Germline structural variations involving the pediatric brain tumor transcriptome include disease-relevant and...

Germline Structural Variants (SVs) represent an important source of genetic diversity, in large part due to their influence on gene transcription. It is necessary to systematically catalog germline SVs and their associated impacted genes across different cohorts and tissue and cellular contexts, including pediatric brain or Central Nervous System (CNS) tumors.

We combined RNA with whole genome sequencing across 1430 pediatric brain or CNS tumor patients from the Children's Brain Tumor Network. We set out to systematically identify genes for which the proximity of germline SVs was recurrently and significantly associated with differential expression in the tumor sample across multiple patients.

For hundreds of genes, recurrent and common germline SV breakpoints within 1 Mb were associated with higher or lower expression in tumors spanning various histologic types. Some germline SV-expression associations involved gene deletion or disruption, while others represented cis-regulatory alterations. Rare and singleton SVs disrupting DNA repair-related and mitochondrial-related genes collectively involved 2.7 and 4.7% of patients, respectively. Genes with germline SV breakpoint patterns and expression associated with patients of African ancestry included ACOT1 and CRYBB2P1. Genes with germline SV breakpoint patterns and expression associated with patient survival included ACTG1 and AHRR. Genes altered in association with both somatic and germline SVs included HGF and BCOR.

Our results capture a class of phenotypic variation at work in the setting of pediatric brain tumors, including genes with cancer roles.