Abstract
BackgroundDNA 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.MethodsWe 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.ResultsThe 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.ConclusionsOur 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.
Highlights
DNA sequencing is increasingly incorporated into the routine care of cancer patients, many of whom carry inherited, moderate/high-penetrance variants associated with other diseases
We systematically investigated pathogenic or likely pathogenic genetic variants in human disease genes not related to cancer or cancer-related syndromes, abbreviated as NC Non-cancer-related pathogenic/likely pathogenic variants (P/LPs), in 10,389 cancer cases across multiple ancestries
NC P/LPs in 10,389 cancer cases We identified NC P/LPs in the The Cancer Genome Atlas (TCGA) cohort of 10,389 adult cancer cases across different ancestral populations
Summary
DNA sequencing is increasingly incorporated into the routine care of cancer patients, many of whom carry inherited, moderate/high-penetrance variants associated with other diseases. In 2015, the American College of Molecular Genetics and Association for Molecular Pathology (ACMG/AMP) established criteria for genetic variant classification on a spectrum from pathogenic to benign as a guide for consistent clinical interpretation [1]. Published large-scale studies that evaluate expression consequences of genomic variants mostly represent European populations with available multi-omics data like GenotypeTissue Expression (GTEx) project [7,8,9,10]. The Cancer Genome Atlas (TCGA) project includes DNA/RNA-Seq data for over 10 K cancer cases of multiple ancestries [11], providing an opportunity to dissect the expression consequences of variants
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