Abstract
BackgroundCancer research to date has largely focused on somatically acquired genetic aberrations. In contrast, the degree to which germline, or inherited, variation contributes to tumorigenesis remains unclear, possibly due to a lack of accessible germline variant data. Here we called germline variants on 9618 cases from The Cancer Genome Atlas (TCGA) database representing 31 cancer types.ResultsWe identified batch effects affecting loss of function (LOF) variant calls that can be traced back to differences in the way the sequence data were generated both within and across cancer types. Overall, LOF indel calls were more sensitive to technical artifacts than LOF Single Nucleotide Variant (SNV) calls. In particular, whole genome amplification of DNA prior to sequencing led to an artificially increased burden of LOF indel calls, which confounded association analyses relating germline variants to tumor type despite stringent indel filtering strategies. The samples affected by these technical artifacts include all acute myeloid leukemia and practically all ovarian cancer samples.ConclusionsWe demonstrate how technical artifacts induced by whole genome amplification of DNA can lead to false positive germline-tumor type associations and suggest TCGA whole genome amplified samples be used with caution. This study draws attention to the need to be sensitive to problems associated with a lack of uniformity in data generation in TCGA data.
Highlights
Cancer research to date has largely focused on somatically acquired genetic aberrations
Technical heterogeneity in The Cancer Genome Atlas (TCGA) whole exome sequence (WXS) Data Generation We obtained TCGA WXS data from Cancer genomics hub (CGhub) in the form of reads aligned to the human reference genome (BAM files) [17]
From the Binary alignment/map (BAM) files and available metadata we identified seven technical sources of variation in the way the sequence data were generated: tissue source of normal DNA, exome capture kit, whole genome amplification of DNA prior to sequencing (WGA), sequencing center, sequencing technology, Burrows wheeler aligner (BWA) version, and capture efficiency (C20X) (Additional file 1: Figure S1, Additional file 2)
Summary
Cancer research to date has largely focused on somatically acquired genetic aberrations. It is known that bMMRD predisposes to childhood cancer, but it was further demonstrated that acquisition of somatic mutations in polymerase genes (POLE, POLD1) led to a hypermutated phenotype in Buckley et al BMC Genomics (2017) 18:458 childhood brain tumors [8]. This demonstrates a synergistic interaction between germline variation and somatic mutation. A comprehensive study of breast cancer whole genomes identified a somatic copy number profile signature associated with BRCA1 inactivation [9] This profile was associated with either inactivation of BRCA1 in the tumor via mutation or promoter hypermethylation, or via inherited germline variants. This shows that somatic mutation and germline variation can both influence tumor phenotype
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