Tumor purity adjusted beta values improve biological interpretability of high-dimensional DNA methylation data

PLoS One. 2022 Sep 9;17(9):e0265557. doi: 10.1371/journal.pone.0265557. eCollection 2022.

Abstract

A common issue affecting DNA methylation analysis in tumor tissue is the presence of a substantial amount of non-tumor methylation signal derived from the surrounding microenvironment. Although approaches for quantifying and correcting for the infiltration component have been proposed previously, we believe these have not fully addressed the issue in a comprehensive and universally applicable way. We present a multi-population framework for adjusting DNA methylation beta values on the Illumina 450/850K platform using generic purity estimates to account for non-tumor signal. Our approach also provides an indirect estimate of the aggregate methylation state of the surrounding normal tissue. Using whole exome sequencing derived purity estimates and Illumina 450K methylation array data generated by The Cancer Genome Atlas project (TCGA), we provide a demonstration of this framework in breast cancer illustrating the effect of beta correction on the aggregate methylation beta value distribution, clustering accuracy, and global methylation profiles.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Breast Neoplasms* / genetics
  • Breast Neoplasms* / pathology
  • Cell Count
  • CpG Islands
  • DNA Methylation*
  • Female
  • Genome
  • Humans
  • Tumor Microenvironment

Grant support

Financial support for this study was provided by the Swedish Cancer Society (JS: CAN 2021/1407 and a 2018 Senior Investigator Award, SIA190013), the Mrs Berta Kamprad Foundation (JS: FBKS-2020-5), the Swedish Research Council (JS: 2021-01800), and governmental funding (JS: ALF, grant 2018/40612). MA has received funding by The Gunnar Nilsson Foundation (GN-2018-5), and by the Mrs Berta Kamprad Foundation for cancer research (FBKS-21-27-328). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.