Translational Research Centre
The Translational Research Centre within the Department of Women’s Cancer, IfWH, has a specialist interest in increasing understanding of the development of women specific cancer, both in women who inherit known genetic mutations, but also in the vast majority of women who do not. Since genetic predisposition only accounts for a limited proportion of women specific cancer, e.g. BRCA mutations account for approximately 5-10% of breast cancer, and 10-15% of ovarian cancer cases, deciphering the role of our environment and lifestyle in cancer formation is fundamental in allowing researchers and clinicians to develop clinical tests of benefit to ALL women. The translational research group has a research emphasis on the ‘epigenetics’ of women specific cancer because the ‘epigenome’ is considered to be the interface between our environment and our genes and therefore potentially explains the development of non-inherited disease. For a video explanation of epigenetics and cancer please click here.
We study all four major women specific cancers: ovarian, breast, endometrial and cervical cancer, and have numerous ongoing research activities, including our ‘EPI-FEM’ programme of research designed to generate new knowledge about women specific cancer and facilitate development of non-invasive tests for:
- Risk Prediction – identifying epigenetic and other biomarkers that are associated with a woman’s risk to develop cancer in the future.
- Early Detection – wherever possible, detecting cancer at an earlier stage will increase chances of recovery and ultimately survival.
- Treatment Prediction – finding ways to discriminate between patients who will benefit from specific treatment versus those who will not means that more women will receive appropriate treatment from which they will benefit on an individual level.
To achieve these aims it is crucial that we understand the origins of cancer. The cell from which breast, endometrial and cervical cancer arise is well understood but that for ovarian cancer is less so. Ovarian cancer is all too often diagnosed at late stage when survival is poor and hence it is difficult to identify and study early cellular morphology in this disease. The complexity of ovarian cancer suggests that this disease arises from multiple cellular origins and not necessarily from the cells surrounding the ovary. Molecular, histological and epidemiological evidence suggests that the origin of ovarian cancer potentially resides in the Mullerian epithelium (See Figure 1). Increased understanding and clarification of the origins of ovarian cancer through epigenetic analysis is a research cornerstone of The Women’s Cancer Translational Research Group.
Epigenetics – Lay Version
Epigenetics literally means ‘upon’ genetics and describes a series of biological processes that affect how our genes behave. Epigenetic processes play a vital role in early and healthy development and are responsible for the cellular diversity throughout our bodies, i.e. whilst all of our cells possess an identical genetic code they both appear and function differently, e.g. our cells in our skin look different and perform a different purpose to those in our bones. This is possible because epigenetic mechanisms turn specific sets of genes ‘on’ and ‘off’ and this determines the cell type. Genes – stretches of DNA that encode a specific protein – are switched ‘on’ and ‘off’ through epigenetic control of gene accessibility, e.g. genes within exposed areas of DNA are considered active (switched ‘on’) whilst those in more densely compacted regions are considered to be inactive (‘switched off’). Epigenetics is therefore important in maintaining health but can become deregulated in diseases including cancer. Click here for a video explaining the concept of epigenetics and cancer.
Epigenetic mechanisms are collectively referred to as the ‘epigenome’ and include one of the best studied epigenetic processes called, ‘DNA methylation’. DNA methylation has been shown to be dramatically altered in cancer tissue and can often be found in normal tissue in areas adjacent to cancer. Furthermore epigenetic mechanisms are responsive to our environment which in turn affects our risk to develop cancer and other disease. Our environmental exposures during development in the womb and after birth, as well as our diet and lifestyle all affect our cancer risk (See Figure 1). Accumulation of epigenetic changes as we age could therefore explain the vast majority of cancer that occurs in women who do not carry a predisposing genetic mutation and furthermore represent valuable biomarkers for disease risk.
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.
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.
Prof Martin Widschwendter
Head of Department of Women's Cancer, Consultant Gynaecological Oncologist
Miss Allison Jones
Dr Kantaraja Chindera
Dr Iona Evans
Dr Rania Fourkala
Mrs Shohreh Ghazali
Dr Daniel Reisel
Funding and Support
The Eve Appeal
The Eve Appeal is a registered charity, formed in 2005. Since then, they have worked hard to raise money to fund the world-class research programme at the Department of Women's Cancer based at University College London (UCL).
The Department's vital and much-needed research will benefit women in the UK and worldwide.
Eve Appeal www.eveappeal.org.uk/
The European Commission Framework Programme 7 (FP7)
EpifemCare (Epigenetics for Female personalized cancer Care)
The EpiFemCare project is being conducted by a pan-European consortium, which was formed in November 2012, and involves 5 European countries. The project is establishing and clinically validating a series of blood tests based upon biochemical changes detected in DNA released from ovarian and breast cancers.
National Institute for Health and Research (NIHR)
Achieving The Translational Potential Of The UCL-UKCTOCS Cohort And Biobank In Disease Risk Assessment, Screening And Prognostic Prediction
General Programme Links
EU FP7 EPIFEMCARE
Page last modified on 20 mar 14 09:53