RESUMO
Most mutations in cancer genomes are thought to be acquired after the initiating event, which may cause genomic instability and drive 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 M3-AML samples with a known initiating event (PML-RARA) versus the genomes of normal karyotype M1-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.
Assuntos
Evolução Clonal , Leucemia Mieloide Aguda/genética , Mutação , Adulto , Idoso , Análise Mutacional de DNA , Progressão da Doença , Feminino , Estudo de Associação Genômica Ampla , Células-Tronco Hematopoéticas/metabolismo , Humanos , Leucemia Mieloide Aguda/fisiopatologia , Masculino , Pessoa de Meia-Idade , Proteínas de Fusão Oncogênica/genética , Recidiva , Pele/metabolismo , Adulto JovemRESUMO
UNLABELLED: Despite recent progress, computational tools that identify gene fusions from next-generation whole transcriptome sequencing data are often limited in accuracy and scalability. Here, we present a software package, BreakFusion that combines the strength of reference alignment followed by read-pair analysis and de novo assembly to achieve a good balance in sensitivity, specificity and computational efficiency. AVAILABILITY: http://bioinformatics.mdanderson.org/main/BreakFusion