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Structural variants drive context-dependent oncogene activation in cancer
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Journal Article
Structural variants drive context-dependent oncogene activation in cancer
2022
Overview
Higher-order chromatin structure is important for the regulation of genes by distal regulatory sequences
1
,
2
. Structural variants (SVs) that alter three-dimensional (3D) genome organization can lead to enhancer–promoter rewiring and human disease, particularly in the context of cancer
3
. However, only a small minority of SVs are associated with altered gene expression
4
,
5
, and it remains unclear why certain SVs lead to changes in distal gene expression and others do not. To address these questions, we used a combination of genomic profiling and genome engineering to identify sites of recurrent changes in 3D genome structure in cancer and determine the effects of specific rearrangements on oncogene activation. By analysing Hi-C data from 92 cancer cell lines and patient samples, we identified loci affected by recurrent alterations to 3D genome structure, including oncogenes such as
MYC
,
TERT
and
CCND1
. By using CRISPR–Cas9 genome engineering to generate de novo SVs, we show that oncogene activity can be predicted by using ‘activity-by-contact’ models that consider partner region chromatin contacts and enhancer activity. However, activity-by-contact models are only predictive of specific subsets of genes in the genome, suggesting that different classes of genes engage in distinct modes of regulation by distal regulatory elements. These results indicate that SVs that alter 3D genome organization are widespread in cancer genomes and begin to illustrate predictive rules for the consequences of SVs on oncogene activation.
Results are presented that indicate that alterations to gene regulatory three-dimensional architecture are a critical mechanism that enables structural variant-based oncogene activation in cancer genomes and sheds light on the essential elements for such gene activation events.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ 13/109
/ 38/15
/ 38/22
/ 38/23
/ 38/32
/ 38/39
/ 38/77
/ 45/15
/ 45/22
/ Cancer
/ Chromosomes, Human - genetics
/ Context
/ Datasets
/ Enhancer Elements, Genetic - genetics
/ Gene Rearrangement - genetics
/ Genes
/ Genomes
/ Genomic Structural Variation - genetics
/ Humanities and Social Sciences
/ Humans
/ Mutation
/ Oncogene Proteins - chemistry
/ Oncogene Proteins - genetics
/ Oncogene Proteins - metabolism
/ Science
