Characteristics of white blood cell count in acute lymphoblastic leukemia: A COST LEGEND phenotype-genotype study

Marianne Helenius, Goda Vaitkeviciene, Jonas Abrahamsson, Ólafur Gisli Jónsson, Bendik Lund, Arja Harila-Saari, Kim Vettenranta, Sirje Mikkel, Martin Stanulla, Elixabet Lopez-Lopez, Esmé Waanders, Hans O Madsen, Hanne Vibeke Marquart, Signe Modvig, Ramneek Gupta, Kjeld Schmiegelow, Rikke Linnemann Nielsen

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Abstract

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 (ρ BCP-ALL= −.17, ρ T-ALL= −.19; p < 3 × 10 −4). Spline functions fitted to age, immunophenotype, and karyotype explained WBC variation better than age alone (ρ =.43, p << 2 × 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.

Original languageEnglish
Article numbere29582
JournalPediatric Blood and Cancer
Volume69
Issue number6
DOIs
Publication statusPublished - 22 Mar 2022

Bibliographical note

Funding Information:
The authors would like to thank the patients for their participation in the studies. Furthermore, we thank the staff and researchers at Bonkolab at Rigshospitalet for organizational support as well as for collection and registration of the patient data. Marianne Helenius and Ramneek Gupta gratefully acknowledge funding from the Danish Childhood Cancer Foundation (TRAVERSE, 2018‐3755). This study was also funded by the Kirsten and Freddy Johansen Foundation, the Swedish Childhood Cancer Foundation, the Nordic Cancer Union, the Otto Christensen Foundation, University Hospital Rigshospitalet, and the Novo Nordisk Foundation. This work is part of Interregional Childhood Oncology Precision Medicine Exploration (iCOPE), a cross‐Oresund collaboration between University Hospital Copenhagen, Rigshospitalet, Lund University, Region Skåne, and Technical University Denmark (DTU), supported by the European Regional Development Fund. This work is also part of Childhood Oncology Network Targeting Research, Organisation & Life expectancy (CONTROL) and supported by Danish Cancer Society (R‐257‐A14720) and the Danish Childhood Cancer Foundation (2019‐5934). This study was facilitated by the EU‐COST action LEGEND (CA16223, https://www.legend‐cost.eu ) for leukemia data sharing and collaboration.

Funding Information:
The authors would like to thank the patients for their participation in the studies. Furthermore, we thank the staff and researchers at Bonkolab at Rigshospitalet for organizational support as well as for collection and registration of the patient data. Marianne Helenius and Ramneek Gupta gratefully acknowledge funding from the Danish Childhood Cancer Foundation (TRAVERSE, 2018-3755). This study was also funded by the Kirsten and Freddy Johansen Foundation, the Swedish Childhood Cancer Foundation, the Nordic Cancer Union, the Otto Christensen Foundation, University Hospital Rigshospitalet, and the Novo Nordisk Foundation. This work is part of Interregional Childhood Oncology Precision Medicine Exploration (iCOPE), a cross-Oresund collaboration between University Hospital Copenhagen, Rigshospitalet, Lund University, Region Skåne, and Technical University Denmark (DTU), supported by the European Regional Development Fund. This work is also part of Childhood Oncology Network Targeting Research, Organisation & Life expectancy (CONTROL) and supported by Danish Cancer Society (R-257-A14720) and the Danish Childhood Cancer Foundation (2019-5934). This study was facilitated by the EU-COST action LEGEND (CA16223, https://www.legend-cost.eu) for leukemia data sharing and collaboration.

Publisher Copyright:
© 2022 The Authors. Pediatric Blood & Cancer published by Wiley Periodicals LLC.

Other keywords

  • Genome-Wide Association Study
  • Genotype
  • Humans
  • Leukocyte Count
  • Phenotype
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
  • Prognosis
  • acute lymphoblastic leukemia (ALL)
  • genome-wide association studies (GWAS)
  • white blood cell count (WBC)
  • genotype
  • spline functions

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