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Substantial batch effects in TCGA exome sequences undermine pan-cancer analysis of germline variants

Authors
  • Rasnic, Roni1
  • Brandes, Nadav1
  • Zuk, Or2
  • Linial, Michal3
  • 1 The Hebrew University of Jerusalem, The Rachel and Selim Benin School of Computer Science and Engineering, Jerusalem, Israel , Jerusalem (Israel)
  • 2 The Hebrew University of Jerusalem, Department of Statistics, Jerusalem, Israel , Jerusalem (Israel)
  • 3 The Hebrew University of Jerusalem, Department of Biological Chemistry, Institute of Life Sciences, Jerusalem, Israel , Jerusalem (Israel)
Type
Published Article
Journal
BMC Cancer
Publisher
Springer (Biomed Central Ltd.)
Publication Date
Aug 07, 2019
Volume
19
Issue
1
Identifiers
DOI: 10.1186/s12885-019-5994-5
Source
Springer Nature
Keywords
License
Green

Abstract

BackgroundIn recent years, research on cancer predisposition germline variants has emerged as a prominent field. The identity of somatic mutations is based on a reliable mapping of the patient germline variants. In addition, the statistics of germline variants frequencies in healthy individuals and cancer patients is the basis for seeking candidates for cancer predisposition genes. The Cancer Genome Atlas (TCGA) is one of the main sources of such data, providing a diverse collection of molecular data including deep sequencing for more than 30 types of cancer from > 10,000 patients.MethodsOur hypothesis in this study is that whole exome sequences from blood samples of cancer patients are not expected to show systematic differences among cancer types. To test this hypothesis, we analyzed common and rare germline variants across six cancer types, covering 2241 samples from TCGA. In our analysis we accounted for inherent variables in the data including the different variant calling protocols, sequencing platforms, and ethnicity.ResultsWe report on substantial batch effects in germline variants associated with cancer types. We attribute the effect to the specific sequencing centers that produced the data. Specifically, we measured 30% variability in the number of reported germline variants per sample across sequencing centers. The batch effect is further expressed in nucleotide composition and variant frequencies. Importantly, the batch effect causes substantial differences in germline variant distribution patterns across numerous genes, including prominent cancer predisposition genes such as BRCA1, RET, MAX, and KRAS. For most of known cancer predisposition genes, we found a distinct batch-dependent difference in germline variants.ConclusionTCGA germline data is exposed to strong batch effects with substantial variabilities among TCGA sequencing centers. We claim that those batch effects are consequential for numerous TCGA pan-cancer studies. In particular, these effects may compromise the reliability and the potency to detect new cancer predisposition genes. Furthermore, interpretation of pan-cancer analyses should be revisited in view of the source of the genomic data after accounting for the reported batch effects.

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