Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2012-01-11

AUTHORS

Li Ding, Timothy J. Ley, David E. Larson, Christopher A. Miller, Daniel C. Koboldt, John S. Welch, Julie K. Ritchey, Margaret A. Young, Tamara Lamprecht, Michael D. McLellan, Joshua F. McMichael, John W. Wallis, Charles Lu, Dong Shen, Christopher C. Harris, David J. Dooling, Robert S. Fulton, Lucinda L. Fulton, Ken Chen, Heather Schmidt, Joelle Kalicki-Veizer, Vincent J. Magrini, Lisa Cook, Sean D. McGrath, Tammi L. Vickery, Michael C. Wendl, Sharon Heath, Mark A. Watson, Daniel C. Link, Michael H. Tomasson, William D. Shannon, Jacqueline E. Payton, Shashikant Kulkarni, Peter Westervelt, Matthew J. Walter, Timothy A. Graubert, Elaine R. Mardis, Richard K. Wilson, John F. DiPersio

ABSTRACT

Most patients with acute myeloid leukaemia (AML) die from progressive disease after relapse, which is associated with clonal evolution at the cytogenetic level. To determine the mutational spectrum associated with relapse, we sequenced the primary tumour and relapse genomes from eight AML patients, and validated hundreds of somatic mutations using deep sequencing; this allowed us to define clonality and clonal evolution patterns precisely at relapse. In addition to discovering novel, recurrently mutated genes (for example, WAC, SMC3, DIS3, DDX41 and DAXX) in AML, we also found two major clonal evolution patterns during AML relapse: (1) the founding clone in the primary tumour gained mutations and evolved into the relapse clone, or (2) a subclone of the founding clone survived initial therapy, gained additional mutations and expanded at relapse. In all cases, chemotherapy failed to eradicate the founding clone. The comparison of relapse-specific versus primary tumour mutations in all eight cases revealed an increase in transversions, probably due to DNA damage caused by cytotoxic chemotherapy. These data demonstrate that AML relapse is associated with the addition of new mutations and clonal evolution, which is shaped, in part, by the chemotherapy that the patients receive to establish and maintain remissions. More... »

PAGES

506

Journal

TITLE

Nature

ISSUE

7382

VOLUME

481

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/nature10738

    DOI

    http://dx.doi.org/10.1038/nature10738

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1003206661

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/22237025


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