Systematic investigation of promoter substitutions resulting from somatic intrachromosomal structural alterations in diverse human cancers

Babak Alaei-Mahabadi,Erik Larsson,Kerryn Elliott

doi:10.1038/s41598-020-74420-2

Babak Alaei-Mahabadi, Erik Larsson + Show 1 more

Open Access

https://doi.org/10.1038/s41598-020-74420-2

Copy DOI

Journal: Scientific Reports	Publication Date: Oct 23, 2020
Citations: 1	License type: open-access

Affiliation: University of Gothenburg

Abstract

One of the ways in which genes can become activated in tumors is by somatic structural genomic rearrangements leading to promoter swapping events, typically in the context of gene fusions that cause a weak promoter to be substituted for a strong promoter. While identifiable by whole genome sequencing, limited availability of this type of data has prohibited comprehensive study of the phenomenon. Here, we leveraged the fact that copy number alterations (CNAs) arise as a result of structural alterations in DNA, and that they may therefore be informative of gene rearrangements, to pinpoint recurrent promoter swapping at a previously intractable scale. CNA data from nearly 9500 human tumors was combined with transcriptomic sequencing data to identify several cases of recurrent activating intrachromosomal promoter substitution events, either involving proper gene fusions or juxtaposition of strong promoters to gene upstream regions. Our computational screen demonstrates that a combination of CNA and expression data can be useful for identifying novel fusion events with potential driver roles in large cancer cohorts.

Highlights

One of the ways in which genes can become activated in tumors is by somatic structural genomic rearrangements leading to promoter swapping events, typically in the context of gene fusions that cause a weak promoter to be substituted for a strong promoter
With the ultimate aim of detecting promoter substitution (PS) events resulting from intrachromosomal structural variations (SVs) in a large multicancer cohort (Fig. 1a), we first sought to identify somatic tandem duplications and deletions using GenomeWide Human SNP Array 6.0 (SNP6) data from The Cancer Genome Atlas (TCGA; Fig. 1b)
By comparing with whole genome sequencing (WGS)-based SVs from a previous study[21], available for a subset of samples (600 tumors), we found that 25% of the copy number alterations (CNAs)-inferred SVs had a correspondence in WGS-based SVs and of these, 97% were coherently classified as deletions or duplications in the two datasets

Summary

Introduction

One of the ways in which genes can become activated in tumors is by somatic structural genomic rearrangements leading to promoter swapping events, typically in the context of gene fusions that cause a weak promoter to be substituted for a strong promoter. Recent studies have uncovered that deletions and duplications may facilitate mRNA level changes by shuffling or amplifying non-coding regions in the genome including cis-regulatory elements such as e nhancers[11,12,13,14] Another known mechanism for a gene to be activated by genomic structural variations (SVs) is to substitute its promoter with a stronger promoter in the context of gene fusions[15,16]. We used 9423 array-based copy number profiles made available by The Cancer Genome Atlas consortium to identify deletions and likely tandem duplications predicted to result in intrachromosomal PS events, due to either proper gene fusions or juxtaposition of strong promoters to upstream regions. By using CNAs as a proxy of SVs, we could investigate this phenomenon in a cohort that is considerably larger than what is currently possible using WGS

Methods

Results

Conclusion