TY - JOUR T1 - The modular network structure of the mutational landscape of Acute Myeloid Leukemia. JF - PLoS One Y1 - 2018 A1 - Ibáñez, Mariam A1 - Carbonell-Caballero, José A1 - Such, Esperanza A1 - García-Alonso, Luz A1 - Liquori, Alessandro A1 - López-Pavía, María A1 - LLop, Marta A1 - Alonso, Carmen A1 - Barragán, Eva A1 - Gómez-Seguí, Inés A1 - Neef, Alexander A1 - Hervás, David A1 - Montesinos, Pau A1 - Sanz, Guillermo A1 - Sanz, Miguel Angel A1 - Dopazo, Joaquin A1 - Cervera, José KW - Adult KW - Aged KW - Cytodiagnosis KW - Female KW - Gene Regulatory Networks KW - Genetic Association Studies KW - Genetic Heterogeneity KW - Humans KW - Karyotype KW - Leukemia, Myeloid, Acute KW - Male KW - Middle Aged KW - mutation KW - Neoplasm Proteins KW - Nucleophosmin KW - Prognosis KW - whole exome sequencing AB -

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.

VL - 13 IS - 10 U1 - https://www.ncbi.nlm.nih.gov/pubmed/30303964?dopt=Abstract ER -