title: The Mutational Landscape of Acute Promyelocytic Leukemia Reveals an Interacting Network of Co-Occurrences and Recurrent Mutations.
abstract: Preliminary Acute Promyelocytic Leukemia (APL) whole exome sequencing (WES) studies have identified a huge number of somatic mutations affecting more than a hundred different genes mainly in a non-recurrent manner, suggesting that APL is a heterogeneous disease with secondary relevant changes not yet defined. To extend our knowledge of subtle genetic alterations involved in APL that might cooperate with PML/RARA in the leukemogenic process, we performed a comprehensive analysis of somatic mutations in APL combining WES with sequencing of a custom panel of targeted genes by next-generation sequencing. To select a reduced subset of high confidence candidate driver genes, further in silico analysis were carried out. After prioritization and network analysis we found recurrent deleterious mutations in 8 individual genes (STAG2, U2AF1, SMC1A, USP9X, IKZF1, LYN, MYCBP2 and PTPN11) with a strong potential of being involved in APL pathogenesis. Our network analysis of multiple mutations provides a reliable approach to prioritize genes for additional analysis, improving our knowledge of the leukemogenesis interactome. Additionally, we have defined a functional module in the interactome of APL. The hypothesis is that the number, or the specific combinations, of mutations harbored in each patient might not be as important as the disturbance caused in biological key functions, triggered by several not necessarily recurrent mutations.
authors.affiliation: Hematology Service, Hospital Universitario y Politécnico La Fe, Valencia, Spain.
authors.forename: Mariam
authors.initials: M
authors.lastname: Ibáñez
authors.affiliation: Computational Genomics Department, Centro de Investigación Príncipe Felipe, Valencia, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Carbonell-Caballero
authors.affiliation: Computational Genomics Department, Centro de Investigación Príncipe Felipe, Valencia, Spain.
authors.forename: Luz
authors.initials: L
authors.lastname: García-Alonso
authors.affiliation: Hematology Service, Hospital Universitario y Politécnico La Fe, Valencia, Spain.
authors.forename: Esperanza
authors.initials: E
authors.lastname: Such
authors.affiliation: Computational Genomics Department, Centro de Investigación Príncipe Felipe, Valencia, Spain.
authors.forename: Jorge
authors.initials: J
authors.lastname: Jiménez-Almazán
authors.affiliation: Computational Genomics Department, Centro de Investigación Príncipe Felipe, Valencia, Spain.
authors.forename: Enrique
authors.initials: E
authors.lastname: Vidal
authors.affiliation: Laboratory of Molecular Biology, Department of Clinical Chemistry, Hospital Universitario La Fe, Valencia, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: Barragán
authors.affiliation: Hematology Service, Hospital Universitario y Politécnico La Fe, Valencia, Spain.
authors.forename: María
authors.initials: M
authors.lastname: López-Pavía
authors.affiliation: Laboratory of Molecular Biology, Department of Clinical Chemistry, Hospital Universitario La Fe, Valencia, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: LLop
authors.affiliation: Hematology Service, Hospital Universitario y Politécnico La Fe, Valencia, Spain.
authors.forename: Iván
authors.initials: I
authors.lastname: Martín
authors.affiliation: Hematology Service, Hospital Universitario y Politécnico La Fe, Valencia, Spain.
authors.forename: Inés
authors.initials: I
authors.lastname: Gómez-Seguí
authors.affiliation: Hematology Service, Hospital Universitario y Politécnico La Fe, Valencia, Spain.
authors.forename: Pau
authors.initials: P
authors.lastname: Montesinos
authors.affiliation: Hematology Service, Hospital Universitario y Politécnico La Fe, Valencia, Spain.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Sanz
authors.affiliation: Computational Genomics Department, Centro de Investigación Príncipe Felipe, Valencia, Spain.|Functional Genomics Node, Spanish National Institute of Bioinformatics at CIPF, 46012, Valencia, Spain.|Bioinformatics of Rare Diseases (BIER), CIBER de Enfermedades Raras (CIBERER), Valencia, Spain.
authors.forename: Joaquín
authors.initials: J
authors.lastname: Dopazo
authors.affiliation: Hematology Service, Hospital Universitario y Politécnico La Fe, Valencia, Spain.|Genetics Unit, Hospital Universitario y Politécnico La Fe, Valencia, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Cervera
mesh_terms: D059472:Exome / Q000235:genetics; D053263:Gene Regulatory Networks; D015894:Genome, Human; D006801:Humans; D054643:INDEL Mutation / Q000235:genetics; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D059645:Mutation Rate; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D015203:Reproducibility of Results