UCL Institute for Women's Health (IfWH)

Epigenetics in Cancer

Lead: Professor Martin Widschwendter

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 human genes. Methylation of these CpG islands is usually associated with silencing of the respective gene. Compared to major efforts that are ongoing to identify genetic variants, epigenetic analysis has, until now, lagged behind due to a lack of adequate technologies and data. Recent development of advanced epigenetic analysis tools will significantly facilitate the discovery and development of DNAm biomarkers.

The epigenetics team is focused on the study of DNA methylation in women’s cancers including, ovarian, breast, endometrial and cervical cancer. We have observed that many genes abnormally silenced in cancer cells are also targets for a family of developmental regulatory proteins known as Polycomb Group proteins (PcG) required to transiently silence genes in stem cells. Based on this observation, we have proposed a stem cell model of carcinogenesis (Figure 1) in which DNA methyltransferase enzymes cross talk with PcG proteins to permanently silence specific genes in stem cells. The affected stem cells are thereby locked into a perpetual state of self-renewal, and accumulation of epigenetic and genetic mutations over time increases the propensity of these cells to become cancerous. We have based our research aims around this concept, which consist of four Programs of Research:

Program P1:
Identification of the influences that drive epigenetic alterations in unaffected cells (transgenerational, developmental, environmental and genetic)

Program P2:
Identification of DNAm based risk & early detection markers for cancer (in unaffected cells and prediagnostic samples)

Program P3:
Identification of aberrant DNAm signatures in body fluids i.e. whole blood, serum and vaginal secretions

Program P4:
Investigation of aberrant DNAm signatures in tumours for the purposes of prediction and prognosis