Pennsylvania University. US: 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).