The meeting on ‘Epigenetics and Environmental Origins of Cancer’ was held as a satellite to the 50-year anniversary meeting of the ‘International Agency for Cancer Research’ (IARC) at the agency’s headquarters in Lyon, France. It drew experts and novices in the field alike, reviewing and evaluating how specific environments and lifestyle influences pose cancer risk factors through epigenetic alterations.
In general, most talks were centered on DNA methylation and to a lesser extent on histone modification. Hence, the classic mediators, such as age, inflammation and smoking were discussed, but also some less popular factors such as pollution, diet, fungal toxins and EDCs, were disputed in several presentations.
Other talks focused on theoretical frameworks for epigenetic signatures, such as the establishment of so called ‘metastable epialleles’ – regions of inter-individual variation in DNA methylation that stochastically gain methylation in the early embryo and subsequently maintain those stably during development. An interesting concept presented by AE Teschendorff (see below) was the ‘mitotic clock’ written in DNA methylation that, when accelerated, could be predictive for cancer risk.
Alongside with many talks, it was also impressive to see the amount and size of the study cohorts that have been established internationally to study early human development during pregnancy and after birth, promising a bright future for the field with many more exciting studies to come.
Here some of the meeting’s highlights:
Developmental Reprogramming of the Epigenome by Endocrine Disrupting Compounds (EDC)s
Cheryl Lyn Walker (Institute of Biosciences & Technology, USA)
EDCs are chemicals (for example Bisphenol A, or Diethylstilbestrol) that alter the physiological functions of endogenous hormones and have been shown to disrupt tissue development and increase tumor risk. Cheryl Walker’s lab has now shed light on the epigenetic mechanism involved: Estrogen receptor signaling in the developing uterus activates PI3K/AKT signaling which results in the phosphorylation and inhibition of EZH2 methytransferase – the active subunit of Polycomb Repressive Complex 2 and the ‘writer’ of the repressive histone mark H3K27me3. While H3K27me3 repression decreases, MLL1 activation leads to an increase of the active H3K4me3 histone mark. The effect of those epigenetic changes lead to changes in gene expression that persist in the affected tissues into adulthood and participate in the development of cancer.
The Effect of the Level and Timing of Folic Acid Supplement During the Life Course
MA Burton (University of Southampton, UK)
Multiple talks during the meeting discussed the influence of folic acid on cancer and the associated epigenetic changes. Whereas there is a considerable large body of evidence showing that folic acid deficit increases risk for a variety of cancers (e.g. colon, lung, breast, cervix), there have been only a few recent studies showing that an increased foliate uptake might also be associated with cancer. MA Burton from the University of South Hampton presented a neat mouse study directly testing the effect of folic acid intake at various stages over an animal’s life course. He found tissue specific expression changes of Oct-4, Brca1, Ezh2, Bmi and Suz12 in the mammary glands as well as increase in the cell proliferative marker Ki67, most of which extended past the period of FA supplementation. There question here arises: Good Vitamin B – or bad Vitamin B?
Smoking-associated DNA methylation changes in buccal cells defines a universal cancer signature
That smoking is a high risk factor for developing lung cancer is well known. That it is also also a risk factor for most other cancer types, is an astonishing insight. In a study comparing buccal cells and matched blood cells from 790 smoking women, AE Teschendorff’s group identified a differential DNA methylation signature that not only correlates with lung cancers risk but also with any other major cancer risk across the TCGA’s cancer collection ( still, the association is highest for lung cancer ). A closer look into the signature revealed that the DNA methylation changes partly represent an epigenetic mitotic clock, whose speed is aggravated in response to inflammation, cancer-risk and cancer. This might just mean that most of what we thought to be disease specific changes are actually in principal naturally occurring events.
The developmental origins of inflammatory bowel diseases and colon cancer
R Kellermayer (Baylor College of Medicine, USA)
We are what we eat. How often have we heard that phrase? Over the last years the genomics field has accumulated an impressive amount of evidence on how environmental exposure and diet especially during our early years affect our wellbeing and modulate disease risk by shaping our microbiome composition. Kellermayer and his colleagues have taken a look at IBD (Inflammatory Bowel’s Disease) and YCRC (young colorectal cancer) in respect to maternal and postnatally evolving gut biomes.
They found inflammation driving mucosal DNA methylation changes in pediatric Ulcerative Colitis, a common subtype of IBD, and a change in the microbiome composition of treated and untreated patients. As microbes secret micronutrients that are absorbed by the mucosal epithelium, one of the questions in the field is whether epigenetic changes are caused as a response to inflammation per se (e.g. upregulated proliferation) or as a response to the changed nutritional environment (i.e. micronutrients directly interacting with the epigenome). Kellermayer and others, however, have found that fetal transplantation slows down epithelial proliferation and diminishes inflammation.
**Thanks to Angelika Merkel, PhD from the Centro Nacional de Análisis Genómico (CNAG-CRG) for covering this great meeting for EpiGenie