PMID- 35316565 OWN - NLM STAT- MEDLINE DCOM- 20220426 LR - 20220509 IS - 1545-5017 (Electronic) IS - 1545-5009 (Linking) VI - 69 IP - 6 DP - 2022 Jun TI - Characteristics of white blood cell count in acute lymphoblastic leukemia: A COST LEGEND phenotype-genotype study. PG - e29582 LID - 10.1002/pbc.29582 [doi] AB - BACKGROUND: White blood cell count (WBC) as a measure of extramedullary leukemic cell survival is a well-known prognostic factor in acute lymphoblastic leukemia (ALL), but its biology, including impact of host genome variants, is poorly understood. METHODS: We included patients treated with the Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL-2008 protocol (N = 2347, 72% were genotyped by Illumina Omni2.5exome-8-Bead chip) aged 1-45 years, diagnosed with B-cell precursor (BCP-) or T-cell ALL (T-ALL) to investigate the variation in WBC. Spline functions of WBC were fitted correcting for association with age across ALL subgroups of immunophenotypes and karyotypes. The residuals between spline WBC and actual WBC were used to identify WBC-associated germline genetic variants in a genome-wide association study (GWAS) while adjusting for age and ALL subtype associations. RESULTS: We observed an overall inverse correlation between age and WBC, which was stronger for the selected patient subgroups of immunophenotype and karyotypes (rho(BCP-ALL ) = -.17, rho(T-ALL ) = -.19; p < 3 x 10(-4) ). Spline functions fitted to age, immunophenotype, and karyotype explained WBC variation better than age alone (rho = .43, p << 2 x 10(-6) ). However, when the spline-adjusted WBC residuals were used as phenotype, no GWAS significant associations were found. Based on available annotation, the top 50 genetic variants suggested effects on signal transduction, translation initiation, cell development, and proliferation. CONCLUSION: These results indicate that host genome variants do not strongly influence WBC across ALL subsets, and future studies of why some patients are more prone to hyperleukocytosis should be performed within specific ALL subsets that apply more complex analyses to capture potential germline variant interactions and impact on WBC. CI - (c) 2022 The Authors. Pediatric Blood & Cancer published by Wiley Periodicals LLC. FAU - Helenius, Marianne AU - Helenius M AUID- ORCID: 0000-0003-3613-8338 AD - Department of Health Technology, Technical University of Denmark, Kongens Lyngby, Copenhagen, Denmark. AD - Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark. FAU - Vaitkeviciene, Goda AU - Vaitkeviciene G AD - Vilnius University Hospital Santaros Klinikos Center for Pediatric Oncology and Hematology and Vilnius University, Vilnius, Lithuania. FAU - Abrahamsson, Jonas AU - Abrahamsson J AD - Department of Paediatrics, Institution for Clinical Sciences, Sahlgrenska University Hospital, Gothenburg, Sweden. FAU - Jonsson, Olafur Gisli AU - Jonsson OG AD - Department of Pediatrics, Landspitali University Hospital, Reykjavik, Iceland. FAU - Lund, Bendik AU - Lund B AD - Department of Pediatrics, St. Olavs Hospital, Trondheim, Norway. FAU - Harila-Saari, Arja AU - Harila-Saari A AUID- ORCID: 0000-0003-2767-5828 AD - Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden. FAU - Vettenranta, Kim AU - Vettenranta K AD - University of Helsinki and Children s Hospital, University of Helsinki, Helsinki, Finland. FAU - Mikkel, Sirje AU - Mikkel S AD - Department of Hematology and Oncology, University of Tartu, Tartu, Estonia. FAU - Stanulla, Martin AU - Stanulla M AD - Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany. FAU - Lopez-Lopez, Elixabet AU - Lopez-Lopez E AD - Department of Genetics, Physical Anthropology and Animal Physiology, Faculty of Science and Technology, University of the Basque Country (UPV/EHU), Leioa, Spain. AD - Pediatric Oncology Group, BioCruces Bizkaia Health Research Institute, Barakaldo, Spain. FAU - Waanders, Esme AU - Waanders E AD - Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands. AD - Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands. FAU - Madsen, Hans O AU - Madsen HO AD - Department of Clinical Immunology, University Hospital Rigshospitalet, Copenhagen, Denmark. FAU - Marquart, Hanne Vibeke AU - Marquart HV AD - Department of Clinical Immunology, University Hospital Rigshospitalet, Copenhagen, Denmark. FAU - Modvig, Signe AU - Modvig S AD - Department of Clinical Immunology, University Hospital Rigshospitalet, Copenhagen, Denmark. FAU - Gupta, Ramneek AU - Gupta R AUID- ORCID: 0000-0001-6841-6676 AD - Department of Health Technology, Technical University of Denmark, Kongens Lyngby, Copenhagen, Denmark. AD - Novo Nordisk Research Centre Oxford, Oxford, UK. FAU - Schmiegelow, Kjeld AU - Schmiegelow K AUID- ORCID: 0000-0002-0829-4993 AD - Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark. AD - Institute of Clinical Medicine, Faculty of Medicine, University of Copenhagen, Copenhagen, Denmark. FAU - Nielsen, Rikke Linnemann AU - Nielsen RL AUID- ORCID: 0000-0003-0173-2134 AD - Department of Health Technology, Technical University of Denmark, Kongens Lyngby, Copenhagen, Denmark. AD - Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark. AD - Novo Nordisk Research Centre Oxford, Oxford, UK. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20220322 PL - United States TA - Pediatr Blood Cancer JT - Pediatric blood & cancer JID - 101186624 SB - IM MH - Genome-Wide Association Study MH - Genotype MH - Humans MH - Leukocyte Count MH - Phenotype MH - *Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics MH - *Precursor T-Cell Lymphoblastic Leukemia-Lymphoma MH - Prognosis OTO - NOTNLM OT - acute lymphoblastic leukemia (ALL) OT - genome-wide association studies (GWAS) OT - genotype OT - spline functions OT - white blood cell count (WBC) EDAT- 2022/03/23 06:00 MHDA- 2022/04/27 06:00 CRDT- 2022/03/22 17:19 PHST- 2021/12/20 00:00 [revised] PHST- 2021/09/13 00:00 [received] PHST- 2021/12/31 00:00 [accepted] PHST- 2022/03/23 06:00 [pubmed] PHST- 2022/04/27 06:00 [medline] PHST- 2022/03/22 17:19 [entrez] AID - 10.1002/pbc.29582 [doi] PST - ppublish SO - Pediatr Blood Cancer. 2022 Jun;69(6):e29582. doi: 10.1002/pbc.29582. Epub 2022 Mar 22.