News Release
January 21, 2015

Mutated ATRX Gene Linked to Brain and Pancreatic Neuroendocrine Tumors is Potential Biomarker for Rare Adrenal Tumors Too

Penn Medicine Findings Come as Professional Societies Call for More Personalized Approach to Treating Pheochromocytoma and Paraganglioma

PHILADELPHIA — A somatic mutation in the ATRX gene has recently been shown as a potential molecular marker for aggressive brain tumors, such as gliomas, neuroblastomas and pancreatic neuroendocrine tumors.  Now, for the first time, researchers at the Perelman School of Medicine at the University of Pennsylvania have found that the same mutated gene may serve as a much-needed biomarker for the pheochromocytomas and paragangliomas (PCC/PGL) that become malignant. These rare neuroendocrine tumors are typically benign, but when they go rogue, they become very aggressive.

The study was published online ahead of print today in Nature Communications.

Several inherited mutated genes, such as VHL and RET, have been found to be associated with PCC/PGL; however, little is known about the somatic genetic changes leading to tumorigenesis in these patients.

 “This is the first step towards a better understanding of this type of disease, and to try to identify better biomarkers of poor outcomes,” said senior author Katherine Nathanson, MD, an associate professor in the division of Translational Medicine and Chief Oncogenomics Physician for the Abramson Cancer Center. “The mutation could not only serve as that biomarker for metastatic disease, but also a potential therapeutic drug target in the future.”

PGLs are rare tumors of nerve ganglia in the body, whereas PCCs form in the center of the adrenal gland, which is responsible for producing adrenaline. The tumor causes the glands to overproduce adrenaline, leading to elevated blood pressure, severe headaches, and heart palpitations.  Both are found in about two out of every million people each year. An even smaller percentage of those tumors become malignant. For that group, the five-year survival rate is about 50 percent.

No reliable predictors of aggressive disease exist other than an inherited mutation in the SDH gene, but only half of patients who develop metastatic disease carry that mutation, meaning the other half have no known predictors.
About 60 percent of PCC/PGLs are sporadic, while the remaining 40 percent are hereditary. Most recurrent somatic mutations are observed almost exclusively in sporadic PCC/PGLs.

Researchers, including Lauren Fishbein, MD, PhD, MTR, an instructor in the division of Endocrinology, Diabetes and Metabolism at the Perelman School of Medicine, investigated the mutations using whole exome sequencing on a set of 21 tumor/matched germline DNA samples of either sporadic or inherited PCC/PGL. The idea was to compare benign tumors to clinically aggressive ones in order to spot markers of malignant potential.

Somatic ATRX mutations were identified in two of seven SDHB-associated tumors, the team reported. To determine the frequency of somatic ATRX mutations in PCC/PGL, the team sequenced the ATRX coding region in a separate set of 103 tumors samples. They found that 13 percent of tumors had ATRX mutations.

“Although our sample set of PCC/PGL with ATRX variants is too small to identify statistically significant associations, many had clinically aggressive features, inherited SDHx mutations and ALT, suggesting an interaction between the somatic and inherited genomes in solid cancers, which needs to be investigated further,” the authors wrote.

The findings come in the wake of new clinical guidelines for PCC/PGL put forth by professional societies, calling for a more personalized and multidisciplinary approach to testing and treating patients.

In the summer of 2014, the Endocrine Society issued the first ever clinical practice guidelines for the management of patients with PCC/PGL. They recommended consideration of genetic testing in all patients, among other evidence-based guidance. Patients with paraganglioma should be tested for SDHx mutations, and those with metastatic disease for SDHB mutations, the report said.
The Endocrine Society Guidelines on PCC/PGL go a long way to recommend consideration of clinical genetic testing for all patients with these tumors,” said Dr. Fishbein. “It is especially important to identify SDHx mutation carriers who have higher incidence of multifocal disease and SDHB mutation carriers at higher risk of malignant disease. Our study suggests that tumor-specific somatic mutations, such as those in ATRX, also may help identify patients within that group at the highest risk for more clinically aggressive disease.”

Co-authors of the study include Sanika Khare, Bradley Wubbenhorst, Daniel DeSloover, Kurt D’Andrea, Shana Merrill, Nam Woo Cho, Roger A. Greenberg, Tobias Else, Kathleen Montone, Virginia LiVolsi, Douglas Fraker, Robert Daber, and Debbie L. Cohen.

The study was funded by PheoPara Alliance, the North American Neuroendocrine Tumor Society (NANETS) Early Career Development Award, and National Center for Research Resources and the National Center for Advancing Translational Sciences (KL2TR000139). 

Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $5.3 billion enterprise.

The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 18 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $373 million awarded in the 2015 fiscal year.

The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center -- which are recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report -- Chester County Hospital; Lancaster General Health; Penn Wissahickon Hospice; and Pennsylvania Hospital -- the nation's first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Chestnut Hill Hospital and Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2015, Penn Medicine provided $253.3 million to benefit our community.


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