Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing
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, 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.
Figures
![Figure 1. Somatic mutations quantified by deep…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3267864/bin/nihms341298f1.jpg)
![Figure 2. Graphical representation of clonal evolution…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3267864/bin/nihms341298f2.jpg)
![Figure 3. Comparison of mutational classes between…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3267864/bin/nihms341298f3.jpg)
References
- Testa JR, Mintz U, Rowley JD, Vardiman JW, Golomb HM. Evolution of karyotypes in acute nonlymphocytic leukemia. Cancer Res. 1979;39:3619–3627.
- Garson OM, et al. Cytogenetic studies of 103 patients with acute myelogenous leukemia in relapse. Cancer Genet Cytogenet. 1989;40:187–202.
- Ley TJ, et al. DNA sequencing of a cytogenetically normal acute myeloid leukaemia genome. Nature. 2008;456:66–72.
- Li H, et al. The Sequence Alignment/Map (SAM) Format and SAMtools. Bioinformatics (Oxford, England) 2009
- Chen K, et al. BreakDancer: an algorithm for high-resolution mapping of genomic structural variation. Nat Methods. 2009;6:677–681.
- Koboldt DC, et al. VarScan: Variant detection in massively parallel sequencing of individual and pooled samples. Bioinformatics (Oxford, England) 2009
- Mardis ER, et al. Recurring mutations found by sequencing an acute myeloid leukemia genome. N Engl J Med. 2009;361:1058–1066.
- Ley TJ, et al. DNMT3A mutations in acute myeloid leukemia. N Engl J Med. 2010;363:2424–2433.
- Nakao M, et al. Internal tandem duplication of the flt3 gene found in acute myeloid leukemia. Leukemia. 1996;10:1911–1918.
- Noguera NI, et al. Simultaneous detection of NPM1 and FLT3-ITD mutations by capillary electrophoresis in acute myeloid leukemia. Leukemia. 2005;19:1479–1482.
- Ward PS, et al. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell. 2010;17:225–234.
- King-Underwood L, Renshaw J, Pritchard-Jones K. Mutations in the Wilms' tumor gene WT1 in leukemias. Blood. 1996;87:2171–2179.
- Gao J, et al. Isolation of a yeast artificial chromosome spanning the 8;21 translocation breakpoint t(8;21)(q22;q22.3) in acute myelogenous leukemia. Proc Natl Acad Sci U S A. 1991;88:4882–4886.
- Kirito K, et al. A novel RUNX1 mutation in familial platelet disorder with propensity to develop myeloid malignancies. Haematologica. 2008;93:155–156.
- Van Vlierberghe P, et al. PHF6 mutations in adult acute myeloid leukemia. Leukemia. 2011;25:130–134.
- Barjesteh van Waalwijk van Doorn-Khosrovani S, et al. Somatic heterozygous mutations in ETV6 (TEL) and frequent absence of ETV6 protein in acute myeloid leukemia. Oncogene. 2005;24:4129–4137.
- Puente XS, et al. Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia. Nature. 2011;475:101–105.
- Ding L, et al. Somatic mutations affect key pathways in lung adenocarcinoma. Nature. 2008;455:1069–1075.
- Mullighan CG, et al. Genomic analysis of the clonal origins of relapsed acute lymphoblastic leukemia. Science. 2008;322:1377–1380.
- Anderson K, et al. Genetic variegation of clonal architecture and propagating cells in leukaemia. Nature. 2011;469:356–361.
- Notta F, et al. Evolution of human BCR-ABL1 lymphoblastic leukaemia-initiating cells. Nature. 2011;469:362–367.
- Ding L, et al. Genome remodelling in a basal-like breast cancer metastasis and xenograft. Nature. 2010;464:999–1005.
- Shah SP, et al. Mutational evolution in a lobular breast tumour profiled at single nucleotide resolution. Nature. 2009;461:809–813.
- Yachida S, et al. Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature. 2010;467:1114–1117.
- Navin N, et al. Tumour evolution inferred by single-cell sequencing. Nature. 2011
- Vago L, et al. Loss of mismatched HLA in leukemia after stem-cell transplantation. N Engl J Med. 2009;361:478–488.
- Villalobos IB, et al. Relapse of leukemia with loss of mismatched HLA resulting from uniparental disomy after haploidentical hematopoietic stem cell transplantation. Blood. 2010;115:3158–3161.
Source: PubMed