期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 113, 期 48, 页码 13768-13773出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1606220113
关键词
cancer genomics; somatic structural variation; gene fusion; gene expression
资金
- Knut and Alice Wallenberg Foundation
- Swedish Foundation for Strategic Research
- Swedish Medical Research Council
- Swedish Cancer Society
- Ake Wiberg Foundation
- Lars Erik Lundberg Foundation for Research and Education
- Region Vastra Gotaland (ALF Grant)
- Adlerbertska Forskningsstiftelsen
- Assar Gabrielsson Foundation
- W&M Lundgren Foundation
- Sahlgrenska Universitetssjukhusets Stiftelser
- SNIC through the Uppsala Multidisciplinary Center for Advanced Computational Science (UPPMAX) [b2012108]
Tumor genomes are mosaics of somatic structural variants (SVs) that may contribute to the activation of oncogenes or inactivation of tumor suppressors, for example, by altering gene copy number amplitude. However, there are multiple other ways in which SVs can modulate transcription, but the general impact of such events on tumor transcriptional output has not been systematically determined. Here we use whole-genome sequencing data to map SVs across 600 tumors and 18 cancers, and investigate the relationship between SVs, copy number alterations (CNAs), and mRNA expression. We find that 34% of CNA breakpoints can be clarified structurally and that most amplifications are due to tandem duplications. We observe frequent swapping of strong and weak promoters in the context of gene fusions, and find that this has a measurable global impact on mRNA levels. Interestingly, several long noncoding RNAs were strongly activated by this mechanism. Additionally, SVs were confirmed in telomere reverse transcriptase (TERT) upstream regions in several cancers, associated with elevated TERT mRNA levels. We also highlight high-confidence gene fusions supported by both genomic and transcriptomic evidence, including a previously undescribed paired box 8 (PAX8)-nuclear factor, erythroid 2 like 2 (NFE2L2) fusion in thyroid carcinoma. In summary, we combine SV, CNA, and expression data to provide insights into the structural basis of CNAs as well as the impact of SVs on gene expression in tumors.
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