Professor Martin Widschwendter is exploring whether changes in the epigenome could provide an early warning sign of increased risk of breast, ovarian, endometrial and cervical cancer.
Most cancers are a result of genetic and environmental factors, both of which trigger distinctive epigenetic changes - the chemical modifications of DNA that alter gene activity but have no direct impact on the DNA sequence. Notably, epigenetic abnormalities may appear at an early stage in the development of cancer, and hence may provide an early warning sign of increased cancer risk.
Although epigenetic changes are tissue-specific, Professor Widschwendter is hopeful that single samples - such as routinely collected cervical smears - could provide risk information relevant to multiple cancers. In pilot studies funded by the Eve Appeal* and the EU Framework Programme 7 EpiFemCare project, he and his team analysed DNA methylation patterns at almost 500,000 points in the genome, using normal breast adjacent to breast cancers  and normal Fallopian tube from women who have inherited a BRCA mutation  and found that epigenetic changes are already present even before a cancer is visible under the microscope.
In addition, his team was the first to describe that silencing of specific genes (e.g. HAND2) triggers endometrial cancer and that detection of epigenetically altered DNA is able to identify women with endometrial cancer with a very high accuracy .
These encouraging results laid the foundation for the £9m FORECEE programme, funded through the EU's Horizon 2020 initiative . Its main aim is to establish whether risk prediction might be possible for four different women's cancers - breast, cervical, endometrial and ovarian cancer - based on epigenomic analysis of cervical smear samples.
Initially, epigenomic patterns in cervical smear cells from women recently diagnosed with cancer but yet to start treatment are being compared with those from similar women without a cancer diagnosis. Potential signatures of the four cancers will be validated by analysis of banked smear samples from Swedish women who went on to develop cancer.
The epigenomic results will be combined with information about other potential risk factors, such as genetic variants implicated in each of the four cancers, background information about women (such as age), and, for cervical and ovarian cancer, the make up of cervical bacterial populations (the microbiome). Collectively, these factors will feed into an algorithm that will generate a risk score for each of the four cancers.
The risk score could then be used to guide more personalised follow-up. Women at high risk of breast cancer, for example, might be recommended for intensive mammography (conversely, those at low risk might not need to be screened at all). Progesterone-targeting drugs for prevention might also be appropriate .
As well as technical feasibility, the FORCEE study is also engaging with multiple stakeholders to examine the practicalities and economics of implementation of screening. Since a key output is likely to be a risk score, it is also discussing perceptions of risk with women, including the thresholds of risk they would consider important when deciding what action to take.
Finally, Professor Widschwendter points out a further advantage of epigenomic assessments. Unlike mutations, epigenetic modifications are dynamic, and reduced exposure to risk factors can reverse epigenetic abnormalities, as illustrated by his group's work on smoking . Epigenomic assessments could therefore provide markers of changing risk over time, as well as an indication of the success of preventive strategies or treatments.
* The Eve Appeal is a charity that raises awareness of, and supports research into, women-specific cancers. It has a unique focus on early detection, risk prediction and prevention, and much of its research funding is supporting innovative programmes in UCL's Department of Women's Cancer, led by Professor Widschwendter.
- Teschendorff AE et al. DNA methylation outliers in normal breast tissue identify field defects that are enriched in cancer. Nat Commun. 2016;7:10478.
- Bartlett TE et al. Epigenetic reprogramming of fallopian tube fimbriae in BRCA mutation carriers defines early ovarian cancer evolution. Nat Commun. 2016;7:11620.
- Jones A et al. Role of DNA methylation and epigenetic silencing of HAND2 in endometrial cancer development. PLoS Med. 2013;10(11):e1001551.
- Widschwendter M et al. Epigenome-based cancer risk prediction: rationale, opportunities and challenges. Nat Rev Clin Oncol. 2018 Feb 27. doi: 10.1038/nrclinonc.2018.30. [Epub ahead of print]
- Widschwendter M et al. Osteoprotegerin (OPG), the endogenous inhibitor of receptor activator of NF-κB ligand (RANKL), is dysregulated in BRCA mutation carriers. EBioMedicine. 2015;2(10):1331-9.
- Teschendorff AE et al. Correlation of smoking-associated DNA methylation changes in buccal cells with dna methylation changes in epithelial cancer. JAMA Oncol. 2015;1(4):476-85.