Journal Article

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

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

2012

Overview

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. Tumour cell evolution in AML 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 level 1 , 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 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/1647/514 / 631/208/737 / 692/308 / 692/699/67/1990/283/1897 / Antineoplastic Agents - adverse effects / Antineoplastic Agents - therapeutic use / Biological and medical sciences / Clonal Evolution - genetics / Clone Cells - drug effects / Clone Cells - metabolism / Clone Cells - pathology / DNA Damage - drug effects / DNA Mutational Analysis / Genes, Neoplasm - genetics / Genome, Human - drug effects / Genome, Human - genetics / Hematologic and hematopoietic diseases / High-Throughput Nucleotide Sequencing / Humanities and Social Sciences / Humans / letter / Leukemia, Myeloid, Acute - drug therapy / Leukemia, Myeloid, Acute - genetics / Leukemia, Myeloid, Acute - pathology / Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis / Medical sciences / multidisciplinary / Mutagenesis - drug effects / Mutagenesis - genetics / Recurrence / Reproducibility of Results / Science / Science (multidisciplinary)