title: Host genetic variants of ABCB1 and IL15 influence treatment outcome in paediatric acute lymphoblastic leukaemia.
abstract: BACKGROUND
  Host germline variations and their potential prognostic importance is an emerging area of interest in paediatric ALL.
  
  
  METHODS
  We investigated the associations between 20 germline variations and various clinical end points in 463 children with ALL.
  
  
  RESULTS
  After adjusting for known prognostic factors, variants in two genes were found to be independently associated with poorer EFS: ABCB1 T/T at either 2677 (rs2032582) or 3435 (rs1045642) position (P=0.003) and IL15 67276493G/G (rs17015014; P=0.022). These variants showed a strong additive effect affecting outcome (P<0.001), whereby patients with both risk genotypes had the worst EFS (P=0.001), even after adjusting for MRD levels at the end of remission induction. The adverse effect of ABCB1 T/T genotypes was most pronounced in patients with favourable cytogenetics (P=0.011) while the IL15 67276493G/G genotype mainly affected patients without common chromosomal abnormalities (P=0.022). In both cytogenetic subgroups, increasing number of such risk genotypes still predicted worsening outcome (P<0.001 and=0.009, respectively).
  
  
  CONCLUSIONS
  These results point to the prognostic importance of host genetic variants, although the specific mechanisms remain unclarified. Inclusion of ABCB1 and IL15 variants may help improve risk assignment strategies in paediatric ALL.
authors.affiliation: Division of Haematology-Oncology, Department of Paediatrics, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, Singapore, Singapore.
authors.forename: Y
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Division of Haematology-Oncology, Department of Paediatrics, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, Singapore, Singapore.
authors.forename: S K Y
authors.initials: SK
authors.lastname: Kham
authors.affiliation: 1] Department of Paediatrics, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia [2] University of Malaya Cancer Research Institute, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: H
authors.initials: H
authors.lastname: Ariffin
authors.affiliation: Department of Paediatric Oncology/Haematology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: A M I
authors.initials: AM
authors.lastname: Oei
authors.affiliation: Department of Paediarics, Sime Darby Medical Centre Subang Jaya, Subang Jaya, Malaysia.
authors.forename: H P
authors.initials: HP
authors.lastname: Lin
authors.affiliation: Department of Paediatric Medicine, Haematology/Oncology Service, KK Women's and Children's Hospital, Singapore, Singapore.
authors.forename: A M
authors.initials: AM
authors.lastname: Tan
authors.affiliation: 1] Division of Haematology-Oncology, Department of Paediatrics, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, Singapore, Singapore [2] Viva-University Children's Cancer Centre, University Children's Medical Institute, National University Hospital, Singapore, Singapore [3] National University Cancer Institute Singapore, National University Health System, Singapore.
authors.forename: T C
authors.initials: TC
authors.lastname: Quah
authors.affiliation: 1] Division of Haematology-Oncology, Department of Paediatrics, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, Singapore, Singapore [2] Viva-University Children's Cancer Centre, University Children's Medical Institute, National University Hospital, Singapore, Singapore [3] National University Cancer Institute Singapore, National University Health System, Singapore.
authors.forename: A E J
authors.initials: AE
authors.lastname: Yeoh
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D019409:Interleukin-15 / Q000235:genetics*; D015810:Linkage Disequilibrium; D008297:Male; D020641:Polymorphism, Single Nucleotide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics*; D011379:Prognosis; D016896:Treatment Outcome
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D019409:Interleukin-15