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CTSI support speeds hunt for new genetic markers for breast cancer risk

Jan. 16, 2014

As a member of one of the first teams to use cutting-edge techniques to assess the genetic risk of breast cancer, Chunyan He, Sc.D., joined IU uniquely qualified to advance innovation in this arena. However, as a young investigator, she needed a sponsor that would to take a risk on an untested idea. 

Chunyan He

Genetic epidemiologist Chunyan He, Sc.D., is an assistant professor at the IU Richard M. Fairbanks School of Public Health and a member of the IU Melvin and Bren Simon Cancer Center.

The recipient of an early pilot grant from the Indiana Clinical and Translational Sciences Institute, Dr. He has been working to advance a project that combines genome-wide association studies, or GWAS, with global gene expression profiling -- two techniques that may soon provide important insights into genetic risk factors for cancer, including their underlying molecular processes.

"Our ultimate goal is to find and understand the mechanisms behind the genes causing the cancer," said Dr. He, assistant professor at the IU Richard M. Fairbanks School of Public Health and a member of the IU Melvin and Bren Simon Cancer Center. "When you identify these causal genes, they open the window for early detection and help with early intervention for the patients and treatments."

GWAS is a form of analysis used to discover the genetic variations in the human genome associated with disease risk. Gene expression profiling involves using next-generation RNA-sequencing technology to measure the activity, or expression, inside thousands of genes to create an overall view of cellular function at the whole genome level. Although GWAS can reveal breast cancer-associated genetic variations that can act as genetic markers for breast cancer, Dr. He asserts the approach is limited since identifying genetic variations does not necessarily identify causal genes, or shed light on mechanisms underlying the disease's development and spread. The addition of gene expression profiling yields stronger insights by digging deeper into the underlying mechanisms that fuel cancer cell development and growth.

Despite strong early results based upon the combination of these methods, Dr. He's project almost didn't get off the ground. It wasn't until she presented a proposal to the Indiana CTSI's Project Development Team program -- which provides free consultations and access to resources such as funding, data analysis and lab technologies to investigators pursuing novel research topics with strong potential to quickly translate into clinical practice -- that she earned $20,000 in start-up funds to perform a crucial feasibility study on 20 breast tissue samples from the Komen Tissue Bank at the IU Simon Cancer Center.

The funds helped carry out the initial work required to reveal the power of GWAS combined with gene expression profiling. The analysis revealed breast cancer-associated genetic variations that may act as markers for breast cancer. 

"You know you're going to find disease-associated genetic variations with GWAS, but you really don't know how they work or how they're related to breast cancer since the underlying molecular mechanisms are still largely unknown," Dr. He said. "GWAS combined with gene expression profiling can identify causal genes whose expression is regulated by these genetic variations, and those genes can act as pre-cursors to breast cancer development -- powerful targets for drugs designed to treat tumor as well as molecular markers for early detection since early changes in their expression drive tumor formation."

Based on the feasability study, Dr. He earned $400,000 from ExpressionAnalysis, a North-Carolina based genomics service company, to advance the project on March 30, 2011. She also earned $100,000 on the same date from the Kay Yow Cancer Fund, in partnership with the V Foundation for Cancer Research, to also advance a breast cancer through a separate project.

Many researchers are also limited by their inability to access truly healthy breast tissue, she said. They're dependent upon comparing tumor tissues removed during surgery to tumor-adjacent tissue contributed from the same patient, which already contains aberrantly expressed genes as the spread of the tumor affects surrounding tissue.

The solution? The Komen Tissue Bank, the only source of healthy breast tissue in the world, which provided the rare opportunity to compare truly healthy tissue with tumor tissue to more accurately pinpoint the differences between cancerous and normal genes.

Chunyan He

Dr. He accepts a check for $100,000 from the Kay Yow Cancer Fund on March 30, 2011.

"You could see the normal cells from the bank really were different from the other 'normal' cells since tumor-adjacent cells aren't really normal," she said. "They're already more similar to cancer calls as the tumor sends signals to the nearby environment in order to facilitate their spread."

The origin of Dr. He's interest in a "next generation" approach to GWAS is her experience as an early pioneer using the technology. As a doctoral student at Harvard University, she was a member of one of the first groups supported by the National Cancer Institute's Cancer Genetic Markers of Susceptibility Project in a cutting-edge project that analyzed breast cancer data using information from the Nurses' Health Study.

The study was a landmark project that has collected long-term health data every two years from 120,000 nurses across in 11 states since 1976 whose study were published in the journal "Nature Genetics" in 2009.

"[BRCA1 and BRCA2] are the most famous breast cancer genes discovered in the pre-GWAS era, but breast cancer-associated mutations in these genes are actually very uncommon," Dr. He said. "I'm aiming to discover genetic markers that are much more common among the general population in order to assess breast cancer risk among a larger proportion of patients."

In addition to funds, Dr. He noted Indiana CTSI also provided access to experts with useful advice on topics outside her area of expertise, such as potential intellectual property issues related to future discovery.

"The potential to discover, and patent, novel genes related to breast cancer risk is one of the implications of this approach," Dr. He said. "But patent issues were new to me; they simply weren't on my radar. I hadn't really considered the intellectual property issues involved in moving any discoveries that might arise from this work toward new industrial testing kits for disease."

Her research's novel approach also isn't limited to breast cancer, she said, as an "integrative approach" could potentially be applied to research on other cancer types, such as lung or testicular. She is already pursuing a collaboration related to testicular cancer research with fellow scientists at the IU Simon Cancer Center.

"When I first joined IU, I had this idea of linking the gene expression with the GWAS, but as a junior scientist without a long research history, you've got to show people you can carry out the experiments in reality," she said. "I want to thank the Indiana CTSI for having the vision to help fund this project."

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