Chen, FengjuZhang, YiqunSedlazeck, Fritz J.Creighton, Chad J.2024-08-092024-08-092024Chen, F., Zhang, Y., Sedlazeck, F. J., & Creighton, C. J. (2024). Germline structural variation globally impacts the cancer transcriptome including disease-relevant genes. Cell Reports Medicine, 5(3). https://doi.org/10.1016/j.xcrm.2024.101446https://hdl.handle.net/1911/117628Germline variation and somatic alterations contribute to the molecular profile of cancers. We combine RNA with whole genome sequencing across 1,218 cancer patients to determine the extent germline structural variants (SVs) impact expression of nearby genes. For hundreds of genes, recurrent and common germline SV breakpoints within 100 kb associate with increased or decreased expression in tumors spanning various tissues of origin. A significant fraction of germline SV expression associations involves duplication of intergenic enhancers or 3′ UTR disruption. Genes altered by both somatic and germline SVs include ATRX and CEBPA. Genes essential in cancer cell lines include BARD1 and IRS2. Genes with both expression and germline SV breakpoint patterns associated with patient survival include GCLM. Our results capture a class of phenotypic variation at work in the disease setting, including genes with cancer roles. Specific germline SVs represent potential cancer risk variants for genetic testing, including those involving genes with targeting implications.engExcept where otherwise noted, this work is licensed under a Creative Commons Attribution (CC BY) license.  Permission to reuse, publish, or reproduce the work beyond the terms of the license or beyond the bounds of fair use or other exemptions to copyright law must be obtained from the copyright holder.Journal articlePIIS2666379124000697https://doi.org/10.1016/j.xcrm.2024.101446