Important growth inhibitors are often switched off in the genetic material of cancer cells by specific chemical DNA modifications. Scientists of the German Cancer Research Centre (Deutsches Krebsforschungszentrum, DKFZ), in collaboration with colleagues from Ohio State University in the United States, have investigated how this happens. They discovered, in mice, that cancer-typical DNA methylation occurs long before the first symptoms of leukaemia appear. A test for the genetic label might, therefore, help to detect the development of cancer at an early point.
In many types of cancer, parts of the genetic material of tumour cells are switched off by chemical labels, i.e. methyl groups. Methylation is one of several epigenetic changes that do not change the sequence of DNA building blocks. Such modifications are found particularly often in genes that act as important inhibitors of pathogenic cell growth.Cancer researchers do not know why healthy cells and cancer cells differ in their methylation patterns or why the cancer inhibitors, in particular, are frequently switched off. The study of these questions is a very promising area of research because there are drugs available that can prevent the attachment of methyl groups or other epigenetic changes and, thus, at minimum delay the onset of cancer.
Professor Dr. Christoph Plass at the German Cancer Research Centre has investigated, jointly with colleagues from Ohio State University in Columbus, USA, the processes that lead to the different methylation patterns in cancer cells. A key question here would be when do these modifications occur in the development of cancer. In their recently published study, the investigators used mice that were affected by chronic lymphocytic leukaemia as a model for studying the disease.The researchers investigated the genetic material of these mice at regular intervals from birth. They first discovered cancer-typical methylation patterns in mice that were only three months old. This means that irregularities in methylation occur long before the first signs of the disease appear. These were not observed before the animals were thirteen months old. Moreover, the researchers were able to show that methylation patterns in murine DNA are largely similar to those found in humans suffering from leukaemia. This confirms that the mouse model is suitable for studying the disease.
“Since the first irregularities in methylation occur so early in mice, it should be researched as to whether this is also true for humans. If so, an early methylation test in high-risk individuals could provide clues about the development of cancer,” Christoph Plass says. In this case, preventive medical intervention might be possible. Drugs preventing methyl group attachment might delay the onset of cancer. Clinical studies are already currently underway to verify this. “This is probably most effective in a very early phase of methylation,” Plass explains. The researchers believe that the first chemically deactivated genes trigger entire cascades of changes in the genetic material, which can hardly be controlled at a later stage.
The cells of the roughly 200 different tissues of the human body can fulfil their special tasks only by regulating the activity of their respective genes very specifically. Although every single gene is equipped with its own control elements, this is insufficient for complex coordination. There is a second code that serves as an additional control level. In addition to the genetic switches that are directly integrated into the genetic material, the DNA, genes can also be switched on or off by the chemical labelling of the DNA or DNA packaging proteins. The most common of such epigenetic mutations is the attachment of methyl groups. The effect of these small chemical compounds is that a gene can no longer be read and translated into proteins.Unlike genetic mutations, which permanently change the sequence of the DNA building blocks, all the epigenetic mutations are reversible and, therefore, are potential target structures of the appropriate drugs.
Original publication: Shih-Shih Chen, Aparna Raval, Amy J. Johnson, Erin Hertlein, Te-Hui Liu, Victor X. Jin, Mara Sherman, Shu-Jun Liu, David W. Dawson, Katie E. Williams, Mark Lanasa, Sandya Liyanarachchi, Thomas S. Lin, Guido Marcucci, Yuri Pekarsky, Ramana Davuluri, Carlo M. Croce, Denis C. Guttridge, Michael A. Teitell, John C. Byrd,, and Christoph Plass: Epigenetic changes during disease progression in a murine model of human chronic lymphocytic leukemia. Proceedings of the National Academy of Science, USA, 2009, DOI: 10.1073/pnas.0906455106
Further information:Dr. Stefanie SeltmannHead of Press and Public RelationsGerman Cancer Research Centre (DKFZ)Im Neuenheimer Feld 280D-69120 HeidelbergTel.: +49 6221 42 2854Fax: +49 6221 42 2968