structural rearrangements in metastatic pheochromocytomas.

Pheochromocytomas (PC) and paragangliomas (PGL) are endocrine tumors for which the genetic and clinicopathological features of metastatic progression remain incompletely understood. As a result, the risk of metastasis from a primary tumor cannot be predicted. Early diagnosis of individuals at high risk of developing metastases is clinically important and the identification of new biomarkers that are predictive of metastatic potential is of high value. Activation of has been associated with a number of malignant tumors, including PC/PGL. However, the mechanism of activation in the majority of PC/PGL remains unclear. As promoter mutations occur rarely in PC/PGL, we hypothesized that other mechanisms - such as structural variations - may underlie activation in these tumors. From 35 PC and four PGL, we identified three primary PCs that developed metastases with elevated expression, each of which lacked promoter mutations and promoter DNA methylation. Using whole genome sequencing, we identified somatic structural alterations proximal to the locus in two of these tumors. In both tumors, the genomic rearrangements led to the positioning of super-enhancers proximal to the promoter, that are likely responsible for the activation of the normally tightly repressed expression in chromaffin cells.