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Cell Syst. 2017 Oct 25;5(4):386-398.e4. doi: 10.1016/j.cels.2017.08.013. Epub 2017 Oct 11.

Widespread Post-transcriptional Attenuation of Genomic Copy-Number Variation in Cancer.

Author information

1
European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Cambridge CB10 1SD, UK.
2
Molecular Tumor Biology, Department of General, Visceral and Transplantation Surgery, RWTH University Hospital, Pauwelsstraße 30, 52074 Aachen, Germany.
3
Molecular Tumor Biology, Department of General, Visceral and Transplantation Surgery, RWTH University Hospital, Pauwelsstraße 30, 52074 Aachen, Germany; NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands; ESCAM - European Surgery Center Aachen Maastricht, Germany and the Netherlands.
4
European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Cambridge CB10 1SD, UK; RWTH Aachen University, Faculty of Medicine, Joint Research Centre for Computational Biomedicine, 52057 Aachen, Germany. Electronic address: saezrodriguez@gmail.com.
5
European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Cambridge CB10 1SD, UK. Electronic address: pedrobeltrao@ebi.ac.uk.

Abstract

Copy-number variations (CNVs) are ubiquitous in cancer and often act as driver events, but the effects of CNVs on the proteome of tumors are poorly understood. Here, we analyze recently published genomics, transcriptomics, and proteomics datasets made available by CPTAC and TCGA consortia on 282 breast, ovarian, and colorectal tumor samples to investigate the impact of CNVs in the proteomes of these cells. We found that CNVs are buffered by post-transcriptional regulation in 23%-33% of proteins that are significantly enriched in protein complex members. Our analyses show that complex subunits are highly co-regulated, and some act as rate-limiting steps of complex assembly, as their depletion induces decreased abundance of other complex members. We identified 48 such rate-limiting interactions and experimentally confirmed our predictions on the interactions of AP3B1 with AP3M1 and GTF2E2 with GTF2E1. This study highlights the importance of post-transcriptional mechanisms in cancer that allow cells to cope with their altered genomes.

KEYWORDS:

cancer; copy-number variation; gene dosage; protein complexes; proteomics

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