The origin and evolution of mutations in Acute Myeloid Leukemia

By J. Welch, T. Ley, D. Link, Christopher A. Miller, David E. Larson, Daniel C. Koboldt, L. Wartman, T. Lamprecht, Fulu Liu, Jun Xia and 44 more. Cell, 2012

1,580 citations recorded by the source corpus.

Summary Most mutations in cancer genomes are thought to be acquired after the initiating event, which may cause genomic instability, driving clonal evolution. However, for acute myeloid leukemia (AML), normal karyotypes are common, and genomic instability is unusual. To better understand clonal evolution in AML, we sequenced the genomes of AML samples with a known initiating event (PML-RARA) vs. normal karyotype AML samples, and the exomes of hematopoietic stem/progenitor cells (HSPCs) from healthy people. Collectively, the data suggest that most of the mutations found in AML genomes are actually random events that occurred in HSPCs before they acquired the initiating mutation; the mutational history of that cell is “captured” as the clone expands. In many cases, only one or two additional, cooperating mutations are needed to generate the malignant founding clone. Cells from the founding clone can acquire additional cooperating mutations, yielding subclones that can contribute to disease progression and/or relapse.

Subfields: Cancer Research, Hematology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/66dd08969db65a00dc65f9d711d4c9f9b0184424

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Citations in the corpus

Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. (2015, background): “2 somatic exonicmutations are acquiredper hematopoietic stemcell per decade.(31) Analysis of inactivation patterns of polymorphic X-linked genes such as glucose-6-phosphate dehydrogenase (G6PD) or the androgen receptor (AR/HUMARA) provided early evidence of the clonal nature of myeloid neoplasms.”
SciClone: Inferring Clonal Architecture and Tracking the Spatial and Temporal Patterns of Tumor Evolution (2014, background): “These subpopulations compete and evolve [1–3], and the mutations ‘‘captured’’ [4] in subsets of cells during this evolution serve as a genetic signature of the resulting (sub)clones.”
A CRISPR Dropout Screen Identifies Genetic Vulnerabilities and Therapeutic Targets in Acute Myeloid Leukemia (2016, background): “Steady progress in deciphering its molecular pathogenesis has been made over the last few decades with a dramatic acceleration in recent years, particularly as a consequence of advances in cancer genomics (Cancer Genome Atlas Research Network, 2013; Welch et al., 2012).”
Age-related clonal hematopoiesis associated with adverse outcomes. (2014, positive): “2C), which is considered to be a somatic mutational signature of aging.(16,29) The median variant allele fraction for the identified mutations was 0.”
Evolution and impact of subclonal mutations in chronic lymphocytic leukemia (2013, positive): “Our study thus uncovers patterns of clonal evolution in CLL, providing insights into its stepwise transformation, and links the presence of subclones with adverse clinical outcomes.”
Genomic Classification and Prognosis in Acute Myeloid Leukemia (2016, methodology): “Under current guidelines,3 84% of patients in this subgroup (232 of 275) would be classified as being at intermediate risk, whereas their outcomes are in fact similar to those for patients in subgroups of AML with adverse outcomes, such as patients with MLL fusion genes (except for MLLT3–MLL fusion)”
Clonal haematopoiesis harbouring AML-associated mutations is ubiquitous in healthy adults (2016, positive): “Conversely, in previous studies of CHIP and AML, C to T (G to A) substitutions comprised B 50–60% of identiﬁed substitutions 8,9,32 .”