The modular network structure of the mutational landscape of Acute Myeloid Leukemia

PLoS One. 2018 Oct 10;13(10):e0202926. doi: 10.1371/journal.pone.0202926. eCollection 2018.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Cytodiagnosis
  • Female
  • Gene Regulatory Networks / genetics
  • Genetic Association Studies
  • Genetic Heterogeneity
  • Humans
  • Karyotype
  • Leukemia, Myeloid, Acute / diagnosis*
  • Leukemia, Myeloid, Acute / genetics*
  • Leukemia, Myeloid, Acute / pathology
  • Male
  • Middle Aged
  • Mutation
  • Neoplasm Proteins / genetics*
  • Prognosis
  • Whole Exome Sequencing*

Substances

  • Neoplasm Proteins

Grant support

This study was supported in part by research funding from FEDER funds (CIBERONC (CB16/12/00284)), “Red Temática de Investigación Cooperativa en Cancer” grant (RD12/0036/0014,); “Instituto de Salud Carlos III” grants PI12/01047, PI13/01640, PI13/02837, PT13/0010/0026, PT13/0001/0007, PIE13/00046, PI16/00665 and PI16/011113; from the “Consellería de Educación, Cultura y Deporte” AC15/00068 and PROMETEOII/2015/008 and supported by grant SAF2017-88908-R from the Spanish Ministry of Economy and Competitiveness (MINECO).