Regional perturbation of gene transcription is associated with intrachromosomal rearrangements and gene fusion transcripts in high grade ovarian cancer

Paul M. Krzyzanowski, Fabrice Sircoulomb, Fouad Yousif, Josee Normand, Jose La Rose, Kyle E. Francis, Fernando Suarez, Tim Beck, John Douglas Mcpherson, Lincoln D. Stein, Robert K. Rottapel

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Abstract

Genomic rearrangements are a hallmark of cancer biology and progression, allowing cells to rapidly transform through alterations in regulatory structures, changes in expression patterns, reprogramming of signaling pathways, and creation of novel transcripts via gene fusion events. Though functional gene fusions encoding oncogenic proteins are the most dramatic outcomes of genomic rearrangements, we investigated the relationship between rearrangements evidenced by fusion transcripts and local expression changes in cancer using transcriptome data alone. 9,953 gene fusion predictions from 418 primary serious ovarian cancer tumors were analyzed, identifying depletions of gene fusion breakpoints within coding regions of fused genes as well as an N-terminal enrichment of breakpoints within fused genes. We identified 48 genes with significant fusion-associated upregulation and furthermore demonstrate that significant regional overexpression of intact genes in patient transcriptomes occurs within 1 megabase of 78 novel gene fusions that function as central markers of these regions. We reveal that cancer transcriptomes select for gene fusions that preserve protein and protein domain coding potential. The association of gene fusion transcripts with neighboring gene overexpression supports rearrangements as mechanism through which cancer cells remodel their transcriptomes and identifies a new way to utilize gene fusions as indicators of regional expression changes in diseased cells with only transcriptomic data.

Original languageEnglish (US)
Article number3590
JournalScientific Reports
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2019

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    Krzyzanowski, P. M., Sircoulomb, F., Yousif, F., Normand, J., La Rose, J., E. Francis, K., Suarez, F., Beck, T., Mcpherson, J. D., Stein, L. D., & Rottapel, R. K. (2019). Regional perturbation of gene transcription is associated with intrachromosomal rearrangements and gene fusion transcripts in high grade ovarian cancer. Scientific Reports, 9(1), [3590]. https://doi.org/10.1038/s41598-019-39878-9