Pan-cancer analysis reveals technical artifacts in TCGA germline variant calls

BMC Genomics

Research Article

Kunal Bhutani¹  Kristopher A. Standish²  Alexandra R. Buckley²  Trey Ideker³  Hannah Carter³  Nicholas J. Schork⁴  Roger S. Lasken⁵  Olivier Harismendy⁶ 

[1] Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, CA, USA;Bioinformatics and Systems Biology Sciences Graduate Program, University of California, San Diego, La Jolla, CA, USA;Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, CA, USA;J. Craig Venter Institute, La Jolla, CA, USA;Division of Medical Genetics, Department of Medicine, University of California San Diego, La Jolla, CA, USA;Moores Cancer Center, University of California San Diego, La Jolla, CA, USA;Cancer Cell Map Initiative (CCMI), University of California San Diego, La Jolla, CA, USA;J. Craig Venter Institute, La Jolla, CA, USA;The Translational Genomics Research Institute, Phoenix, AZ, USA;Microbial Genomics Program, J. Craig Venter Institute, La Jolla, CA, USA;Moores Cancer Center, University of California San Diego, La Jolla, CA, USA;Division of Biomedical Informatics, Department of Medicine, University of California San Diego, La Jolla, CA, USA;

关键词: Cancer genomics;    TCGA;    Cancer germline;    Whole exome sequencing;    Variant calling;    GATK;    Batch effects;    Whole genome amplification;    Variant annotation;    Genetic association testing;   

DOI  :  10.1186/s12864-017-3770-y

 received in 2017-03-14, accepted in 2017-05-07,  发布年份 2017

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY   
© The Author(s). 2017