RESUMEN
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.
Asunto(s)
Evolución Clonal , Leucemia Mieloide Aguda/genética , Mutación , Adulto , Anciano , Análisis Mutacional de ADN , Progresión de la Enfermedad , Femenino , Estudio de Asociación del Genoma Completo , Células Madre Hematopoyéticas/metabolismo , Humanos , Leucemia Mieloide Aguda/fisiopatología , Masculino , Persona de Mediana Edad , Proteínas de Fusión Oncogénica/genética , Recurrencia , Piel/metabolismo , Adulto JovenRESUMEN
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