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Global analysis of somatic structural genomic alterations and their impact on gene expression in diverse human cancers.

Artikel i vetenskaplig tidskrift
Författare Babak Alaei-Mahabadi
Joydeep Bhadury
Joakim Karlsson
Jonas Nilsson
Erik Larsson
Publicerad i Proceedings of the National Academy of Sciences of the United States of America
Volym 113
Nummer/häfte 48
Sidor 13768-13773
ISSN 1091-6490
Publiceringsår 2016
Publicerad vid Institutionen för kliniska vetenskaper, sektionen för kirurgi och kirurgisk gastroforskning, Avdelningen för kirurgi
Institutionen för biomedicin, avdelningen för medicinsk kemi och cellbiologi
Sidor 13768-13773
Språk en
Länkar dx.doi.org/10.1073/pnas.1606220113
www.ncbi.nlm.nih.gov/entrez/query.f...
Ämneskategorier Bioinformatik och systembiologi, Medicinsk genetik, Annan medicinsk grundvetenskap

Sammanfattning

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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