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The genomic landscape of high hyperdiploid childhood acute lymphoblastic leukemia

Nature Genetics volume 47, pages 672–676 (2015)Cite this article

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Abstract

High hyperdiploid (51–67 chromosomes) acute lymphoblastic leukemia (ALL) is one of the most common childhood malignancies, comprising 30% of all pediatric B cell–precursor ALL. Its characteristic genetic feature is the nonrandom gain of chromosomes X, 4, 6, 10, 14, 17, 18 and 21, with individual trisomies or tetrasomies being seen in over 75% of cases, but the pathogenesis remains poorly understood. We performed whole-genome sequencing (WGS) (n = 16) and/or whole-exome sequencing (WES) (n = 39) of diagnostic and remission samples from 51 cases of high hyperdiploid ALL to further define the genomic landscape of this malignancy. The majority of cases showed involvement of the RTK-RAS pathway and of histone modifiers. No recurrent fusion gene–forming rearrangement was found, and an analysis of mutations on trisomic chromosomes indicated that the chromosomal gains were early events, strengthening the notion that the high hyperdiploid pattern is the main driver event in this common pediatric malignancy.

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Figure 1: Circos plots showing all somatic genetic events in three representative cases.
Figure 2: Mutational signature of high hyperdiploid childhood ALL.
Figure 3: Overview of the mutations and structural events affecting genes involved in the RTK-RAS pathway and histone modifiers.
Figure 4: Mutant allele fraction (MAF) in relation to relative copy number for the trisomic chromosomes in case 11.

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Acknowledgements

This study was supported by grants from the Swedish Cancer Society (K.P., grant reference CAN 2013/545; B.J., grant reference CAN 2014/357), the Swedish Childhood Cancer Foundation (K.P., grant reference PROJ12/7050; B.J., grant reference PROJ12/009) and the Swedish Research Council (K.P., grant reference 521-2012-864; B.J., grant reference 521-2011-4090).

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Authors and Affiliations

  1. Department of Laboratory Medicine, Division of Clinical Genetics, Lund University, Lund, Sweden

    Kajsa Paulsson, Henrik Lilljebjörn, Andrea Biloglav, Linda Olsson, Marianne Rissler, Thoas Fioretos & Bertil Johansson

  2. Department of Pediatrics, Skåne University Hospital, Lund University, Lund, Sweden

    Anders Castor

  3. Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden

    Gisela Barbany & Ann Nordgren

  4. Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden

    Linda Fogelstrand & Helene Sjögren

  5. Laboratory of Clinical Chemistry, Sahlgrenska University Hospital, Gothenburg, Sweden

    Linda Fogelstrand

  6. Department of Clinical Genetics, University and Regional Laboratories Region Skåne, Lund, Sweden

    Thoas Fioretos & Bertil Johansson

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  1. Kajsa Paulsson
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Contributions

K.P. performed the whole-genome and exome sequencing analyses. H.L., M.R. and T.F. performed RNA-seq. A.B. and L.O. performed validation experiments. A.C. provided clinical data. G.B., L.F., A.N. and H.S. provided samples and clinical data. K.P. and B.J. conceived the study and wrote the manuscript, which was reviewed and edited by the other co-authors.

Corresponding author

Correspondence to Kajsa Paulsson.

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The authors declare no competing financial interests.

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Supplementary Figures 1–7, Supplementary Tables 1–3, 10 and 12, and Supplementary Note. (PDF 5418 kb)

Supplementary Tables 4–9 and 11

Supplementary Tables 4–9 and 11. (XLSX 154 kb)

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Paulsson, K., Lilljebjörn, H., Biloglav, A. et al. The genomic landscape of high hyperdiploid childhood acute lymphoblastic leukemia. Nat Genet 47, 672–676 (2015). https://doi.org/10.1038/ng.3301

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