Non-cancer-related pathogenic germline variants and expression consequences in ten-thousand cancer genomes

Abstract

Background: DNA sequencing is increasingly incorporated into the routine care of cancer patients, many of whom also carry inherited, moderate/high-penetrance variants associated with other diseases. Yet, the prevalence and consequence of such variants remain unclear. Methods: We analyzed the germline genomes of 10,389 adult cancer cases in the TCGA cohort, identifying pathogenic/likely pathogenic variants in autosomal-dominant genes, autosomal-recessive genes, and 59 medically actionable genes curated by the American College of Molecular Genetics (i.e., the ACMG 59 genes). We also analyzed variant- and gene-level expression consequences in carriers. Results: The affected genes exhibited varying pan-ancestry and population-specific patterns, and overall, the European population showed the highest frequency of pathogenic/likely pathogenic variants. We further identified genes showing expression consequence supporting variant functionality, including altered gene expression, allelic specific expression, and mis-splicing determined by a massively parallel splicing assay. Conclusions: Our results demonstrate that expression-altering variants are found in a substantial fraction of cases and illustrate the yield of genomic risk assessments for a wide range of diseases across diverse populations.