title: Global analysis of somatic structural genomic alterations and their impact on gene expression in diverse human cancers.
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.
authors.affiliation: Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, SE-405 30 Gothenburg, Sweden.
authors.forename: Babak
authors.initials: B
authors.lastname: Alaei-Mahabadi
authors.affiliation: Department of Surgery, Sahlgrenska Cancer Center, Institute of Clinical Sciences, University of Gothenburg, SE-405 30 Gothenburg, Sweden.
authors.forename: Joydeep
authors.identifier: 0000-0002-4333-9974
authors.initials: J
authors.lastname: Bhadury
authors.affiliation: Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, SE-405 30 Gothenburg, Sweden.
authors.forename: Joakim W
authors.initials: JW
authors.lastname: Karlsson
authors.affiliation: Department of Surgery, Sahlgrenska Cancer Center, Institute of Clinical Sciences, University of Gothenburg, SE-405 30 Gothenburg, Sweden.
authors.forename: Jonas A
authors.initials: JA
authors.lastname: Nilsson
authors.affiliation: Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, SE-405 30 Gothenburg, Sweden; erik.larsson@gu.se.
authors.forename: Erik
authors.initials: E
authors.lastname: Larsson
mesh_terms: D056915:DNA Copy Number Variations / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D015894:Genome, Human / Q000235:genetics*; D056914:Genomic Structural Variation / Q000235:genetics*; D006801:Humans; D051267:NF-E2-Related Factor 2 / Q000235:genetics; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D019098:Telomerase / Q000235:genetics
chemical_list: D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D015514:Oncogene Proteins, Fusion; D012333:RNA, Messenger; C509186:TERT protein, human; D019098:Telomerase
keywords: cancer genomics; gene expression; gene fusion; somatic structural variation