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Mutated ATRX Gene Linked To Brain Tumors Potential Biomarker for Rare Adrenal Tumors Too

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It has been recently shown that a somatic mutation in the ATRX gene is a potential molecular marker for aggressive brain tumors like gliomas, neuroblastomas and pancreatic neuroendocrine tumors. However, in a new study researchers at the Penn's Abramson Cancer Center have for the first time found that the same mutated gene can be a biomarker for the pheochromocytomas and paragangliomas (PCC/PGL) that become malignant. Typically, these rare neuroendocrine tumors are harmless. But, if they become bad, they can be quite aggressive.

Scientists have known that quite a few inherited genes like the VHL and RET are associated with PCC/PGL. However, there is not much known about the somatic genetic changes that lead to tumorigenesis in these patients.

The study was published online in Nature Communications.


Katherine Nathanson, MD, study's senior author and an associate professor in the division of Translational Medicine and Chief Oncogenomics Physician for the ACC said – that their study is a first step towards understanding such diseases in a better way. It will also help in identifying biomarkers of poor outcome. Not only the mutation could be a biomarker for metastatic diseases, it could also be a potential therapeutic drug target in future.

PGLs are rare tumor that occurs in nerve ganglia in the body. PCCs on the other hand occur in the center of the adrenal gland “ this part is responsible for producing adrenaline. Because of the tumor, the glands start overproducing adrenaline and it leads to elevated blood pressure, severe headaches, and heart palpitations. Statistics reveal that both of these tumors are found in about two out of every million people each year. Not all tumors become malignant, however when it does, the five-year survival rate of the patient is about 50 percent.

About 60 percent of PCC/PGLs are sporadic in nature and the remaining 40 percent are hereditary. It is seen that recurrent somatic mutations are observed almost exclusively in sporadic PCC/PGLs.

Till now, no reliable predictors for the disease are known, other than an inherited mutation in the SDH gene. However, it is also seen that only half of patients who develop metastatic disease carry that mutation, meaning the other half have no known predictors.

Researchers investigated the mutations using whole exome sequencing on a set of 21 tumors/matched germline DNA samples of either sporadic or inherited PCC/PGL. They wanted to find out the difference between benign tumors and the clinically aggressive ones, so that markers of malignant potential could be spotted. Their study revealed that in two of seven SDHB-associated tumors, somatic ATRX mutations were present. They determined the frequency of somatic ATRX mutations in PCC/PGL, by sequencing the ATRX coding region in a separate set of 103 tumors samples. It was found that 13 percent of tumors had ATRX mutations.

The authors remarked that even though their 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, which suggests that there is an interaction between the somatic and inherited genomes in solid cancers, which needs further investigation.

In the early months of 2014, the Endocrine Society issued the first ever clinical practice guidelines for the management of patients with PCC/PGL. It was recommended by them that genetic testing in all patients should be considered among other evidence-based guidance. The Patients with paraganglioma should be tested for SDHx mutations, and those with metastatic disease for SDHB mutations.

Dr. Fishbein sadi the guidelines are well thought. He added that it is especially important to identify SDHx mutation carriers and SDHB mutation carriers as they are at higher risk of malignant disease. As per the results of their study, tumor-specific somatic mutations, such as those in ATRX, can also be useful in identifying patients at the highest risk for more clinically aggressive disease.