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

Abstract

SummaryCopy-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.

BAP1 Loss Predicts Therapeutic Vulnerability in Malignant Peritoneal Mesothelioma

“…4d). These results corroborate previous findings from studies analyzing breast, ovarian and colorectal cancer datasets [23]. These attenuated proteins were found to be involved in mRNA processing, DNA repair pathway, cell cycle regulation, the immune system, and in carbohydrate and lipid metabolism.…”

“…4e-g). Although mRNA transcripts are transcribed proportional to the changes in copy-number profile of the gene, the corresponding proteins are often stabilized when in complex, and free proteins in excess are usually ubiquitinated and targeted for proteosomal degradation to maintain stoichiometry [23].…”

Paralog dependency indirectly affects the robustness of human cells

“…The authors showed that some paralogs can replace each other through changes in expression within protein complexes, supporting the fact that paralogs have preserved the ability to interact with the same partners. Another study reported observations consistent with this model using proteomics analyses of cancer cell lines (Gonçalves et al, 2017). In this case, an increased copy number for one gene led to increased protein abundance and a decrease in abundance of its paralogs, as if a feedback mechanism was affecting the balance between paralogs.…”

ComplexBrowser: a tool for identification and quantification of protein complexes in large scale proteomics datasets

“…proteomics data had been performed in a number of studies [13,14] https://www.biorxiv.org/content/early/2018/07/11/367227). It is now clear that the majority of known protein complexes are translationally and post-translationally regulated and therefore exhibit co-expression when compared across cell types and tissues.…”