Tissue of Origin Determines Cancer-associated CpG Island Promoter Hypermethylation Patterns

It has been proposed that DNA methylation of tumour suppressor genes is a key event in carcinogenesis, driving cells to become cancer cells. In previous work (PMID: 21368160), the authors could not identify de novo methylated genes in breast cancer that fitted with this view. Instead they implicated aberrant DNA methylation as a marker of cell lineage rather than tumour progression.  In most cases, DNA methylation did not appear to cause the repression with which it is associated. In their present work they extended this observation to 6 additional tumour types. Their recent analysis supports the view that the bulk of aberrant promoter hypermethylation in cancer occurs predominantly at genes that are repressed in pre-cancerous tissue and therefore does not directly contribute to tumour progression by silencing tumour suppressor genes. This epigenetic alteration is common to all the cancer types, but does not result in a universal set of methylated genes, implying that a common mechanism is responsible for promoter hypermethylation at distinct sets of repressed genes in different cancers. Future research in this field should, therefore, focus on confirming whether aberrant hypermethylation does directly suppress rare ‘driver’ genes and if the mechanism responsible for driver gene suppression is the same or different to that acting at already repressed target genes.

This study contributes to the provocative question list raised by the National Cancer Institute (http://provocativequestions.nci.nih.gov/rfa). Specifically question, PQB – 2; As we improve methods to identify epigenetic changes that occur during tumor development, can we develop approaches to discriminate between "driver" and "passenger" epigenetic events?

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Author list: Duncan Sproul, Robert R Kitchen, Colm E Nestor, J Michael Dixon, Andrew H Sims, David J Harrison, Bernard H Ramsahoye and Richard R Meehan

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

Journal: Genome Biology

 

Summary

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.