Casting one of the largest genomic nets to date for the rare tumours of the autonomic nervous system known as pheochromocytoma and paraganglioma (PCC\/PGL) captured several new mutations driving the disease that could serve as potential drug targets, researchers from Penn Medicine and other institutions report.<\/p>\n
Analysing genetic data of 173 patients from The Cancer Genome Atlas, researchers, including senior author Katherine Nathanson, MD, 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\u2019s 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.
\n\u201cWhat\u2019s interesting about these tumours 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,\u201d Nathanson said. \u201cThis characteristic makes these tumours ideal candidates for targeted therapy.\u201d Other cancer types typically contain anywhere from two to eight of these driver mutations.<\/p>\n
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.<\/p>\n
PGLs are rare tumours of nerve ganglia in the body, whereas PCCs form in the centre of the adrenal gland, which is responsible for producing adrenaline. The tumour 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 tumours become malignant \u2013 and become very aggressive. For that group, the five-year survival rate is about 50 percent.<\/p>\n
Matthew D. Wilkerson, MD, the Bioinformatics Director at the Collaborative Health Initiative Research Program at the Uniformed Services University, is the paper\u2019s co-senior author.<\/p>\n
To identify and characterize the genetic missteps, researchers analysed tumour 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-signalling subtype, a pseudohypoxia subtype, a cortical admixture subtype, and a Wnt-altered subtype. The last two have been newly classified.<\/p>\n
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 \u2013 a genetic hybrid, of sorts \u2013 in MAML3.<\/p>\n
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 tumours.<\/p>\n