Oncology

Cancer is a consequence of a breakdown in gene regulation. Dysregulation of gene expression in cancers may be driven by inherited mutations or by somatic mutations in specific tissues. Our research team has carried out several studies on tumor-specific patterns of gene expression in Glioblastoma multiforme (GBM) and other primary brain tumors. One study identified several thousand mutations, which significantly covaried with patterns of gene dysregulation in GBM, while another compared tumor gene expression patterns between long-term GBM survivors to those in the general patient population. More recently, we have contributed samples and collaborated in a study of regulatory elements in the cancer genome with researchers at The University of Texas at Austin.

Cancer cells are characterized by unique somatic mutations that distinguish them from healthy cells. Some of these mutations can be beneficial to the cancer cells, increasing their fitness by enhancing their rates of growth or proliferation relative to normal cells. Cancer progression is an evolutionary process whereby competition among cell lines favors those mutations that enhance the performance of tumor cells. In order to identify mutations subject to selection in tumors, we compare the rates of synonymous and non-synonymous mutations (i.e., “silent” mutations vs. those that lead to amino acid substitution) in GBM, low-grade glioma, and meningioma genomes. We have also used “deep sequence” data to study the genetic heterogeneity with tumors. Such data will facilitate the application of more sensitive tests for detecting natural selection between cell lineages, and the identification of key genes responsible for tumor progression.

Tumor progression entails competition among cell lines, both between cancer cells and healthy cell types, and among cancer cells within a tumor. This process leads to selection for cancer-specific mutations, and potentially selection for genes that modify mutation rates. We use population genetics-based models to understand how mutation rates evolve in cancer cells, and analyze the statistical properties of next generation sequence data sampled within and among tumors.

Approximately every 9 minutes, someone in the U.S. dies from a blood cancer (American Cancer Society; 2017). The high incidence and mortality rates highlight the need for the development of novel and effective treatments. St. David’s Blood and Marrow Transplant Center, in affiliation with the Texas Transplant Institute at Methodist Hospital in San Antonio, the Sarah Cannon Blood Cancer Network and Texas Oncology, is the area’s only blood and marrow transplant program. This Center, located at St. David’s South Austin Medical Center, will house a wide range of research studies investigating novel treatments for blood cancers.

After decades of research and development, we are on the brink of a new era in the treatment of blood cancer. The treatment known as chimeric antigen receptor T-cell (CAR-T) therapy has produced a remarkable response in adult and pediatric patients for whom all other treatments had stopped working. The U.S. FDA Oncologic Drugs Advisory Committee unanimously recommended approval of an investigational CAR-T therapy in July 2017. The BMT Program in Austin will be the first in the area to offer the leading-edge CAR-T cell therapy to its patients.

The Austin Brain Tumor Repository (ABTR) at St. David’s Medical Center (SDMC) was established to facilitate the collection, storage and distribution of primary brain tumor tissue and paired blood samples (not required for routine medical care) donated by patients undergoing surgical resection. The mission of the ABTR is to provide SDMC researchers, their collaborators, and outside institutions with the opportunity to use donated specimens suitable for research that will advance our understanding of brain tumors in the areas of genetics, cell biology, biochemical engineering, and drug discovery.

The tissue collection is maintained in a -80 degree C freezer, which is optimal for long-term storage of tissues intended for use by molecular biologists. In addition to DNA samples for partial and whole-genome sequencing, the tissue samples are suitable for RNA extraction (i.e., for gene expression studies) and protein assays.

The ABTR will distribute tissue specimens to qualified researchers with Institutional Review Board approved research studies and will never distribute donated tissue for financial gain. Please also note that priority in tissue sample loans will be granted to SDMC researchers and their immediate collaborators. Please contact the ABTR program manager for additional information.

Austin Brain Tumor Repository has been instrumental in supporting several research projects involving collaborations between St. David’s Medical Center and The University of Texas at Austin. Some recent projects includes:

Epigenetics of Glioblastoma multiforme

Vishy Iyer’s lab at UT Austin conducted a study of the regulation of gene expression in brain cancer cells by identifying modifications of histone core proteins that are associated with either up or down-regulation of adjacent genes. Many of the observed chromatin marks are found to be consistent with patterns of tumor-specific gene expression, some of which resemble those of stem cells and the regulatory cascades characteristic of early developmental pathways. The results of this study are currently under review.

Inference of Tumor Genotypes from Deep Sequence Data

The research team of Peter Mueller (UT Austin) has developed a Bayesian algorithm for reconstructing multi-point genotypes using short reads (fragments) sampled from different cells in a tissue. We collaborated with Dr. Mueller to optimize this algorithm on ultra-deep sequence data (1000x rather than 100x average coverage) from Glioblastoma samples in the ABTR. The improved algorithm gave more robust inferences of tumor genotypes from deep sequence data than existing algorithms, and inferred several subclonal genotypes from within the GBM tumors. The results of this study were recently submitted to the Proceedings of the Midwest Biopharmaceutical Statistics Workshop.

What is the Austin Brain Tumor Repository?

The Austin Brain Tumor Repository (ABTR) at St. David’s Medical Center has been established to advance our knowledge of brain tumors and how to treat them.

What is a brain tumor repository?

A brain tumor repository stores brain tumor tissue that has been removed during a medical procedure such as an operation or biopsy. This extra tissue is not needed for your diagnosis or treatment. With your written consent, this tissue is sent to the ABTR, where it is carefully preserved and protected.

Scientists will use specimens from the repository to study disease and find better ways to diagnose, prevent, and treat brain tumors in the future.

Will donating my tissue change my surgery or medical care?

Regardless of whether you decide to donate your tissue or not, your operation and medical care will be exactly the same.

During your medical procedure, your doctor will remove all the brain tumor tissue needed for a thorough diagnosis and treatment. A portion of your tissue is not needed for your brain tumor care. This leftover tissue, which would otherwise be discarded, is sent to the ABTR.

Who will benefit from my tissue donation?

If you donate your tissue for research, you probably will not benefit directly. Your donation may lead to scientific discoveries that will benefit brain tumor patients in the future. Discoveries include:

• Learning how the brain tumor cells work
• Determining the causes of brain tumors
• Developing new drugs and diagnostic tests
• “Markers” that predict who will respond to treatment

How will my privacy be protected?

Federal laws and regulations protect the privacy and confidentiality of your medical information.

The ABTR is only a storing house for your brain tumor tissue and requires your written consent. The informed consent form explains:

• How your tissue will be collected and stored
• How your medical information will be stored
• How scientists with approved research studies gain access to your tissueHow to contact the Principal Investigator if you would like to withdraw your consent for future research

Tissue donated for medical research is not used in either organ transplantation or blood transfusions.

What are the financial implications of tissue donation?

There is no charge to you or to your insurance company for donating your tissue. You will not be paid a fee for your tissue or for any of the discoveries that might result from research using your tissue.

The ABTR will never sell your donated brain tumor tissue. Only researchers with approved research projects will receive your donated tissue at no charge.

What if I change my mind after donating tissue?

You can change your mind at any time about allowing your tissue to be used in future research. The consent form explains how to contact the ABTR Principal Investigator.

Will I get the result of research using my tissue?

The ABTR will not directly report to you the results of any research using your donated tissue. Research studies take many years and the results are often published in scientific journals.

Can I download a copy of Your Guide to the Austin Brain Tumor Repository?

Yes you can.

How can I find out more about my brain tumor treatment options?

By visiting our St. David’s Medical Center website you can find valuable information about brain tumors and their treatment options.

Please contact the Office of Research if you have interest in collaboration.