A somatic mutation in the ATRX gene has recently been identified as a potential molecular marker for gliomas, neuroblastomas, and pancreatic neuroendocrine tumors. Now, 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 pheochromocytomas and paragangliomas that become malignant, according to a study reported by Fishbein et al in Nature Communications. These rare neuroendocrine tumors are typically benign, but when they are malignant, they become very aggressive.
Several inherited mutated genes, such as VHL and RET, have been found to be associated with pheochromocytoma and paraganglioma; 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 L. 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.”
Rare Adrenal Tumors
Paragangliomas are rare tumors of nerve ganglia in the body. Pheochromocytomas form in the center of the adrenal gland, and cause the gland 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 5-year survival rate is about 50%.
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% of pheochromocytomass and paragangliomas are sporadic, while the remaining 40% are hereditary. Most recurrent somatic mutations are observed almost exclusively in sporadic pheochromocytomas and paragangliomas.
Study Details
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 pheochromocytoma and paraganglioma. 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 pheochromocytoma and paraganglioma, the team sequenced the ATRX coding region in a separate set of 103 tumor samples. They found that 13% of tumors had ATRX mutations.
“Although our sample set of [pheochromocytoma and paraganglioma] with ATRX variants is too small to identify statistically significant associations, many had clinically aggressive features, inherited SDHx mutations, and alanine aminotransferase (ALT), suggesting an interaction between the somatic and inherited genomes in solid cancers”, the authors wrote.
Clinical Practice Guidlines
In the summer of 2014, the Endocrine Society issued the first-ever Clinical Practice Guidelines for the management of patients with pheochromocytoma and paraganglioma. 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 [pheochromocytoma and paraganglioma] 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.”
Katherine L. Nathanson, MD, of the Perelman School of Medicine at the University of Pennsylvania, is the corresponding author for the Nature Communications article.
The study was supported 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.
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