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Detecting Somatic Genetic Alterations in Tumor Specimens by Exon Capture and Massively Parallel Sequencing
Published on: October 18, 2013
Global analysis of somatic structural genomic alterations and their impact on gene expression in diverse human
Babak Alaei-Mahabadi1, Joydeep Bhadury2, Joakim W Karlsson1
1Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, SE-405 30 Gothenburg, Sweden.
Abstract:
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.
Insights
Somatic structural variants (SVs) significantly impact tumor gene expression by altering copy numbers and gene fusions. These genomic changes, including promoter swapping and TERT alterations, provide new insights into cancer development.
Area of Science:
- Genomics
- Cancer Biology
- Transcriptomics
Background:
- Tumor genomes contain somatic structural variants (SVs) that can influence oncogene activation and tumor suppressor inactivation.
- The precise impact of SVs on overall tumor transcriptional output remains incompletely understood.
Purpose of the Study:
- To systematically map SVs across a large tumor cohort and investigate their relationship with copy number alterations (CNAs) and mRNA expression.
- To elucidate the mechanisms by which SVs modulate gene expression in cancer.
Main Methods:
- Whole-genome sequencing of 600 tumors across 18 cancer types.
- Integration of SV, CNA, and mRNA expression data.
- Analysis of structural variants, gene fusions, and their impact on gene transcription.
Main Results:
- 34% of CNA breakpoints were structurally resolved, with tandem duplications being the primary cause of most amplifications.
- Gene fusions frequently involved promoter swapping, measurably impacting global mRNA levels, including long noncoding RNAs.
- Structural variants in telomere reverse transcriptase (TERT) upstream regions correlated with elevated TERT mRNA levels.
- Identified high-confidence gene fusions, including a novel PAX8-NFE2L2 fusion in thyroid carcinoma.
Conclusions:
- SVs play a significant role in shaping tumor genomes and transcriptomes.
- Structural variations provide a mechanistic basis for CNAs and directly impact gene expression through various mechanisms.
- This study offers comprehensive insights into the structural underpinnings of cancer gene expression modulation.
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