Translational compensation of genomic instability in neuroblastoma.

Erik Dassi,Valentina Greco,Natalia Arseni,Gian Paolo Tonini,Alessandro Quattrone,Viktoryia Sidarovich,Paola Zuccotti,Paola Scaruffi

doi:10.1038/srep14364

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.

Highlights

Cancer-associated gene expression imbalances are conventionally studied at the genomic, epigenomic and transcriptomic levels
Because RNA-binding proteins (RBPs) and miRNAs are the most documented trans-factors involved in post-transcriptional regulation, we reported their genomic distribution (Fig. 1A), observing a considerable proportion of them within altered regions in high-risk neuroblastomas
Given the prevalence of MYCN-amplified tumors in the high-risk class, their relatively homogeneous genomic alteration profile, their sheer aggressiveness[2] and their unfavorable prognosis, we focused our analysis on this specific neuroblastoma subtype

Summary

Introduction

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 cancerdriving genes and by the presence of several segmental chromosomal aberrations that produce gene-copy imbalances that guide aggressiveness. Incorporating translational efficiency estimation into mRNA profiling would generate molecular portraits that are closer to actual protein levels, helping to reveal the involvement of translational control alterations in tumor onset and progression, as previously proposed[12] Such information could be obtained by translatomic profiling, which consists of polysome isolation by sucrose-gradient separation[13] and the evaluation of mRNA content by high-throughput methods. The use of this approach in tumor cell lines or mouse tissues has so far been limited to a few reports[10,11,12] and, to the best of our knowledge, no translatomic study has been performed on human tumor samples

Methods

Results

Conclusion