title: The multi-omic landscape of transcription factor inactivation in cancer.
abstract: Hypermethylation of transcription factor promoters bivalently marked in stem cells is a cancer hallmark. However, the biological significance of this observation for carcinogenesis is unclear given that most of these transcription factors are not expressed in any given normal tissue.
  
  
  
  We analysed the dynamics of gene expression between human embryonic stem cells, fetal and adult normal tissue, as well as six different matching cancer types. In addition, we performed an integrative multi-omic analysis of matched DNA methylation, copy number, mutational and transcriptomic data for these six cancer types.
  
  
  
  We here demonstrate that bivalently and PRC2 marked transcription factors highly expressed in a normal tissue are more likely to be silenced in the corresponding tumour type compared with non-housekeeping genes that are also highly expressed in the same normal tissue. Integrative multi-omic analysis of matched DNA methylation, copy number, mutational and transcriptomic data for six different matching cancer types reveals that in-cis promoter hypermethylation, and not in-cis genomic loss or genetic mutation, emerges as the predominant mechanism associated with silencing of these transcription factors in cancer. However, we also observe that some silenced bivalently/PRC2 marked transcription factors are more prone to copy number loss than promoter hypermethylation, pointing towards distinct, mutually exclusive inactivation patterns.
  
  
  
  These data provide statistical evidence that inactivation of cell fate-specifying transcription factors in cancer is an important step in carcinogenesis and that it occurs predominantly through a mechanism associated with promoter hypermethylation.
authors: CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Chinese Academy of Sciences, Shanghai Institute for Biological Sciences, 320 Yue Yang Road, Shanghai, 200031, China. a.teschendorff@ucl.ac.uk.|Statistical Cancer Genomics, UCL Cancer Institute, University College London, Paul O'Gorman Building, 72 Huntley Street, London, WC1E 6BT, UK. a.teschendorff@ucl.ac.uk.|Department of Women's Cancer, University College London, 74 Huntley Street, London, WC1E 6BT, UK. a.teschendorff@ucl.ac.uk.
authors: Andrew E
authors: AE
authors: Teschendorff
authors: CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Chinese Academy of Sciences, Shanghai Institute for Biological Sciences, 320 Yue Yang Road, Shanghai, 200031, China.
authors: Shijie C
authors: SC
authors: Zheng
authors: Medical Genomics, UCL Cancer Institute, University College London, Paul O'Gorman Building, 72 Huntley Street, London, WC1E 6BT, UK.
authors: Andy
authors: A
authors: Feber
authors: CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Chinese Academy of Sciences, Shanghai Institute for Biological Sciences, 320 Yue Yang Road, Shanghai, 200031, China.
authors: Zhen
authors: Z
authors: Yang
authors: Medical Genomics, UCL Cancer Institute, University College London, Paul O'Gorman Building, 72 Huntley Street, London, WC1E 6BT, UK.
authors: Stephan
authors: S
authors: Beck
authors: Department of Women's Cancer, University College London, 74 Huntley Street, London, WC1E 6BT, UK.
authors: Martin
authors: M
authors: Widschwendter
mesh_terms: D000328:Adult; D063646:Carcinogenesis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019295:Computational Biology; D018899:CpG Islands; D056915:DNA Copy Number Variations; D019175:DNA Methylation; D005333:Fetus; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D000066449:Human Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D009369:Neoplasms / Q000145:classification / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D063151:Polycomb Repressive Complex 2 / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D009363:Neoplasm Proteins; D014157:Transcription Factors; D063151:Polycomb Repressive Complex 2