Newly Identified Fusion Gene Could Help Diagnose Rare Sarcoma

Dr. Shuanzeng (Sam) Wei, investigator on the study and associate professor in the Department of Pathology and medical director of the Clinical Genomics Laboratory at Fox Chase.
Dr. Shuanzeng (Sam) Wei, associate professor in the Department of Pathology and medical director in the Clinical Genomics Laboratory at Fox Chase

PHILADELPHIA (February 24, 2022)—Extraskeletal myxoid chondrosarcoma is a rare soft-tissue cancer that can be misdiagnosed. Now researchers at Fox Chase Cancer Center have identified a fusion gene that can help pathologists positively identify these tumors.

It’s the first time this fusion gene, SMARCA2-NR4A3, has been described, said Shuanzeng “Sam” Wei, MD, PhD, associate professor in the Department of Pathology and medical director in the Clinical Genomics Laboratory at Fox Chase. The discovery could help clinicians provide better, more targeted therapies, said Wei, who conducted the research with colleagues at Fox Chase.

“If we have an accurate diagnosis, that means we can give the patient more optimal treatment and management,” Wei said. Margaret von Mehren, MD, vice chair of the Department of Hematology/Oncology and one of the study co-authors, added that finding novel biomarkers like this may also allow patients to participate in clinical trials.

Extraskeletal myxoid chondrosarcoma, or EMC, is rare—a cancer center like Fox Chase typically sees only three to five cases each year, Wei noted. However, those numbers might be so low in part because this cancer can be hard to diagnose. Using routine diagnostic methods, including standard genetic testing, it can be easily confused with other cancers that have similar morphologies, including soft tissue myoepithelial tumors.

The discovery arose from a case study of a single patient with EMC. For the study, researchers conducted advanced RNA sequencing on cancer cells taken from the patient’s tumor.

Scientists already knew that EMC was characterized by fusions of the gene NR4A3 with different gene partners. Five of these fusion genes had previously been identified. This investigation discovered a sixth: a fusion between NR4A3 and the gene SMARCA2.

The finding is significant because one of the fusion partners, EWSR1, is also found in the sarcomas that mimic EMC. That makes SMARCA2-NR4A3 an important clue to accurately diagnose EMC and differentiate it from the lookalikes.

The case highlights the importance of having access to advanced molecular/genetic testing capabilities in diagnosing a rare cancer like EMC, Wei said. Standard molecular/genetic testing, such as fluorescence in situ hybridization or RT PCR testing, target only a specific gene or a limited number of gene pairs and would not detect the new fusion gene. Wei added that Fox Chase now routinely conducts RNA sequencing on soft-tissue tumors.

“In sarcoma it’s very common to have a fusion gene, and these fusion genes are often very specific,” he said. “Once you find it, you can pinpoint a diagnosis that’s very accurate, very reliable—like this.”

Next, the researchers plan to gather more cases and determine whether the new fusion gene offers any clues about how the cancer grows and behaves. Wei noted that the tumor in the case study contained some atypical features and appeared to be more aggressive.

“We don’t have enough cases to know if this fusion pair is associated with more aggressive behavior or not, so we’re still collecting data,” he said. “That’s why we need to conduct further research.”

The report was a collaboration between researchers from the Department of Pathology, the Department of Hematology/Oncology, and the Department of Surgical Oncology at Fox Chase, including Harry S. Cooper, MD; Jianming Pei, MD; John A. Abraham, MD, FACS; and Arthur Patchefsky, MD.

The report, “SMARCA2-NR4A3 is a Novel Fusion Gene of Extraskeletal Myxoid Chondrosarcoma Identified by RNA Next-Generation Sequencing,” was published in Genes, Chromosomes & Cancer.

Fox Chase Cancer Center (Fox Chase), which includes the Institute for Cancer Research and the American Oncologic Hospital and is a part of Temple Health, is one of the leading comprehensive cancer centers in the United States. Founded in 1904 in Philadelphia as one of the nation’s first cancer hospitals, Fox Chase was also among the first institutions to be designated a National Cancer Institute Comprehensive Cancer Center in 1974. Fox Chase is also one of just 10 members of the Alliance of Dedicated Cancer Centers. Fox Chase researchers have won the highest awards in their fields, including two Nobel Prizes. Fox Chase physicians are also routinely recognized in national rankings, and the Center’s nursing program has received the Magnet recognition for excellence five consecutive times. Today, Fox Chase conducts a broad array of nationally competitive basic, translational, and clinical research, with special programs in cancer prevention, detection, survivorship, and community outreach. It is the policy of Fox Chase Cancer Center that there shall be no exclusion from, or participation in, and no one denied the benefits of, the delivery of quality medical care on the basis of race, ethnicity, religion, sexual orientation, gender, gender identity/expression, disability, age, ancestry, color, national origin, physical ability, level of education, or source of payment.

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