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

作者：Li Ding, Timothy James Ley, David E. Larson, Christopher A. Miller, Daniel C. Koboldt, John Sutton Welch, Julie Ritchey, Margaret A. Young, Tamara L. Lamprecht, Michael D. McLellan, Joshua F. McMichael, John W. Wallis, Charles Lu, Dong Shen, Christopher Harris, David J. Dooling, Robert S. Fulton, Lucinda Fulton, Ken Chen, Heather K. Schmidt, Joelle Kalicki-Veizer, Vincent J. Magrini, Lisa L. Cook, Sean D McGrath, Tammi L. Vickery, Michael C. Wendl, Sharon E. Heath, Mark A. Watson, Daniel C. Link, Michael H. Tomasson, William D. Shannon, Jacqueline E. Payton, Shashikant Kulkarni, Peter Westervelt, Matthew J. Walter, Timothy Aaron Graubert, Elaine R. Mardis, Richard K. Wilson, John F. DiPersio · 发表于：Nature · 年份：2012 · DOI：10.1038/nature10738 · 被引用次数：2045 · 研究领域：Acute Myeloid Leukemia Research、Cancer Genomics and Diagnostics、Multiple Myeloma Research and Treatments

The sequencing of AML genomes of eight patients before and after relapse reveals two major patterns of clonal evolution, with chemotherapy appearing to have a role in both patterns. Many patients with acute myeloid leukaemia (AML) achieve remission, but it is often short-lived and the returned disease is usually refractory to therapy. Genome sequencing of eight patients with AML before and after relapse reveals two major patterns of tumour cell evolution. The founding clone survives chemotherapy in all patients, and, in one clonal pattern, it acquires new mutations and expands at relapse. In the other, a subclone surviving from the original tumour expands and then acquires new mutations. Comparisons of relapse-specific and primary tumour mutations point to an increase in transversions, implying DNA damage caused by cytotoxic chemotherapy. This work demonstrates that the AML genome in an individual patient presents a moving target, and highlights the importance of striving to eradicate both the founding clone and all of its subclones. Most patients with acute myeloid leukaemia (AML) die from progressive disease after relapse, which is associated with clonal evolution at the cytogenetic level1,2 . 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 ...