Abstract
The impact of somatic structural variants (SVs) on gene expression in cancer is largely unknown. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole-genome sequencing data and RNA sequencing from a common set of 1220 cancer cases, we report hundreds of genes for which the presence within 100 kb of an SV breakpoint associates with altered expression. For the majority of these genes, expression increases rather than decreases with corresponding breakpoint events. Up-regulated cancer-associated genes impacted by this phenomenon include TERT, MDM2, CDK4, ERBB2, CD274, PDCD1LG2, and IGF2. TERT-associated breakpoints involve ~3% of cases, most frequently in liver biliary, melanoma, sarcoma, stomach, and kidney cancers. SVs associated with up-regulation of PD1 and PDL1 genes involve ~1% of non-amplified cases. For many genes, SVs are significantly associated with increased numbers or greater proximity of enhancer regulatory elements near the gene. DNA methylation near the promoter is often increased with nearby SV breakpoint, which may involve inactivation of repressor elements.
| Original language | English |
|---|---|
| Article number | 736 |
| Journal | Nature Communications |
| Volume | 11 |
| Issue number | 1 |
| DOIs | |
| State | Published - 5 Feb 2020 |
Bibliographical note
Publisher Copyright:© 2020, The Author(s).
Funding
This work was supported in part by National Institutes of Health (NIH) grant P30CA125123 (C. Creighton) and Cancer Prevention and Research Institute of Texas (CPRIT) grant RP120713 C2 (C. Creighton). This work was made possible through the resources and datasets made available by the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) consortium. In particular, we wish to acknowledge the PCAWG Transcriptome Working Group (led by Alvis Brazma, Gunnar Rätsch, and Angela N. Brooks) and the PCAWG Structural Variation Working Group (led by Peter J. Campbell and Rameen Beroukhim). Furthermore, we acknowledge the contributions of the many clinical networks across ICGC and TCGA who provided samples and data to the PCAWG Consortium, and the contributions of the Technical Working Group and the Germline Working Group of the PCAWG Consortium for collation, realignment and harmonized variant calling of the cancer genomes used in this study. We thank the patients and their families for their participation in the individual ICGC and TCGA projects.
| Funders | Funder number |
|---|---|
| National Institutes of Health | P30CA125123 |
| National Cancer Institute | R01CA218112 |
| Cancer Prevention and Research Institute of Texas | RP120713 C2 |
