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Pathways to Discovery: Winter 2014

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Special Series on Personalized Medicine

The UCCCC is transforming the future of medicine by using genetic, social, and environmental factors to predict cancer risk and customize prevention and treatment strategies for our patients. In this installment of a special series on personalized medicine, we describe collaborative efforts by our members to understand cancer epigenetics – alterations in gene expression or cell behavior not due to DNA sequence changes –and translate these findings into innovative clinical tools and treatment strategies for cancer patients.

Collaboration Drives Cancer Epigenome Mapping and Translation to the Clinic

Sometimes it takes a new discovery to put puzzling research findings into the right framework and bring their implications into sharper focus. This was the case for Lucy Godley, MD, PhD, associate professor of medicine, when the modified cytosine base known as 5-hydroxymethylcytosine (5-hmC) was described. Unexplained data collected in her cancer epigenetics research laboratory finally made sense. The standard techniques that everyone had been using to identify these marks on DNA, such as bisulfite sequencing, could not distinguish between the well-characterized 5-methylcytosine (5mC) and 5-hmC. These new insights also suggested that distinct epigenetic modifications might hold promise as a basis for new personalized medicine approaches for cancer patients.

Epigenetics is the study of heritable changes in gene activity that are not caused by alterations in DNA sequence but rather by modifications to DNA bases and histones. DNA methylation, typically at cytosine bases (i.e. 5-mC), is the best studied epigenetic mark that differs between normal and cancer cells. In many but not all cases, the genome of tumor cells contains significantly less global methylation compared to normal cells although specific tumor suppressor genes can be more highly methylated locally, leading to silencing of that gene. These modifications are thought to be so important to cancer cells that inhibitors of the enzymes that catalyze the addition of the methyl group onto DNA, called DNA methyltransferases, have been approved for use in some blood cancers and are in clinical trials for others. However, the discovery of 5-hmC suggests that in the future, we may have a better understanding of the predictive power of 5-mC and/or 5-hmC genome signatures or profiles that predict response to these drugs.

A major advance in these efforts came when Chuan He, PhD, professor of chemistry and investigator of the Howard Hughes Medical Institute, and his colleagues developed the first chemical labeling approach to isolate 5-hmC-enriched DNA sequences. Using innovative chemistries, this strategy allowed for the construction of the first genome-wide maps of 5-hmC marks in a number of cell lines and tissue types in a collaborative project between his group, Dr. Godley, and other colleagues. Further fine-tuning of the technical approaches has allowed for single-base resolution genome-wide sequencing of 5-mC compared to 5-hmC marks and reduction of the amount of starting material necessary for analysis. He’s group also demonstrated that TET proteins, which are required for 5-hmC formation, can catalyze additional cytosine modifications, including 5-formylcytosine (5-fC) and 5-carboxycytosine (5-caC). Currently, he is teaming up with other cancer researchers at the University of Chicago and world-wide to assess changes in the epigenome among various tumor types, including breast and colorectal cancer, with his eye toward developing new diagnostic and prognostic tools.

“By achieving these technological breakthroughs, we are able to define the epigenetic signature of cancers with only 1,000 cells. This was unthinkable just a year ago,” said Dr. He. He predicts that these tools may be used routinely in the clinical setting in less than five years, provided there are enough resources and samples available to validate the diagnostic and prognostic value of these signatures.

As an oncologist who treats patients with blood cancers, including leukemias and lymphomas, Dr. Godley is also interested in translating her research into the clinic. Her team has recently discovered, in collaboration with Amittha Wickrema, PhD, associate professor of medicine, and Dr. He, that 5-hmC levels are dynamically controlled during the differentiation of human red blood cells. The function of these marks appears to control transcription factor binding and subsequent gene expression during differentiation, such that dysregulation of the epigenome in TET2-mutant human chronic myelomonocytic leukemia cells is associated with a block in red blood cell differentiation (a hallmark of this cancer).

In a separate study, the Godley group has collaborated with M. Eileen Dolan, PhD, professor of medicine, and Wei Zhang, PhD (University of Illinois at Chicago), to examine how covalent cytosine modifications influence the phenotype of gliomas, an aggressive type of brain tumor. In early work using glioma cell lines, this group has shown that by changing the local cytosine modification patterns in a single gene called MGMT, glioma cells could be coerced to become more sensitive to the chemotherapeutic agent temozolomide. Since this is the mainstay for glioma patient treatment, these findings suggest that physicians could use MGMT methylation patterns to dictate therapy drugs, doses, or timing and improve outcomes.

According to Godley, “This work is exciting because we are now considering epigenetic changes, just like DNA mutations, as determinants of cancer behavior and therapeutic response. We can study the impact of these modifications on the tumor’s biology like never before because we have the tools to detect these modifications at a high resolution comprehensively across the tumor genome.”

 

Ernst Lengyel

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