Research Summary Research topic:
Sequencing repetitive GGAA microsatellite DNA to learn how variations in these sequences influence susceptibility and gene expression in Ewing sarcoma.
Sequence variation in these GGAA microsatellites demonstrate a unique pattern in Ewing sarcoma cells as compared to the general population, providing insight into how these genetic elements may predispose certain populations to Ewing sarcoma. Patient care application of results:
Genetic tests that could help orthopaedics predict who is at risk for developing Ewing sarcoma, and the prognosis for those with the disease. Simplified patient care application:
More accurate suscpetibility and prognosis predictions for Ewing sarcoma patients.
Searching for Ewing Sarcoma Genetic Triggers
OREF grant recipient works to solve random onset of this childhood cancer
Ewing Sarcoma is the third most common primary malignancy of bone. Most cases occur in patients who are between 10 and 20 years of age.1
The disease has a high propensity to metastasize.
The cure rate for patients with localized disease is between 60 percent and 70 percent when treated with standard multi-agent chemotherapy protocols and surgical excision or radiation therapy. 2, 3
But survival rates for patients who present with clinically detectable metastases or recurrence are dismal—between 10 percent and 20 percent. Moreover, the last few decades have shown no significant improvements in cure rates for patients who present with metastatic or recurrent disease.
Michael J. Monument, MD, a surgeon-scientist who recently completed a fellowship at the Sarcoma Array Research Consortium (SARC) lab in the Huntsman Cancer Institute/Department of Orthopaedic Surgery at the University of Utah, is investigating strategies to answer questions related to the molecular pathogenesis of cancer—especially Ewing sarcoma. He received a 2012 Orthopaedic Research and Education Foundation (OREF) Young Investigator Grant to design and implement a clinical study translating recent laboratory advances in the regulation of Ewing sarcoma oncogenesis by testing a large sample of tumors that were collected as part of a comprehensive pediatric clinical trial. The goal of this research is to further the understanding of ethnic discrepancies in Ewing sarcoma susceptibility and to identify critical genetic pathways involved in initiation of Ewing sarcoma.”
“We’re pretty excited about this OREF grant,” said Dr. Monument. “We believe that we’re on to something that could be quite important in Ewing sarcoma, and we’re grateful to OREF for sponsoring our research and helping us move forward.”
Predicting susceptibility and prognosis in Ewing sarcoma
A previous study found microsatellite DNA enables the activation of certain genes in Ewing sarcoma. With funding from OREF, Dr. Monument and his research team examined more than 100 Ewing sarcoma specimens and matched genomic DNA (peripheral blood, bone marrow aspirates). They sequenced repetitive DNA sequences known as GGAA microsatellites—to learn the following: whether GGAA microsatellite sequences are unstable (expand or contract in size) in patient-derived Ewing sarcoma cells when compared to matched genomic control DNA whether or not the length variation in GGAA microsatellite response elements provides a unique genetic signature in patients diagnosed with Ewing sarcoma and whether these unique genetic signatures influence overall survival the influence of GGAA microsatellite length variation on in vitro gene expression
“If a strong association between GGAA microsatellite length polymorphisms and the development and/or clinical outcome of Ewing sarcoma can be established, this could pave the way for the development of simple genetic testing that may predict who is at risk for developing Ewing sarcoma, as well as, of those who have the disease, who will do better or worse.”
Researchers are at a loss to explain why people get this disease.
“Ultimately, Ewing sarcoma is a poorly understood cancer; we really don’t know why some patients develop this rare condition,” said Dr. Monument. “We feel length variations of critical GGAA microsatellite DNA may provide tremendous insight into why some human populations are more likely to be diagnosed with this cancer than others.”
Dr. Monument is highly sympathetic to the plight of sarcoma patients.
“We do not know why sarcoma patients, develop these cancers that are quite aggressive and eventually lethal. Our research has the potential to make a difference, not only on our patients’ musculoskeletal function but also on their survival,” he said.
Dr. Monument believes that a clear understanding of the molecular process involved in disease is vital to being an orthopaedic oncologist.
He also applauds the role of OREF in sponsoring significant research. “It’s important to give back and to contribute to organizations that help sponsor those emerging treatments and the new science behind what we do, whether it’s basic science or mechanical science,” he said. “Funding agencies really help people like me who are keen to research new treatments and new approaches to conditions at the scientific or biomechanical level.”
“In the field of orthopaedics, OREF grants provide a wonderful and consistent funding opportunity for established investigators, as well as new investigators who are trying to gain momentum and get a foothold in the scientific community,” Dr. Monument continued. “It’s terrific for us as orthopaedic surgeons to have OREF as a funding source.”
Dr. Monument is currently an assistant professor in the Department of Surgery at the University of Calgary, Canada, with an active basic science sarcoma research laboratory.
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1. Balamuth NJ, Womer RB: Ewing's sarcoma. Lancet Oncol 2010;11(2):184-192.
2. Rodriguez-Galindo C, Spunt SL, Pappo AS: Treatment of Ewing sarcoma family of tumors: Current status and outlook for the future. Med Pediatr Oncol 2003;40(5):276-287.
3. Grier HE, Krailo MD, Tarbell NJ, et al. Addition of ifosfamide and etoposide to standard chemotherapy for Ewing’s sarcoma and primitive neuroectodermal tumor of bone. N Engl J Med 2003;348(8):694-701.