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The key to better cancer treatments lies in our genes. That’s what Joshua Schiffman, MD, and his colleagues at Huntsman Cancer Institute (HCI) at the University of Utah believed when they began researching the genomics, or genetic makeup, of Ewing sarcoma. Schiffman, the study’s principal investigator, and his colleagues—HCI’s R. Lor Randall, MD, FACS; Kevin B. Jones, MD; Stephen L. Lessnick, MD, PhD; and Ken Boucher, PhD, and Primary Children’s Medical Center’s Angela Putnam, MD—discovered several new findings in the genomes of Ewing sarcoma: a new subtype of the disease, genetic factors that relate to patient survival, and a genetic change found only in tumors that have spread but not seen in the original tumor. Schiffman says these discoveries may lead to more effective, targeted treatments for this deadly children’s cancer.
Only three children in 1 million are diagnosed with Ewing sarcoma each year. “Because there are so few cases, it has been difficult in the past to find enough tissue samples to conduct valid studies of the genetics and biology of this disease,” says Schiffman. The researchers used a new technology called molecular inversion probes (MIPs) to look at several tissue samples collected over 12 years. The technology made it possible to obtain high-quality data from the archived tumor samples that previously weren’t available for molecular analysis.
Clinical samples are usually preserved in formalin and encased in paraffin wax blocks, referred to as formalin-fixed paraffin embedded (FFPE) samples. This process can degrade DNA in the samples, making it hard to get high-quality, accurate genomic data. But MIP technology needs a much smaller sample of DNA than other methods and can work on degraded DNA in order to give high quality data.
The study, published in the journal Cancer Genetics, showed 10% of the tumor samples were missing DNA in a certain area of the genome, which included a missing gene called SMARCB1. This same DNA deletion has been seen in another type of pediatric sarcoma called a rhabdoid tumor, but never before in Ewing sarcoma.
“Discovering this new subtype of Ewing sarcoma is especially important because the patients with this deletion were among the long-term survivors,” says Schiffman. “It opens up questions about the biology of this tumor and whether patients with this type of cancer need different treatment.” Schiffman and his colleagues at HCI think these Ewing sarcoma tumors with SMARCB1 deletions may even represent a new type of sarcoma, a hybrid tumor with features of both Ewing sarcoma and rhabdoid tumors.
This genomic study also revealed a different gene in the Ewing sarcoma tumors that had metastasized, or spread. This gene wasn’t found in the primary tumor, where the cancer started.
“People don’t die from a primary tumor,” says Schiffman. “It’s cancer spreading through the body that kills. As we learn what makes tumors metastatic, we can search for treatments that may keep primary tumors from making that change, or target this specific genetic change once it already has occurred.”
The researchers also found factors in eight areas of the genome linked to different survival rates. For patients with none of the factors, 80% had no recurrence of the disease after initial treatment, and 100% survived more than 12 years after diagnosis. For patients with one or more of the factors, only about 40% survived that long.
Schiffman says the goal is to bring these discoveries to the patients.
“If we can start analyzing the genomes of tumors from Ewing sarcoma patients, we can start thinking about which prognostic category each patient falls into and we can really personalize his or her care. We can design the treatment that will be most effective for that patient.”
Schiffman serves as the interim director for the new Translational Oncology Core at HCI, where he is working with collaborators to bring personalized genomic medicine to HCI patients with other cancers.