Germline Structural Variation Globally Impacts the Cancer Transcriptome Including Disease-Relevant Genes

Authors

Fengju Chen
Yiqun Zhang
Fritz J Sedlazeck
Chad J Creighton

Publication Date

3-19-2024

Journal

Cell Reports Medicine

DOI

10.1016/j.xcrm.2024.101446

PMID

38442712

PMCID

PMC10983041

PubMedCentral® Posted Date

3-4-2024

PubMedCentral® Full Text Version

Post-Print

Published Open-Access

yes

Keywords

Humans, Transcriptome, Neoplasms, RNA, Germ Cells, cancer, structural variation, structural variants, germline, PCAWG, Pan-Cancer Analysis of Whole Genomes, Whole Genome Sequencing, GWAS, eQTL, expression quantitative trait loci

Abstract

Germline 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.

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