Paraganglioma (PGLs) are rare tumors of nerve ganglia in the body, whereas pheochromocytoma (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
Both are found in about two out of every million people
each year. An even smaller percentage of those tumors become malignant -
and become very aggressive. For that group, the five-year survival rate
is about 50%.
‘Single mutations make pheochromocytoma and paraganglioma ideal candidates for targeted therapy.’
Casting one of the largest genomic nets to date for these rare tumors
of the autonomic nervous system captured several new mutations driving the
disease that could serve as potential drug targets, researchers from
Penn Medicine and other institutions reported this week in Cancer Cell
Analyzing genetic data of 173 patients from The Cancer Genome Atlas,
researchers, including senior author Katherine Nathanson, a
professor in the division of Translational Medicine and Human Genetics
at the Perelman School of Medicine at the University of Pennsylvania and
associate director for Population Science at Penn's Abramson Cancer
Center, identified CSDE1 and fusion genes in MAML3 as drivers of the
disease, both a first for any cancer type. The researchers also
classified PCC/PGL into four distinct subtypes, each driven by mutations
in distinct biological pathways, two of which are novel.
"What's interesting about these tumors is that while they are
astonishingly diverse genetically, with both inherited and somatic
drivers influencing tumorigenesis, each has a single driver mutation,
not multiple mutations," Nathanson said. "This characteristic makes
these tumors ideal candidates for targeted therapy." Other cancer types
typically contain anywhere from two to eight of these driver mutations.
The discovery of these single drivers in PCC/PGL provides more
opportunities for molecular diagnosis and prognosis in these patients,
particularly those with more aggressive cancers, the authors said.
Matthew D. Wilkerson, the Bioinformatics Director at the
Collaborative Health Initiative Research Program at the Uniformed
Services University, is the paper's co-senior author.
To identify and characterize the genetic missteps, researchers
analyzed tumor specimens using whole-exome sequencing, mRNA and microRNA
sequencing, DNA-methylation arrays, and reverse-phase protein arrays.
The four molecularly defined subgroups included: a kinase-signaling
subtype, a pseudohypoxia subtype, a cortical admixture subtype, and a
Wnt-altered subtype. The last two have been newly classified.
The results also provided clinically actionable information by
confirming and identifying several molecular markers associated with an
increased risk of aggressive and metastatic disease, including germline
mutations in SDBH, somatic mutations in ATRX (previously established in a
Penn Medicine study), and new gene fusions - a genetic hybrid, of sorts
- in MAML3.
Because the MAML3 fusion gene activates the Wnt-altered subtype, the
authors said, existing targeted therapies that inhibit the beta-catenin
and STAT3 pathways may also prove effective in certain PCC/PGL tumors.
Other mutations identified in the analysis may also serve as potential
targets for drugs currently being investigated in other cancers. For
example, glutaminase inhibitors are being tested in SDH-mutant tumors,
including breast and lung, and ATR inhibitors are being investigated in
blood cancers. Today, there are several U.S. Food and Drug Administration-approved targeted therapies for mutations, such as BRAF and FGFR1, among others, also found in PCC/PGL.
"The study gives us the most comprehensive understanding of this
disease to date - which we believe will help researchers design better
trials and target mutations that will ultimately help improve treatment
for these patients," Nathanson said. "The next step is to focus more on
aggressive cancers that metastasize and the drivers behind those