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Cited by 191Epigenetics and DNA MethylationGenomics and Chromatin DynamicsGenetic Syndromes and Imprinting

Tissue of origin determines cancer-associated CpG island promoter hypermethylation patterns

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Sproul, Duncan, Kitchen, Robert R, Nestor, Colm E, Dixon, J Michael, Sims, Andrew H, Harrison, David J, Ramsahoye, Bernard H, Meehan, Richard R·2012·Genome Biology
DOI 10.1186/gb-2012-13-10-r84PMC PMC3491412
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Abstract

Background: Aberrant CpG island promoter DNA hypermethylation is frequently observed in cancer and is believed to contribute to tumor progression by silencing the expression of tumor suppressor genes. Previously, we observed that promoter hypermethylation in breast cancer reflects cell lineage rather than tumor progression and occurs at genes that are already repressed in a lineage-specific manner. To investigate the generality of our observation we analyzed the methylation profiles of 1,154 cancers from 7 different tissue types. Results: We find that 1,009 genes are prone to hypermethylation in these 7 types of cancer. Nearly half of these genes varied in their susceptibility to hypermethylation between different cancer types. We show that the expression status of hypermethylation prone genes in the originator tissue determines their propensity to become hypermethylated in cancer; specifically, genes that are normally repressed in a tissue are prone to hypermethylation in cancers derived from that tissue. We also show that the promoter regions of hypermethylation-prone genes are depleted of repetitive elements and that DNA sequence around the same promoters is evolutionarily conserved. We propose that these two characteristics reflect tissue-specific gene promoter architecture regulating the expression of these hypermethylation prone genes in normal tissues. Conclusions: As aberrantly hypermethylated genes are already repressed in pre-cancerous tissue, we suggest that their hypermethylation does not directly contribute to cancer development via silencing. Instead aberrant hypermethylation reflects developmental history and the perturbation of epigenetic mechanisms maintaining these repressed promoters in a hypomethylated state in normal cells.

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Authors
Sproul, D., Kitchen, R. R., Nestor, C. E., Dixon, J. M., Sims, A. H., Harrison, D. J., Ramsahoye, B. H., & Meehan, R. R.
Affiliations
  • Western General Hospital (GB)
  • University of St Andrews (GB)
Corresponding author
Meehan, Richard R
ORCID
Venue
Genome Biology
Publisher
Springer Science and Business Media LLC
Published
2012-10-03
Volume
13
Issue
10
Pages
R84-R84
ISSN
  • 1465-6906 (ISSN-L)
  • 1474-760X
DOI
10.1186/gb-2012-13-10-r84
PMC
PMC3491412
OpenAlex
W2077919940
Cited by
191
References
83
Citations by year
2026: 5 · 2025: 10 · 2024: 11 · 2023: 14 · 2022: 6 · 2021: 16 · 2020: 10 · 2019: 11 · 2018: 7 · 2017: 20 · 2016: 19 · 2015: 17 · 2014: 25 · 2013: 18 · 2012: 2
FWCI
7.96
Type
journal article
Language
en
Open access
Licence
Locations
  • Genome biology (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • KTH Publication Database DiVA (KTH Royal Institute of Technology) (submittedVersion, other-oa)
  • Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
  • St Andrews Research Repository (St Andrews Research Repository) (submittedVersion, cc-by)
Funders
Medical Research Council
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Syndromes and Imprinting
Keywords
cancer epigenetics, tissue of origin, cell lineage, tumor suppressor gene silencing, repetitive elements, evolutionary conservation, promoter architecture, epigenetic maintenance
MeSH terms
Brain, Colon, Humans, Lung, Neoplasms, Organ Specificity, Promoter Regions, Genetic, Gene Expression Regulation, Neoplastic, CpG Islands, DNA Methylation, Genes, Neoplasm

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