title: Association of germline genetic variants in RFC, IL15 and VDR genes with minimal residual disease in pediatric B-cell precursor ALL.
abstract: Minimal residual disease (MRD) enables reliable assessment of risk in acute lymphoblastic leukemia (ALL). However, little is known on association between MRD status and germline genetic variation. We examined 159 Caucasian (Slavic) patients with pediatric ALL, treated according to ALL-IC-BFM 2002/2009 protocols, in search for association between 23 germline polymorphisms and MRD status at day 15, day 33 and week 12, with adjustment for MRD-associated clinical covariates. Three variants were significantly associated with MRD: rs1544410 in VDR (MRD-day15); rs1051266 in RFC (MRD-day33, MRD-week12), independently and in an additive effect with rs10519613 in IL15 (MRD-day33). The risk alleles for MRD-positivity were: A allele of VDR (OR = 2.37, 95%CI = 1.07-5.21, P = 0.03, MRD-day15); A of RFC (OR = 1.93, 95%CI = 1.05-3.52, P = 0.03, MRD-day33 and MRD-week12, P < 0.01); A of IL15 (OR = 2.30, 95%CI = 1.02-5.18, P = 0.04, MRD-day33). The risk for MRD-day33-positive status was higher in patients with risk alleles in both RFC and IL15 loci than in patients with risk alleles in one locus or no risk alleles: 2 vs. 1 (OR = 3.94, 95% CI = 1.28-12.11, P = 0.024), 2 vs. 0 (OR = 6.75, 95% CI = 1.61-28.39, P = 0.012). Germline variation in genes related to pharmacokinetics/pharmacodynamics of anti-leukemic drugs and to anti-tumor immunity of the host is associated with MRD status and might help improve risk assessment in ALL.
authors.affiliation: Department of Molecular and Clinical Genetics, Institute of Human Genetics Polish Academy of Sciences, Poznan, Poland.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Dawidowska
authors.affiliation: Department of Molecular and Clinical Genetics, Institute of Human Genetics Polish Academy of Sciences, Poznan, Poland.
authors.forename: Maria
authors.initials: M
authors.lastname: Kosmalska
authors.affiliation: Department of Pediatric Hematology and Oncology, Medical University of Silesia, Zabrze, Poland.
authors.forename: Łukasz
authors.initials: Ł
authors.lastname: Sędek
authors.affiliation: Laboratory of Molecular and Cell Biology, Department of Pediatric Pulmonology, Allergy and Clinical Immunology, Poznan University of Medical Sciences, Poland.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Szczepankiewicz
authors.affiliation: Department of Pediatric Hematology and Oncology, Medical University of Silesia, Zabrze, Poland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Twardoch
authors.affiliation: Department of Pediatric Hematology and Oncology, Medical University of Silesia, Zabrze, Poland.
authors.forename: Alicja
authors.initials: A
authors.lastname: Sonsala
authors.affiliation: Department of Molecular and Clinical Genetics, Institute of Human Genetics Polish Academy of Sciences, Poznan, Poland.
authors.forename: Bronisława
authors.initials: B
authors.lastname: Szarzyńska-Zawadzka
authors.affiliation: Department of Pediatric Hematology, Oncology and Transplantology, University of Medical Sciences, Poznan, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Derwich
authors.affiliation: Department of Pediatric Hematology, Oncology and Transplantology, Cytogenetic Laboratory, Children's University Hospital, Medical University of Lublin, Poland.
authors.forename: Monika
authors.initials: M
authors.lastname: Lejman
authors.affiliation: Department of Pediatric Hematology and Oncology, Medical University of Warsaw, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Pawelec
authors.affiliation: Department of Pediatric Hematology and Oncology, Medical University of Warsaw, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Obitko-Płudowska
authors.affiliation: Department of Pediatric Oncology and Hematology, Jagiellonian University Collegium Medicum, Kraków, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Pawińska-Wąsikowska
authors.affiliation: Department of Pediatric Oncology and Hematology, Jagiellonian University Collegium Medicum, Kraków, Poland.
authors.forename: Kinga
authors.initials: K
authors.lastname: Kwiecińska
authors.affiliation: Department of Pediatric Hematology and Oncology, Collegium Medicum, Nicolaus Copernicus University in Bydgoszcz, Poland.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Kołtan
authors.affiliation: Department of Paediatric Bone Marrow Transplantation, Oncology and Hematology, Wroclaw Medical University, Wrocław, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Dyla
authors.affiliation: Department of Internal Diseases, Diabetology and Nephrology, Medical University of Silesia, Zabrze, Poland.
authors.forename: Władysław
authors.initials: W
authors.lastname: Grzeszczak
authors.affiliation: Department of Pediatric Hematology, Oncology and Transplantology, Cytogenetic Laboratory, Children's University Hospital, Medical University of Lublin, Poland.
authors.forename: Jerzy R
authors.initials: JR
authors.lastname: Kowalczyk
authors.affiliation: Department of Pediatric Hematology and Oncology, Medical University of Silesia, Zabrze, Poland.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Szczepański
authors.affiliation: Department of Molecular and Clinical Genetics, Institute of Human Genetics Polish Academy of Sciences, Poznan, Poland.
authors.forename: Ewa
authors.initials: E
authors.lastname: Ziętkiewicz
authors.affiliation: Department of Molecular and Clinical Genetics, Institute of Human Genetics Polish Academy of Sciences, Poznan, Poland.
authors.forename: Michał
authors.initials: M
authors.lastname: Witt
mesh_terms: D000483:Alleles; D002648:Child; D002675:Child, Preschool; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D018095:Germ-Line Mutation; D006801:Humans; D007223:Infant; D019409:Interleukin-15 / Q000235:genetics*; D008297:Male; D018365:Neoplasm, Residual; D011044:Poland; D011110:Polymorphism, Genetic; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D018167:Receptors, Calcitriol / Q000235:genetics*; D058978:Reduced Folate Carrier Protein / Q000235:genetics*; D012074:Remission Induction; D018570:Risk Assessment
chemical_list: C569274:IL15 protein, human; D019409:Interleukin-15; D018167:Receptors, Calcitriol; D058978:Reduced Folate Carrier Protein; C548699:SLC19A1 protein, human; C579457:VDR protein, human