News Release

Posted: February 2, 2017

View the TCGA study of pheochromocytoma and paraganglioma here.

TCGA study identifies four subtypes of rare nervous system cancers

Researchers with The Cancer Genome Atlas Network determined that pheochromocytomas (PCC) and paragangliomas (PGL) can be classified into four distinct subtypes and also found several novel alterations never before seen in these rare cancers of the autonomic nervous system, a system that regulates our internal organs. Several genes that cause hereditary susceptibility to PCCs and PGLs have already been identified but changes to the genome that occur during the lifespan, termed somatic, have not been comprehensively studied. Led by Matthew Wilkerson, Ph.D., University of North Carolina, Chapel Hill, the scientists published an integrated genomic analysis of 173 PCC and PGL tumors in Cancer Cell on February 2, 2017.

Specifically, the analysis is the first to report a significant role of mutations to the cold shock domain-containing E-1 gene (CSDE1) in any type of cancer. Mutations in this gene resulted in decreased expression, which the researchers suggest may lead to inhibition of apoptosis, or programmed cell death. By diminishing apoptosis, CSDE1 mutations may prevent the cell’s normal process of self-destruction. The analysis also discovered the first gene fusion, two originally separate DNA sequences that fuse together, to drive PCC or PGL. In these cases, MAML3, a gene that promotes tumor development, is fused to regulatory DNA sequences that increase its expression. The study found an association between MAML3 overexpression and activation of the Wnt signaling pathway, which leads to increased cell proliferation and metastasis. Together, alterations to CSDE1 and MAML3 were strongly associated with an expression profile that the authors identified as a new subtype of PCCs and PGLs, termed the Wnt-altered subtype. This subtype was associated with clinically aggressive tumors. The study also identified another novel subtype called the cortical admixture subtype, and two subtypes that had been previously described, the pseudohypoxia and kinase signaling subtypes. Approximately 25 percent of the 2 million to 9 million persons per year who are diagnosed with PCC or PGL develop their cancer in the setting of a hereditary syndrome. By providing insight into the molecular nature of the 75 percent of cases driven by somatic alterations, this analysis may help build a foundation for more precise diagnosis and treatment of PCC and PGL. TCGA is a collaboration jointly supported and managed by the National Cancer Institute and the National Human Genome Research Institute, both parts of the National Institutes of Health.