors: Department of Paediatric Oncology, John Radcliffe Hospital, Oxford, United Kingdom;
authors: Christopher D
authors: CD
authors: Mitchell
authors: Department of Haematology, Great Ormond Street Hospital, London, United Kingdom; and.
authors: Nicholas
authors: N
authors: Goulden
authors: Department of Haematology, Sheffield Children's Hospital, Sheffield, United Kingdom.
authors: Ajay
authors: A
authors: Vora
authors: Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom;
authors: Christine J
authors: CJ
authors: Harrison
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics; D020732:Cytogenetic Analysis; D005260:Female; D017353:Gene Deletion; D018628:Gene Dosage; D019942:Genes, p16; D023281:Genomics; D006801:Humans; D007223:Infant; D053208:Kaplan-Meier Estimate; D008297:Male; D009363:Neoplasm Proteins / Q000235:genetics; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D051757:PAX5 Transcription Factor / Q000235:genetics; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000145:classification / Q000188:drug therapy / Q000235:genetics*; D011379:Prognosis; D050783:Proto-Oncogene Proteins c-ets / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics; D012307:Risk Factors; D000097764:ETS Translocation Variant 6 Protein
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; D051757:PAX5 Transcription Factor; D050783:Proto-Oncogene Proteins c-ets; D012097:Repressor Proteins; D000097764:ETS Translocation Variant 6 Protein; C497281:PAX5 protein, human; C102421:TEL-AML1 fusion protein; C074086:BTG1 protein, human