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Epigenetics provides an explanation for differences in susceptibility to disease between monozygotic twins or cloned animals despite identical DNA sequences. In eukaryotic cells epigenetic modifications are encoded via two primary modes which differ dramatically in their information content: Histone modification and DNA methylation (DNAm). The process of DNAm involves the addition of a methylation group to the fifth carbon of the cytosine ring to form 5-methylcytosine (5meC). Methylation of cytosine occurs when the base precedes a guanosine in the DNA sequence. These ‘CpG dinucleotides’ are uncommon in the vertebrate genome except in small stretches of DNA termed CpG islands, usually 500 to 2,000 base pairs in length, that are frequently located in and around the transcription start sites of genes. Methylation of these CpG islands is usually associated with silencing of the respective gene.
Over the past few years the epigenetic landscape has become extensively studied and more detailed definitions established. CpG island ‘shores’ have been described (CpG clusters that occur outside and up to 2Kb of CpG islands) and have been shown to be important in tissue specific gene expression but also differential methylation occurring in cancer. The tissue specific nature of DNA methylation means that methylation analyses using samples from established biobanks, i.e. whole blood collections would be ineffective owing to cellular heterogeneity of white blood cell types. Consequently, novel prospective tissue specific collections (EPIFEMPRO and EPIFEMGEN) are required to facilitate the optimal discovery of cancer specific differentially methylated regions (DMRs) for clinical development.
The Epigenetic Stem Cell Model of Cancer
In 2007, we and others, published evidence for an ‘epigenetic stem cell model’ of cancer. Embryonic stem cells rely on Polycomb group (PcG) proteins to reversibly repress genes required for differentiation. On cellular differentiation specific gene sets are re-expressed after removal of the PcG proteins from these genes.
Epigenetic Stem Cell Model
We reported (Widschwendter et al Nature Genetics 2007) that stem cell Polycomb group targets are up to 12-fold more likely to have cancer-specific promoter DNA hypermethylation than non-targets (See Figure 1), supporting a stem cell origin of cancer in which reversible gene repression is replaced by permanent silencing as a consequence of this acquired DNA methylation. The model further suggests that as a result of this permanent silencing the stem cell persistently self-replicates owing to an inability to differentiate increasing the risk of subsequent malignant transformation. The observation of an overlap of cancer specific differential methylation and tissue specific methylation at CpG island shores further supports this model.
EFI-FEM (Epigenetics and Female Cancer) Research Programmes
EPIFEMCARE - Epigenetics For Female Personalised Cancer Care. EPIFEMCARE is funded by the EU FP7 programme and is an academic-industrial collaboration that aims to develop new methods for screening, diagnosis and personalised treatment of breast and ovarian cancers.
EPIFEMPRO - EpiFemPro (Epigenetics for Female Malignancies – Prediction of Risk programme) is focused on the discovery of epigenetic biomarkers that determine a woman’s risk to develop a women specific cancer.
EPIFEMGEN - EpiFemGen (Epigenetics of Female Malignancies with Genetic Predisposition): This element of the EpiFem programme involves the study of hormonal, genetic and epigenetic changes in cells and body fluids of women who are known to be genetically predisposed to breast, ovarian and womb/uterine cancers.