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  • Review Article
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Somatic and germline genomics in paediatric acute lymphoblastic leukaemia

Nature Reviews Clinical Oncology volume 16, pages 227–240 (2019)Cite this article

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Abstract

Advances in genomic research and risk-directed therapy have led to improvements in the long-term survival and quality of life outcomes of patients with childhood acute lymphoblastic leukaemia (ALL). The application of next-generation sequencing technologies, especially transcriptome sequencing, has resulted in the identification of novel molecular subtypes of ALL with prognostic and therapeutic implications, as well as cooperative mutations that account for much of the heterogeneity in clinical responses observed among patients with specific ALL subtypes. In addition, germline genetic variants have been shown to influence the risk of developing ALL and/or the responses of non-malignant and leukaemia cells to therapy; shared pathways for drug activation and metabolism are implicated in treatment-related toxicity and drug sensitivity or resistance, depending on whether the genetic changes are germline, somatic or both. Indeed, although once considered a non-hereditary disease, genomic investigations of familial and sporadic ALL have revealed a growing number of genetic alterations or conditions that predispose individuals to the development of ALL and treatment-related second cancers. The identification of these genetic alterations holds the potential to direct genetic counselling, testing and possibly monitoring for the early detection of ALL and other cancers. Herein, we review these advances in our understanding of the genomic landscape of childhood ALL and their clinical implications.

Key points

  • Application of next-generation sequencing methods, especially transcriptome sequencing, has resulted in the discovery of many novel genetic rearrangements and mutations with prognostic and therapeutic implications in patients with acute lymphoblastic leukaemia (ALL).

  • A growing number of genetic conditions that predispose patients to develop ALL have been identified.

  • Pathogenic germline variants and common somatic mutations associated with ALL can affect the same genes (for example, PAX5, ETV6 and IKZF1).

  • Germline genetic variants influence the risk of developing ALL as well as the cellular response to anti-leukaemic therapy.

  • Germline genetic polymorphisms are usually retained in leukaemia cells; thus, they can affect drug responses in not only the non-malignant tissues of the host but also the leukaemia cells and, therefore, can affect the toxicities and anti-leukaemic activity of treatment.

  • Leukaemia cell genotype, pharmacogenetics and early treatment response assessed by minimal residual disease measurements should be used in concert to direct the treatment of patients with ALL.

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Fig. 1: Improvements in the overall survival of paediatric patients with ALL over time with the evolution of treatment.
Fig. 2: Estimated frequencies of specific genetic subtypes of childhood ALL.
Fig. 3: Germline and somatic pharmacogenomics of thiopurine sensitivity in children with ALL.

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Acknowledgements

The work of the authors is supported by US National Cancer Institute (NCI) grants CA21765 (to C.-H.P., K.E.N. and J.J.Y), R21 AI113490 (to K.E.N.) and P50 GM115279 (to C.-H.P. and J.J.Y.). C.-H.P., K.E.N. and J.J.Y. also receive support from the American Lebanese Syrian Associated Charities (ALSAC).

Review criteria

The information presented in this Review was compiled by searching PubMed for articles published between 1 January 2007 and 31 July 2018. The search terms used include “pediatric acute lymphoblastic leukaemia” in association with “germline mutations”, “somatic mutations”, “genotype” or “targeted therapy”. Selected relevant articles were reviewed, and references were checked for additional material, when appropriate. Only articles published in English were considered.

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Nature Reviews Clinical Oncology thanks G. Basso, A. Biondi, G. Henze and M. Stanulla for their contribution to the peer review of this work.

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Authors and Affiliations

  1. Department of Oncology, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Ching-Hon Pui & Kim E. Nichols

  2. Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Jun J. Yang

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  1. Ching-Hon Pui
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C.-H.P., K.E.N. and J.J.Y. contributed equally to all stages of the preparation of this manuscript.

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Correspondence to Ching-Hon Pui.

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Pui, CH., Nichols, K.E. & Yang, J.J. Somatic and germline genomics in paediatric acute lymphoblastic leukaemia. Nat Rev Clin Oncol 16, 227–240 (2019). https://doi.org/10.1038/s41571-018-0136-6

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