title: Integration of genetic and clinical risk factors improves prognostication in relapsed childhood B-cell precursor acute lymphoblastic leukemia.
abstract: Somatic genetic abnormalities are initiators and drivers of disease and have proven clinical utility at initial diagnosis. However, the genetic landscape and its clinical utility at relapse are less well understood and have not been studied comprehensively. We analyzed cytogenetic data from 427 children with relapsed B-cell precursor ALL treated on the international trial, ALLR3. Also we screened 238 patients with a marrow relapse for selected copy number alterations (CNAs) and mutations. Cytogenetic risk groups were predictive of outcome postrelapse and survival rates at 5 years for patients with good, intermediate-, and high-risk cytogenetics were 68%, 47%, and 26%, respectively (P < .001). TP53 alterations and NR3C1/BTG1 deletions were associated with a higher risk of progression: hazard ratio 2.36 (95% confidence interval, 1.51-3.70, P < .001) and 2.15 (1.32-3.48, P = .002). NRAS mutations were associated with an increased risk of progression among standard-risk patients with high hyperdiploidy: 3.17 (1.15-8.71, P = .026). Patients classified clinically as standard and high risk had distinct genetic profiles. The outcome of clinical standard-risk patients with high-risk cytogenetics was equivalent to clinical high-risk patients. Screening patients at relapse for key genetic abnormalities will enable the integration of genetic and clinical risk factors to improve patient stratification and outcome. This study is registered at www.clinicaltrials.org as #ISCRTN45724312.
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom;
authors.forename: Julie A E
authors.initials: JA
authors.lastname: Irving
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom;
authors.forename: Amir
authors.initials: A
authors.lastname: Enshaei
authors.affiliation: Children's Cancer Group, Institute of Cancer, Faculty of Medical & Human Sciences, The University of Manchester, Manchester, United Kingdom; Royal Manchester Children's Hospital, Central Manchester University Hospitals Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom;
authors.forename: Catriona A
authors.initials: CA
authors.lastname: Parker
authors.affiliation: Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Sydney, Australia;
authors.forename: Rosemary
authors.initials: R
authors.lastname: Sutton
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands;
authors.forename: Roland P
authors.initials: RP
authors.lastname: Kuiper
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom;
authors.forename: Amy
authors.initials: A
authors.lastname: Erhorn
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom;
authors.forename: Lynne
authors.initials: L
authors.lastname: Minto
authors.affiliation: Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Sydney, Australia;
authors.forename: Nicola C
authors.initials: NC
authors.lastname: Venn
authors.affiliation: Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Sydney, Australia;
authors.forename: Tamara
authors.initials: T
authors.lastname: Law
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands;
authors.forename: Jiangyan
authors.initials: J
authors.lastname: Yu
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom;
authors.forename: Claire
authors.initials: C
authors.lastname: Schwab
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom;
authors.forename: Rosanna
authors.initials: R
authors.lastname: Davies
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom;
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Matheson
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom;
authors.forename: Alysia
authors.initials: A
authors.lastname: Davies
authors.affiliation: Dutch Childhood Oncology Group, The Hague, The Netherlands;
authors.forename: Edwin
authors.initials: E
authors.lastname: Sonneveld
authors.affiliation: Dutch Childhood Oncology Group, The Hague, The Netherlands; Department of Paediatric Oncology and Haematology, Erasmus MC-Sophia Children's Hospital, University Medical Centre, Rotterdam, The Netherlands;
authors.forename: Monique L
authors.initials: ML
authors.lastname: den Boer
authors.affiliation: Centre for Statistics in Medicine, University of Oxford, Oxford, United Kingdom;
authors.forename: Sharon B
authors.initials: SB
authors.lastname: Love
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom;
authors.forename: Christine J
authors.initials: CJ
authors.lastname: Harrison
authors.affiliation: Dutch Childhood Oncology Group, The Hague, The Netherlands; Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands;
authors.forename: Peter M
authors.initials: PM
authors.lastname: Hoogerbrugge
authors.affiliation: Department of Haematology-Oncology, SA Pathology at Women's and Children's Hospital and University of Adelaide, Adelaide, Australia; and.
authors.forename: Tamas
authors.initials: T
authors.lastname: Revesz
authors.affiliation: Children's Cancer Group, Institute of Cancer, Faculty of Medical & Human Sciences, The University of Manchester, Manchester, United Kingdom; Royal Manchester Children's Hospital, Central Manchester University Hospitals Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom; Tata Translational Cancer Research Centre, Tata Medical Center, New Town, Kolkata, India.
authors.forename: Vaskar
authors.initials: V
authors.lastname: Saha
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom;
authors.forename: Anthony V
authors.identifier: 0000-0002-9781-6107
authors.initials: AV
authors.lastname: Moorman
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D002869:Chromosome Aberrations; D015331:Cohort Studies; D020732:Cytogenetic Analysis; D056915:DNA Copy Number Variations / Q000235:genetics; D003710:Demography; D018572:Disease-Free Survival; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation / Q000235:genetics; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D011379:Prognosis; D012008:Recurrence; D012307:Risk Factors