Global Impact of Somatic Structural Variation on the Cancer Proteome

Authors

Fengju Chen
Yiqun Zhang
Darshan S Chandrashekar
Sooryanarayana Varambally
Chad J Creighton

Publication Date

9-13-2023

Journal

Nature Communications

DOI

10.1038/s41467-023-41374-8

PMID

37704602

PMCID

PMC10499989

PubMedCentral® Posted Date

9-13-2023

PubMedCentral® Full Text Version

Post-Print

Published Open-Access

yes

Keywords

Humans, Proteome, Neoplasms, Cell Line, DNA Methylation, Mass Spectrometry

Abstract

Both proteome and transcriptome data can help assess the relevance of non-coding somatic mutations in cancer. Here, we combine mass spectrometry-based proteomics data with whole genome sequencing data across 1307 human tumors spanning various tissues to determine the extent somatic structural variant (SV) breakpoint patterns impact protein expression of nearby genes. We find that about 25% of the hundreds of genes with SV-associated cis-regulatory alterations at the mRNA level are similarly associated at the protein level. SVs associated with enhancer hijacking, retrotransposon translocation, altered DNA methylation, or fusion transcripts are implicated in protein over-expression. SVs combined with altered protein levels considerably extend the numbers of patients with tumors somatically altered for critical pathways. We catalog both SV breakpoint patterns involving patient survival and genes with nearby SV breakpoints associated with increased cell dependency in cancer cell lines. Pan-cancer proteogenomics identifies targetable non-coding alterations, by virtue of the associated deregulated genes.

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