Clonal Architecture of Secondary Acute Myeloid Leukemia

By M. Walter, D. Shen, Li Ding, J. Shao, Daniel C. Koboldt, Ken Chen, David E. Larson, M. McLellan, D. Dooling, R. Abbott and 19 more. New England Journal of Medicine, 2012

794 citations recorded by the source corpus.

BACKGROUND The myelodysplastic syndromes are a group of hematologic disorders that often evolve into secondary acute myeloid leukemia (AML). The genetic changes that underlie progression from the myelodysplastic syndromes to secondary AML are not well understood. METHODS We performed whole-genome sequencing of seven paired samples of skin and bone marrow in seven subjects with secondary AML to identify somatic mutations specific to secondary AML. We then genotyped a bone marrow sample obtained during the antecedent myelodysplastic-syndrome stage from each subject to determine the presence or absence of the specific somatic mutations. We identified recurrent mutations in coding genes and defined the clonal architecture of each pair of samples from the myelodysplastic-syndrome stage and the secondary-AML stage, using the allele burden of hundreds of mutations. RESULTS Approximately 85% of bone marrow cells were clonal in the myelodysplastic-syndrome and secondary-AML samples, regardless of the myeloblast count. The secondary-AML samples contained mutations in 11 recurrently mutated genes, including 4 genes that have not been previously implicated in the myelodysplastic syndromes or AML. In every case, progression to acute leukemia was defined by the persistence of an antecedent founding clone containing 182 to 660 somatic mutations and the outgrowth or emergence of at least one subclone, harboring dozens to hundreds of new mutations. All founding clones and subclones contained at least one mutation in a coding gene. CONCLUSIONS Nearly all the bone marrow cells in patients with myelodysplastic syndromes and secondary AML are clonally derived. Genetic evolution of secondary AML is a dynamic process shaped by multiple cycles of mutation acquisition and clonal selection. Recurrent gene mutations are found in both founding clones and daughter subclones. (Funded by the National Institutes of Health and others.)

Subfields: Genetics, Hematology

View Paper: https://www.semanticscholar.org/paper/99c239ec7156a96671492085691918851e450589

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In Genetics

In Hematology

Michael R. Stratton

Citations in the corpus

Clinical and biological implications of driver mutations in myelodysplastic syndromes. (2013, background): “driven by clonal evolution associated with acquisition of new driver mutations.(42,43) The International Prognostic Scoring System (IPSS), revised in 2012,(33) is the most widely used prognostication scheme in MDS.”
Absolute quantification of somatic DNA alterations in human cancer (2012, background): “0 Lung adeno (317) Esophageal adeno (52) Breast cancer (91) RCC (84) HCC (94) Colorectal cancer (104) TCGA-GBM (182) TCGA-OV (469) ALL (191) Medulloblastoma (79)”
Evolution and impact of subclonal mutations in chronic lymphocytic leukemia (2013, neutral): “…School, Boston, MA 02114, USA 9Massachusetts General Hospital Cancer Center and Department of Pathology, Boston, MA 02114, USA 10These authors contributed equally to this work *Correspondence: gadgetz@broadinstitute.org (G.G.), cwu@partners.org (C.J.W.) http://dx.doi.org/10.1016/j.cell.2013.01.019”
Cancer heterogeneity: implications for targeted therapeutics (2013, background): “…with transformed myelodysplastic syndromes, matched samples from the antecedent myelodysplastic stage and the secondary AML stage were also clonal; transformation to AML was associated with acquisition of many new mutations in a founding clone to form a daughter subclone (Walter et al, 2012).”
Widespread genetic heterogeneity in multiple myeloma: implications for targeted therapy (2014, neutral): “…studies have documented the existence of clonal heterogeneity in solid tumors and acute myeloid leukemia, albeit in small numbers of patients (Campbell et al., 2010; Carter et al., 2012; Ding et al., 2012; Gerlinger et al., 2012; Nik-Zainal et al., 2012; Shah et al., 2012; Walter et al., 2012).”
The origin and evolution of mutations in Acute Myeloid Leukemia (2012, positive): “Although this number is unknown, the analysis of clonal progression of secondary AML (Walter et al., 2012) suggests that each cooperatingmutationmay capture dozens to hundreds ofmutations.”