Journal article
Characteristics of white blood cell count in acute lymphoblastic leukemia: A COST LEGEND phenotype-genotype study
Disease Data Intelligence, Bioinformatics, Department of Health Technology, Technical University of Denmark1
University of Tartu2
Hannover Medical School3
University of the Basque Country4
University Medical Centre Utrecht5
Rigshospitalet6
University of Copenhagen7
Bioinformatics, Department of Health Technology, Technical University of Denmark8
Department of Health Technology, Technical University of Denmark9
Vilnius University Hospital Santaros Klinikos10
Sahlgrenska University Hospital11
Landspitali University Hospital12
St. Olav's University Hospital13
Uppsala University14
University of Helsinki15
...and 5 moreBackground: 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 (ρBCP-ALL = -.17, ρT-ALL= -.19; p < 3 x 10-4). Spline functions fitted to age, immunophenotype, and karyotype explained WBC variation better than age alone (ρ= .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.
Language: | English |
---|---|
Year: | 2022 |
Pages: | e29582 |
ISSN: | 15455017 , 15455009 and 07408226 |
Types: | Journal article |
DOI: | 10.1002/pbc.29582 |
ORCIDs: | Helenius, Marianne , 0000-0003-2767-5828 , Gupta, Ramneek , 0000-0002-0829-4993 and Nielsen, Rikke Linnemann |
Acute lymphoblastic leukemia (ALL) Genome-wide association studies (GWAS) Genotype Spline functions White blood cell count (WBC)
Genome-Wide Association Study Humans Leukocyte Count Phenotype Precursor Cell Lymphoblastic Leukemia-Lymphoma Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics Precursor T-Cell Lymphoblastic Leukemia-Lymphoma Prognosis acute lymphoblastic leukemia (ALL) genome-wide association studies (GWAS) genome‐wide association studies (GWAS) genotype spline functions white blood cell count (WBC)