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INFLUENCE OF RISK FACTORS ON DNA METHYLATION

Many epidemiological studies have implicated environmental factors in cancer development. Since the epigenome is considered as the main interface between the genome and environmental factors, epigenetic changes induced by environmental exposures may play a considerable role in tumorigenesis. However, the mechanisms underlying the effect of environmental factors on cellular processes and epigenetic modifications are poorly understood.

It is not a coincidence that Zdenko Herceg decided to explore this field of research: "Around two thirds of cancers are potentially preventable. While the bulk of available resources are devoted to searching for new therapeutic targets and drugs, it is important to keep in mind that we must also invest in cancer prevention, a critical research area that is currently underfunded. In addition to mechanistic studies, we also aim to understand upstream events: how do specific risk factors induce critical epigenetic changes? In doing this, we hope to provide important information for developing prevention strategies.”

As a consequence, he and his Group have been addressing several questions about cancer etiology: "At IARC we work with epidemiologists, benefiting from their expertise, with many cohort studies and their associated biobanks, and as well with high quality exposure data. This permits us to test different ideas using these human samples, while taking advantage of the revolution in epigenomics".

The group looked at DNA methylation patterns in a large panel of tumor suppressors and other cancer associated genes in lung and head and neck cancers, as well as their possible association with known or suspected risk factors. A quantitative measure of methylation at CpG promoters was assessed using a pyrosequencer (PSG 96MA, Qiagen, see picture). It allows specific DNA methylation analysis and assessment of DNA methylation profiles with high sensitivity and quantitative accuracy.

This technique is intensively used by Dr Herceg’s Group as well as by several other research groups at IARC and the pyrosequencer was partly obtained through the ARC “Jeune équipe” funding in 2005. Zdenko Herceg states that "the pyrosequencing platform was important to address different questions. But it was also essential to set up a new activity, collaborations and to develop the Group".

Both in lung and head and neck cancers, a high methylation incidence of specific genes was observed. Moreover the methylation patterns of several genes were severely influenced by several factors such as gender and nutrition, but also risk factors (smoking and alcohol) in lung cancer [1] and head and neck cancer [2].These studies highlight the epigenetic response, mediated by methylation patterns, to environmental factors and its role in tumor development. But they also show that these epigenetic events are tightly connected to intrinsic factors. Together, these data altogether could be exploited for the discovery of new biomarkers, as well as therapeutic strategies based on the use of epigenetics.

Further research work is based on a European case control study, specifically aimed at studying the methylation profile of several genes related to lung cancer. Nicotinic acetylcholine receptor (nAChR) genes form a highly conserved gene cluster characterized as a lung cancer susceptibility locus [3].  One of these genes, CHRNalpha3, that encodes the subunit alpha3 of nAChR, was found as hypermethylated in lung tumor cells. This repression could lead to inhibition of apoptosis, which would favor the tumoral progression of cells [4]. Again, this highlights the contribution of epigenetic modifications in tumor development, in parallel with genetic mutations.

[1] T. Vaissière and al, Cancer Res 2009

[2] S. Mani and al, Epigenetics, 2012

[3] Hung and al, Nature, 2008

[4] A. Paliwal and al, Cancer Res, 2010