Mutated ATRX gene linked to brain tumors is also potential biomarker for rare adrenal tumors

A somatic mutation in the ATRX gene has 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 Penn's Abramson Cancer Center have found that the same mutated gene may serve as a much-needed biomarker for 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 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.

PGLs are rare tumors of nerve ganglia in the body, whereas PCCs form in the center of the adrenal gland. 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 40 percent are hereditary. Most recurrent somatic mutations are observed almost exclusively in sporadic PCC/PGLs.

Researchers 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 tumor samples. They found that 13 percent of tumors had ATRX mutations.