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

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.

%B PLoS One %V 13 %P e0202926 %8 2018 %G eng %N 10 %1 https://www.ncbi.nlm.nih.gov/pubmed/30303964?dopt=Abstract %R 10.1371/journal.pone.0202926