title: Genomic profiling of thousands of candidate polymorphisms predicts risk of relapse in 778 Danish and German childhood acute lymphoblastic leukemia patients.
abstract: Childhood acute lymphoblastic leukemia survival approaches 90%. New strategies are needed to identify the 10-15% who evade cure. We applied targeted, sequencing-based genotyping of 25 000 to 34 000 preselected potentially clinically relevant single-nucleotide polymorphisms (SNPs) to identify host genome profiles associated with relapse risk in 352 patients from the Nordic ALL92/2000 protocols and 426 patients from the German Berlin-Frankfurt-Munster (BFM) ALL2000 protocol. Patients were enrolled between 1992 and 2008 (median follow-up: 7.6 years). Eleven cross-validated SNPs were significantly associated with risk of relapse across protocols. SNP and biologic pathway level analyses associated relapse risk with leukemia aggressiveness, glucocorticosteroid pharmacology/response and drug transport/metabolism pathways. Classification and regression tree analysis identified three distinct risk groups defined by end of induction residual leukemia, white blood cell count and variants in myeloperoxidase (MPO), estrogen receptor 1 (ESR1), lamin B1 (LMNB1) and matrix metalloproteinase-7 (MMP7) genes, ATP-binding cassette transporters and glucocorticosteroid transcription regulation pathways. Relapse rates ranged from 4% (95% confidence interval (CI): 1.6-6.3%) for the best group (72% of patients) to 76% (95% CI: 41-90%) for the worst group (5% of patients, P<0.001). Validation of these findings and similar approaches to identify SNPs associated with toxicities may allow future individualized relapse and toxicity risk-based treatments adaptation.
authors.affiliation: Center for Biological Sequence Analysis, Technical University of Denmark, Kgs. Lyngby, Denmark.
authors.forename: A
authors.initials: A
authors.lastname: Wesołowska-Andersen
authors.affiliation: Pediatrics and Adolescent Medicine, The Juliane Marie Centre, The University Hospital Rigshospitalet, Copenhagen, Denmark.
authors.forename: L
authors.initials: L
authors.lastname: Borst
authors.affiliation: Center for Biological Sequence Analysis, Technical University of Denmark, Kgs. Lyngby, Denmark.
authors.forename: M D
authors.initials: MD
authors.lastname: Dalgaard
authors.affiliation: Center for Biological Sequence Analysis, Technical University of Denmark, Kgs. Lyngby, Denmark.
authors.forename: R
authors.initials: R
authors.lastname: Yadav
authors.affiliation: Pediatrics and Adolescent Medicine, The Juliane Marie Centre, The University Hospital Rigshospitalet, Copenhagen, Denmark.
authors.forename: K K
authors.initials: KK
authors.lastname: Rasmussen
authors.affiliation: Department of Pediatric Hematology and Oncology, HC Andersen Children's Hospital, Odense University Hospital, Odense, Denmark.
authors.forename: P S
authors.initials: PS
authors.lastname: Wehner
authors.affiliation: Centre for GeoGenetics, Natural History Museum of Denmark, The University of Copenhagen, Copenhagen, Denmark.
authors.forename: M
authors.initials: M
authors.lastname: Rasmussen
authors.affiliation: Institute of Clinical Medicine, Århus University Hospital, Århus, Denmark.
authors.forename: T F
authors.initials: TF
authors.lastname: Ørntoft
authors.affiliation: Institute of Clinical Medicine, Århus University Hospital, Århus, Denmark.
authors.forename: I
authors.initials: I
authors.lastname: Nordentoft
authors.affiliation: Department of Human Genetics, University of Heidelberg, Heidelberg, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Koehler
authors.affiliation: Department of Human Genetics, University of Heidelberg, Heidelberg, Germany.
authors.forename: C R
authors.initials: CR
authors.lastname: Bartram
authors.affiliation: Department of General Pediatrics, University Medical Center Schleswig-Holstein, Kiel, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Schrappe
authors.affiliation: Center for Biological Sequence Analysis, Technical University of Denmark, Kgs. Lyngby, Denmark.
authors.forename: T
authors.initials: T
authors.lastname: Sicheritz-Ponten
authors.affiliation: Center for Biological Sequence Analysis, Technical University of Denmark, Kgs. Lyngby, Denmark.
authors.forename: L
authors.initials: L
authors.lastname: Gautier
authors.affiliation: Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Marquart
authors.affiliation: Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
authors.forename: H O
authors.initials: HO
authors.lastname: Madsen
authors.affiliation: Center for Biological Sequence Analysis, Technical University of Denmark, Kgs. Lyngby, Denmark.
authors.forename: S
authors.initials: S
authors.lastname: Brunak
authors.affiliation: Department of Clinical Immunology, Diagnostic Centre, The University Hospital Rigshospitalet, Copenhagen, Denmark.
authors.forename: M
authors.initials: M
authors.lastname: Stanulla
authors.affiliation: Center for Biological Sequence Analysis, Technical University of Denmark, Kgs. Lyngby, Denmark.
authors.forename: R
authors.initials: R
authors.lastname: Gupta
authors.affiliation: 1] Pediatrics and Adolescent Medicine, The Juliane Marie Centre, The University Hospital Rigshospitalet, Copenhagen, Denmark [2] Institute of Clinical Medicine, Faculty of Health and Medical Sciences, The University of Copenhagen, Copenhagen, Denmark.
authors.forename: K
authors.initials: K
authors.lastname: Schmiegelow
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D003718:Denmark; D005260:Female; D015894:Genome, Human; D023281:Genomics; D005838:Genotype; D005858:Germany; D006801:Humans; D007223:Infant; D008297:Male; D009364:Neoplasm Recurrence, Local / Q000175:diagnosis* / Q000235:genetics*; D018365:Neoplasm, Residual / Q000235:genetics; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000175:diagnosis* / Q000235:genetics*; D012307:Risk Factors; D016896:Treatment Outcome