TY - JOUR
T1 - Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing
AU - Ding, Li
AU - Ley, Timothy J.
AU - Larson, David E.
AU - Miller, Christopher A.
AU - Koboldt, Daniel C.
AU - Welch, John S.
AU - Ritchey, Julie K.
AU - Young, Margaret A.
AU - Lamprecht, Tamara
AU - McLellan, Michael D.
AU - McMichael, Joshua F.
AU - Wallis, John W.
AU - Lu, Charles
AU - Shen, Dong
AU - Harris, Christopher C.
AU - Dooling, David J.
AU - Fulton, Robert S.
AU - Fulton, Lucinda L.
AU - Chen, Ken
AU - Schmidt, Heather
AU - Kalicki-Veizer, Joelle
AU - Magrini, Vincent J.
AU - Cook, Lisa
AU - McGrath, Sean D.
AU - Vickery, Tammi L.
AU - Wendl, Michael C.
AU - Heath, Sharon
AU - Watson, Mark A.
AU - Link, Daniel C.
AU - Tomasson, Michael H.
AU - Shannon, William D.
AU - Payton, Jacqueline E.
AU - Kulkarni, Shashikant
AU - Westervelt, Peter
AU - Walter, Matthew J.
AU - Graubert, Timothy A.
AU - Mardis, Elaine R.
AU - Wilson, Richard K.
AU - Dipersio, John F.
N1 - Funding Information:
Acknowledgements We thank the Analysis Pipeline group for developing the automated sequence analysis pipelines; the LIMS group for developing tools and software to manage samples and sequencing; the Systems group for providing the IT infrastructure and HPC solutions required for sequencing and analysis; and R. T. Demeter for experimental support. We also thank The Cancer Genome Atlas for allowing us to use unpublished data for this study, and the Washington University Cancer Genome Initiative for their support. This work was funded by grants to R.K.W. and the National Human Genome Research Institute (NHGRI U54 HG003079), and grants to T.J.L. from the National Cancer Institute (PO1 CA101937) and the Barnes-Jewish Hospital Foundation (00335-0505-02).
PY - 2012/1/26
Y1 - 2012/1/26
N2 - 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.
AB - 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.
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U2 - 10.1038/nature10738
DO - 10.1038/nature10738
M3 - Article
C2 - 22237025
AN - SCOPUS:84862776906
SN - 0028-0836
VL - 481
SP - 506
EP - 510
JO - Nature
JF - Nature
IS - 7382
ER -