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Cytogenetics and Molecular Genetics

13q deletion anatomy and disease progression in patients with chronic lymphocytic leukemia

Leukemia volume 25, pages 489–497 (2011)Cite this article

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Abstract

Historically, genes targeted by recurrent chromosomal deletions have been identified within the smallest genomic region shared in all patients, the minimally deleted region (MDR). However, deletions this small do not occur in all patients and are a simplification of the impact larger heterogeneous deletions have during carcinogenesis. We use the example of 13q14 deletions in chronic lymphocytic leukemia to show that genes outside MDRs are associated with disease progression. Genomic profiling of 224 patients identified 205 copy number alterations on chromosome 13 in 132 cases. Deletions including DLEU2 were heterogeneous (845 Kb–96.2 Mb) and identified two breakpoint cluster regions within short interspersed nuclear elements proximal to DLEU2 and within long interspersed nuclear elements/L1 repeats distal to GUCY1B2. After defining a deletion class on the basis of size and location, we show that (a) at diagnosis, larger deletions (class II) were associated with a significantly increased risk of disease progression (odds ratio=12.3; P=0.005), (b) in progressive patients, class II deletions were enriched (P=0.02) and (c) this association was independent of IgVH mutational status, ZAP70 expression and ATM/TP53 deletion. Deletion of a 1 Mb gene cluster (48.2–49.2 Mb), including SETDB2, PHF11 and RCBTB1, was significantly associated (P<0.01) with disease progression. Here, we show that the deletion of genes outside MDRs can influence clinical outcome.

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Acknowledgements

This study was funded by Leukaemia and Lymphoma Research and Cancer Research UK. The LRF CLL4 trial was funded by a core grant from Leukaemia and Lymphoma Research, with associated research work supported by the MRC (G8223452) and Cancer Research UK, and laboratory studies by the Arbib Foundation, Schering Healthcare UK, Schering AG—Germany and Leukaemia and Lymphoma Research. The authors gratefully acknowledge all patients and clinicians who participated in the trial. We would like to thank Professor Nick Cross for help with the preparation of this manuscript.

Author contributions

This work was funded by grants awarded to JCS; HP, TC and BDY performed the genomic profiling experiments; MG coordinated the array-CGH profiling; HP, MJRZ and JCS performed the microarray analysis. AG and AP performed the cytogenetic and molecular diagnostic assays. MJRZ, RW, AP and AC conducted statistical analyses; DGO contributed patient samples and data; DGO and JCS initiated and designed the study; JCS wrote the manuscript with contributions from HP, MJRZ and DGO; and all authors critically reviewed the final manuscript.

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Author notes

  1. H Parker and M J J Rose-Zerilli: These authors contributed equally to this work

  2. D G Oscier and J C Strefford: These authors share senior authorship

Authors and Affiliations

  1. Cancer Sciences Division, Cancer Genomics Group, School of Medicine, University of Southampton, Southampton, UK

    H Parker, M J J Rose-Zerilli & J C Strefford

  2. Department of Pathology, Royal Bournemouth Hospital, Bournemouth, UK

    A Parker, A Gardiner & D G Oscier

  3. Medical Oncology Group, Institute of Cancer, St Bartholomew's Hospital, London, UK

    T Chaplin & B D Young

  4. Clinical Trial Service Unit, University of Oxford, Oxford, UK

    R Wade

  5. West Midlands Regional Genetics Laboratory, Birmingham Women's Hospital, Birmingham, UK

    M Griffiths

  6. Human Genetics Division, The Genetic Epidemiology and Bioinformatics Research Group, University of Southampton, Southampton, UK

    A Collins

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  1. H Parker
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Correspondence to J C Strefford.

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Parker, H., Rose-Zerilli, M., Parker, A. et al. 13q deletion anatomy and disease progression in patients with chronic lymphocytic leukemia. Leukemia 25, 489–497 (2011). https://doi.org/10.1038/leu.2010.288

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