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(Last updated 10/1/04)


COLUMBUS, Ohio – A team of scientists in the Ohio State University Comprehensive Cancer CenterArthur G. James Cancer Hospital and Richard J. Solove Research Institute will receive $7.4 million from the National Cancer Institute (NCI) to study two key chemical and structural changes throughout the human genome that appear to be linked to the growth and development of many types of cancer.

Unlike genetic mutation, these complex processes – methylation and chromatin remodeling – can shut down or restrict the activity of key genes and other cellular structures that would normally protect cells from malignant transformation. Scientists are especially interested in these two processes because again – unlike genetic mutation – they are potentially reversible with appropriate drug therapy.

The grant is among only six this year to be awarded nationwide from the NCI as part of a new initiative to foster translational research that takes a systematic, collaborative and mathematically-grounded approach to projects in basic science that potentially offer the most impact on patient care.

Tim Hui-Ming Huang, associate professor of human cancer genetics, will lead the project and coordinate activity among scientists from several departments at Ohio State and Indiana University. Key among them is the Mathematical Biosciences Institute at Ohio State that will provide support in computational modeling to help predict cancer biology and behavior.

The grant is among only six this year to be awarded nationwide from the NCI as part of a new initiative to foster translational research that takes a systematic, collaborative and mathematically-grounded approach to projects in basic science that potentially offer the most impact on patient care.

“We know that methylation and chromatin remodeling occur throughout the entire genome and we know that they contribute to cancer. The more we understand the patterns of these changes, where they occur, when, and under what conditions, the better equipped we will be to identify targets for new treatments,” says Huang. “Hopefully, it will all lead to better diagnosis, treatment, and outcomes.”

The grant will fund four major projects seeking to identify and analyze key changes in methylation and chromatin remodeling patterns specific to breast and ovarian cancer. All will focus heavily on the development and use of novel bioinformatics and computational strategies in analyzing considerable existing data from earlier studies at Ohio State.

Methylation is the addition of a methyl molecule to certain parts of DNA called CpG islands. It is a normal process – the body routinely uses methylation to silence or deactivate genes it doesn’t need at any given time. Problems can arise, however, when methylation alters key tumor suppressor genes that would normally protect the body from cancer. When that happens, cells are more likely to grow out of control.

In earlier studies, Huang and his colleagues discovered that the degree of methylation may correlate with the seriousness of a tumor and may even help predict a patient’s outcome. In studying specific genes in breast cancer, he also discovered evidence suggesting that methylation begins in the exons – regions outside a gene’s main regulatory area, spreading later to the promoter region of the gene, its control center.

In contrast to methylation, which is a chemical process, chromatin remodeling refers to alterations in the structure of the protein core that helps keep DNA tightly packaged inside the nucleus of a cell. DNA and that core together are referred to as chromatin.

Remodeling occurs when DNA has to be “loosened” from the core in order for it to properly code for proteins. Scientists believe that methylation and a similar process, acetylation, can sometimes modify or remodel the chromatin improperly, thus causing errors in protein production that could lead to the development of cancer.

In Project 1, under Huang’s leadership, scientists will define molecular events that lead to the silencing of several important genes in the estrogen-signaling pathway. Mathematical models will be created that may be able to reveal how the multiple repressors, histone deacetylases and DNA transferases are utilized in the process.

Charis Eng, professor of medicine and human genetics, will direct Project 2. The goal of this effort will be to identify chromosomal and genetic changes that take place in the development and progression of invasive breast cancer.

In Project 3, under the direction of co-leaders Joel Saltz, professor and chair of biomedical informatics, and Ramana Davuluri, assistant professor of bioinformatics and computational biology, researchers will try to discover any role that chromatin remodeling has in the growth and development of ovarian cancer. They will also try to identify epigenetic patterns unique to ovarian cancer.

Kenneth Nephew, associate professor of cellular and integrative physiology at Indiana University, will lead Project 4. Investigators in this team will try to identify characteristics of select DNA sequences that may be more prone than others to methylation. Scientists will also develop computational models of DNA methylation associated with resistance to cisplatin, a widely used drug to treat ovarian cancer.

Additional collaborators at Ohio State include Mike Caligiuri, Albert de la Chapelle, Michael Chen, Frederick Cope, Jeffrey Fowler, Avner Friedman, Sam Jacob, Victor Jin, Yu-Wei Leu, Joseph Liu, Sandya Liyanarachchi, Carl Morrison, Saranyan Palaniswamy, Srinivasan Parthasarathy, Dennis Pearl, Christoph Plass, Lei Shen, Gregory Singer, Hao Sun and Pearlly Yan. Additional collaborators are from Indiana University and the University of Missouri.


Contact: Michelle Gailiun, Medical Center Communications, 614-293-3737, or Gailiun.1@osu.edu.