Constructing germline research cohorts from the discarded reads of clinical tumor sequences

Abstract

BackgroundHundreds of thousands of cancer patients have had targeted (panel) tumor sequencing to identify clinically meaningful mutations. In addition to improving patient outcomes, this activity has led to significant discoveries in basic and translational domains. However, the targeted nature of clinical tumor sequencing has a limited scope, especially for germline genetics. In this work, we assess the utility of discarded, off-target reads from tumor-only panel sequencing for recovery of genome-wide germline genotypes through imputation. MethodsWe develop a framework for inference of germline variants from tumor panel sequencing, including imputation, quality control, inference of genetic ancestry, germline polygenic risk scores, and HLA alleles. We benchmark our framework on 833 individuals with tumor sequencing and matched germline SNP array data. We then apply our approach to a prospectively collected panel sequencing cohort of 25,889 tumors. ResultsWe demonstrate high to moderate accuracy of each inferred feature relative to direct germline SNP array genotyping: individual common variants were imputed with a mean accuracy (correlation) of 0.86; genetic ancestry was inferred with a correlation of >0.98; polygenic risk scores were inferred with a correlation of >0.90; and individual HLA alleles were inferred with correlation of >0.89. We demonstrate a minimal influence on accuracy of somatic copy number alterations and other tumor features. We showcase the feasibility and utility of our framework by analyzing 25,889 tumors and identifying relationships between genetic ancestry, polygenic risk, and tumor characteristics that could not be studied with conventional data. ConclusionsWe conclude that targeted tumor sequencing can be leveraged to build rich germline research cohorts from existing data, and make our analysis pipeline publicly available to facilitate this effort.