title: Translational compensation of genomic instability in neuroblastoma.
abstract: Cancer-associated gene expression imbalances are conventionally studied at the genomic, epigenomic and transcriptomic levels. Given the relevance of translational control in determining cell phenotypes, we evaluated the translatome, i.e., the transcriptome engaged in translation, as a descriptor of the effects of genetic instability in cancer. We performed this evaluation in high-risk neuroblastomas, which are characterized by a low frequency of point mutations or known cancer-driving genes and by the presence of several segmental chromosomal aberrations that produce gene-copy imbalances that guide aggressiveness. We thus integrated genome, transcriptome, translatome and miRome profiles in a representative panel of high-risk neuroblastoma cell lines. We identified a number of genes whose genomic imbalance was corrected by compensatory adaptations in translational efficiency. The transcriptomic level of these genes was predictive of poor prognosis in more than half of cases, and the genomic imbalances found in their loci were shared by 27 other tumor types. This homeostatic process is also not limited to copy number-altered genes, as we showed the translational stoichiometric rebalance of histone genes. We suggest that the translational buffering of fluctuations in these dose-sensitive transcripts is a potential driving process of neuroblastoma evolution.
authors.affiliation: Laboratory of Translational Genomics, Centre for Integrative Biology, University of Trento, Italy.
authors.forename: Erik
authors.initials: E
authors.lastname: Dassi
authors.affiliation: Laboratory of Translational Genomics, Centre for Integrative Biology, University of Trento, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Greco
authors.affiliation: Laboratory of Translational Genomics, Centre for Integrative Biology, University of Trento, Italy.
authors.forename: Viktoryia
authors.initials: V
authors.lastname: Sidarovich
authors.affiliation: Laboratory of Translational Genomics, Centre for Integrative Biology, University of Trento, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Zuccotti
authors.affiliation: Laboratory of Translational Genomics, Centre for Integrative Biology, University of Trento, Italy.
authors.forename: Natalia
authors.initials: N
authors.lastname: Arseni
authors.affiliation: Center of Physiopathology of Human Reproduction, Unit of Obstetrics and Gynecology, IRCSS A.O.U. San Martino IST, Genova, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Scaruffi
authors.affiliation: Neuroblastoma Laboratory, Pediatric Research Institute, Fondazione Città della Speranza, Padova, Italy.
authors.forename: Gian Paolo
authors.initials: GP
authors.lastname: Tonini
authors.affiliation: Laboratory of Translational Genomics, Centre for Integrative Biology, University of Trento, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Quattrone
mesh_terms: D045744:Cell Line, Tumor; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations; D005784:Gene Amplification; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D016259:Genes, myc; D042822:Genomic Instability; D006657:Histones / Q000378:metabolism; D006801:Humans; D009447:Neuroblastoma / Q000235:genetics* / Q000378:metabolism; D014176:Protein Biosynthesis
chemical_list: D006657:Histones