Constitutional polymorphisms in ARID5B are associated with an increased risk of developing high hyperdiploid (HeH; 51-67 chromosomes) pediatric B-cell precursor acute lymphoblastic leukemia (BCP ALL). Here, we investigated constitutional and somatic ARID5B variants in 1335 BCP ALL cases from five different cohorts, with a particular focus on HeH cases. In 353 HeH ALL that were heterozygous for risk alleles and trisomic for chromosome 10, where ARID5B is located, a significantly higher proportion of risk allele duplication was seen for the SNPs rs7090445 (p = 0.009), rs7089424 (p = 0.005), rs7073837 (p = 0.03), and rs10740055 (p = 0.04). Somatic ARID5B deletions were seen in 16/1335 cases (1.2%), being more common in HeH than in other genetic subtypes (2.2% vs. 0.4%; p = 0.002). The expression of ARID5B in HeH cases with genomic deletions was reduced, consistent with a functional role in leukemogenesis. Whole-genome sequencing and RNA-sequencing in HeH revealed additional somatic events involving ARID5B, resulting in a total frequency of 3.6% of HeH cases displaying a somatic ARID5B aberration. Overall, our results show that both constitutional and somatic events in ARID5B are involved in the leukemogenesis of pediatric BCP ALL, particularly in the HeH subtype.

Childhood Leukaemia Investigation Prague Prague Czech Republic

Department of Clinical Genetics Pathology and Molecular Diagnostics Office for Medical Services Region Skåne Lund Sweden

Department of Paediatric Haematology and Oncology 2nd Faculty of Medicine Charles University University Hospital Motol Prague Czech Republic

Department of Paediatrics Skåne University Hospital Lund University Lund Sweden

Division of Clinical Genetics Department of Laboratory Medicine Lund University Lund Sweden

Laboratory of Haematology Centre Hospitalier Universitaire Lille University of Lille INSERM Unité 1277 Canther Lille France

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