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Contact: Peggy Calicchia
calicchi@cshl.edu
516-422-4012
Cold Spring Harbor Laboratory

Camouflaging of viral DNA could be crucial step in progression of cancers

An estimated 15% of cancer cases can be linked to a viral infection, however the biological changes that cause some asymptomatic carriers of a virus to develop full-blown tumors are not well understood. In a study published online in Genome Research (www.genome.org), scientists have mapped a chemical modification of DNA in three oncogenic viruses (Epstein-Barr, human papilloma virus, and hepatitis B virus) and found that the viral genome undergoes critical changes during the progression of disease, with implications for the development of new methods of prevention, diagnosis, and treatment.

Worldwide, most people are already infected with the Epstein-Barr virus, and millions are infected with the human papilloma virus and the hepatitis B virus. Many of these individuals will develop disease, and some will eventually develop a viral-related cancer such as lymphoma, liver cancer, or cervical cancer. Understanding how infections of viruses such as these can progress to cancer in some individuals is essential to the development of new methods to attack the virus and prevent malignancies.

Similarly to cellular organisms, the viral genome is subject to chemical modification. In animals, it is now appreciated that these "epigenetic" properties of genomes are variable in different tissues of the same individual, between identical twins, and in disease states. There are considerable efforts underway to map the landscape of epigenetic marks in the genomes of many organisms, yet it remains technically challenging to resolve the catalog of modifications at every base of DNA. However, significant clinical importance and a relatively small genome make viruses excellent targets for whole-genome epigenetic mapping.

In this study, an international team of scientists has determined the complete map of DNA methylation, a specific type of chemical modification, for the entire genome of the Epstein-Barr virus, the human papilloma virus, and the hepatitis B virus. Importantly, the researchers compared the DNA "methylomes" of asymptomatic carriers of each virus, patients with active infections, and patients harboring cancerous tumors. "When we move from asymptomatic carriers of the virus to intermediate stages of the disease, and we end with the established associated cancer, the genome of the virus did not change that much," explained Dr. Manel Esteller of the Bellvitge Institute for Biomedical Research (IDIBELL) in Barcelona, senior author of the report. "But its epigenome is completely different." Remarkably, Esteller and colleagues found that the viral genomes become progressively methylated in patients who had developed cancer.

Esteller noted that the viruses use our cell's DNA methylation machinery to modify its own DNA, and could be using methylation to hide itself from the immune system, effectively escaping the body's defense mechanisms in malignant cells. "This a very exciting result that can explain why some of these viruses can survive for such prolonged times in our body."

These findings could lead to several new avenues for the study, diagnosis, and treatment of viral-related disease and cancer. It is likely that the changes observed in the methylomes of these three DNA viruses could extend to other oncogenic viruses, and perhaps even viruses that cause illnesses ranging from the flu to AIDS. Esteller also explained that viral DNA methylation could be used as a biomarker for progression of disease, and furthermore, drugs that remove methylation from DNA could be used against viruses to prevent and erase the camouflaging employed to evade the immune system.

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Scientists from the Spanish National Cancer Research Centre (Madrid, Spain), the Bellvitge Institute for Biomedical Research (Barcelona, Spain), the Catalan Institute of Oncology (Barcelona, Spain), Vrije Universiteit Medical Center (Amsterdam, The Netherlands), the Pasteur Institute (Paris, France), Hospital Vall Hebron (Barcelona, Spain), the National Center for Epidemiology (Budapest, Hungary), the Hospital Universitari de Bellvitge (Catalonia, Spain), the Amedeo Avogadro University of Eastern Piedmont (Vercelli, Italy), the Universitario de Vigo (Vigo, Spain), Harvard University (Boston, MA), Brigham and Women's Hospital (Boston, MA), and the Institucio Catalana de Recerca i Estudis Avançats (ICREA) (Barcelona, Spain).

This work was supported by the National Institute for Bioinformatics (Spain), the Spanish Association Against Cancer, Fundación Mutua Madrileña, and the Swiss Bridge Award.

Media contacts:

Manel Esteller, M.D., Ph.D. (mesteller@iconcologia.net, +34-932607253) may be contacted for more information.

Interested reporters may obtain copies of the manuscript from Peggy Calicchia, Editorial Secretary, Genome Research (calicchi@cshl.edu; +1-516-422-4012).

About the article:

The manuscript will be published online ahead of print on February 10, 2009. Its full citation is as follows:

Fernandez, A.F., Rosales, C., Lopez-Nieva, P., Graña, O., Ballestar, E., Ropero, S., Espada, J., Melo, S., Lujambio, A., Fraga, M.F., Pino, I., Javierre, B., Carmona, F.J., Acquadro, F., Steenbergen, R.D.M., Snijders, P.J.F., Meijer, C.J., Pinaeu, P., Dejean, A., Lloveras, B., Capella, G., Quer, J., Buti, M., Esteban, J., Allende, H., Rodriguez-Frias, F., Castellsague, G., Minarovits, J., Ponce, J., Capello, D., Gaidano, G., Cigudosa, J.C., Gomez-Lopez, G., Pisano, D.G., Valencia, A., Piris, M.A., Bosch, F.X., Cahir-McFarland, E., Kieff, E., and Esteller, M. The dynamic DNA methylomes of double-stranded DNA viruses associated with human cancer. Genome Res. doi:10.1101/gr.083550.108.

About Genome Research:

Launched in 1995, Genome Research (www.genome.org) is an international, continuously published, peer-reviewed journal that focuses on research that provides novel insights into the genome biology of all organisms, including advances in genomic medicine. Among the topics considered by the journal are genome structure and function, comparative genomics, molecular evolution, genome-scale quantitative and population genetics, proteomics, epigenomics, and systems biology. The journal also features exciting gene discoveries and reports of cutting-edge computational biology and high-throughput methodologies.

About Cold Spring Harbor Laboratory Press:

Cold Spring Harbor Laboratory is a private, nonprofit institution in New York that conducts research in cancer and other life sciences and has a variety of educational programs. Its Press, originating in 1933, is the largest of the Laboratory's five education divisions and is a publisher of books, journals, and electronic media for scientists, students, and the general public.

Genome Research issues press releases to highlight significant research studies that are published in the journal.



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