|Title||The modular network structure of the mutational landscape of Acute Myeloid Leukemia.|
|Publication Type||Journal Article|
|Year of Publication||2018|
|Authors||Ibáñez, M, Carbonell-Caballero, J, Such, E, García-Alonso, L, Liquori, A, López-Pavía, M, LLop, M, Alonso, C, Barragán, E, Gómez-Seguí, I, Neef, A, Hervás, D, Montesinos, P, Sanz, G, Sanz, MAngel, Dopazo, J, Cervera, J|
|Keywords||Adult; Aged; Cytodiagnosis; Female; Gene Regulatory Networks; Genetic Association Studies; Genetic Heterogeneity; Humans; Karyotype; Leukemia, Myeloid, Acute; Male; Middle Aged; mutation; Neoplasm Proteins; Nucleophosmin; Prognosis; whole exome sequencing|
Acute myeloid leukemia (AML) is associated with the sequential accumulation of acquired genetic alterations. Although at diagnosis cytogenetic alterations are frequent in AML, roughly 50% of patients present an apparently normal karyotype (NK), leading to a highly heterogeneous prognosis. Due to this significant heterogeneity, it has been suggested that different molecular mechanisms may trigger the disease with diverse prognostic implications. We performed whole-exome sequencing (WES) of tumor-normal matched samples of de novo AML-NK patients lacking mutations in NPM1, CEBPA or FLT3-ITD to identify new gene mutations with potential prognostic and therapeutic relevance to patients with AML. Novel candidate-genes, together with others previously described, were targeted resequenced in an independent cohort of 100 de novo AML patients classified in the cytogenetic intermediate-risk (IR) category. A mean of 4.89 mutations per sample were detected in 73 genes, 35 of which were mutated in more than one patient. After a network enrichment analysis, we defined a single in silico model and established a set of seed-genes that may trigger leukemogenesis in patients with normal karyotype. The high heterogeneity of gene mutations observed in AML patients suggested that a specific alteration could not be as essential as the interaction of deregulated pathways.
|Alternate Journal||PLoS One|
|PubMed Central ID||PMC6179200|