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Pan-Cancer Analysis Reveals Technical Artifacts in The Cancer Genome Atlas (TCGA) Germline Variant Calls

By Alexandra R Buckley, Kristopher A Standish, Kunal Bhutani, Trey Ideker, Hannah W Carter, Olivier Harismendy, Ali Torkamani

Posted 07 Dec 2016
bioRxiv DOI: 10.1101/092163 (published DOI: 10.1186/s12864-017-3770-y)

The degree to which germline variation drives cancer development and shapes tumor phenotypes remains largely unexplored, possibly due to a lack of large scale publicly available germline data for a cancer cohort. Here we called germline variants on 9,618 cases from The Cancer Genome Atlas (TCGA) database representing 31 cancer types. We 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. Due to the inherent noise we chose to remove all 614 amplified DNA samples, including all acute myeloid leukemia and virtually all ovarian cancer samples, from the final dataset. This study demonstrates how insufficient quality control can lead to false positive germline-tumor type associations and draws attention to the need to be sensitive to problems associated with a lack of uniformity in data generation in TCGA data.

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