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The multi-omic landscape of transcription factor inactivation in cancer

Teschendorff, AE; Zheng, SC; Feber, A; Yang, Z; Beck, S; Widschwendter, M; (2016) The multi-omic landscape of transcription factor inactivation in cancer. Genome Medicine , 8 , Article 89. 10.1186/s13073-016-0342-8. Green open access

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Abstract

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Type: Article
Title: The multi-omic landscape of transcription factor inactivation in cancer
Open access status: An open access version is available from UCL Discovery
DOI: 10.1186/s13073-016-0342-8
Publisher version: http://dx.doi.org/10.1186/s13073-016-0342-8
Language: English
Additional information: This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Keywords: Comprehensive molecular characterization, pluripotent stem-cells, dna methylation, tumor-suppressor, hepatocyte differentiation, gene-expression, biliary cancer, hypermethylation, gata4, lung
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Cancer Bio
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Surgery and Interventional Sci
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL EGA Institute for Womens Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL EGA Institute for Womens Health > Womens Cancer
URI: https://discovery.ucl.ac.uk/id/eprint/1514773
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