Open AccessThe Mutational Landscape of Acute Promyelocytic Leukemia Reveals an Interacting Network of Co-Occurrences and Recurrent Mutations
Author(s) -
Mariam Ibáñez,
José Carbonell-Caballero,
Luz García-Alonso,
Esperanza Such,
Jorge Jiménez-Almazán,
Enrique Vidal,
Eva Barragán,
María López-Pavía,
Marta Llop,
Iván Martín,
Inés Gómez-Seguí,
Pau Montesinos,
Miguel Á. Sanz,
Joaquín Dopazo,
José Cervera
Publication year - 2016
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0148346
Subject(s) - biology , interactome , genetics , ptpn11 , gene , mutation , in silico , computational biology , exome sequencing , lyn , kras , signal transduction , tyrosine kinase
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.