Background
Succinate dehydrogenase (SDH) loss and mastermind-like 3 (MAML3) translocation are two clinically important genetic alterations that correlate with increased rates of metastasis in subtypes of human paraganglioma and pheochromocytoma (PPGL) neuroendocrine tumors. Although hypotheses propose that succinate accumulation after SDH loss poisons dioxygenases and activates pseudohypoxia and epigenomic hypermethylation, it remains unclear whether these mechanisms account for oncogenic transcriptional patterns. Additionally, MAML3 translocation has recently been identified as a genetic alteration in PPGL, but is poorly understood. We hypothesize that a key to understanding tumorigenesis driven by these genetic alterations is identification of the transcription factors responsible for the observed oncogenic transcriptional changes.
Conclusions
The unbiased analyses presented here nominate specific transcription factors that are likely drivers of oncogenic transcription in PPGL tumors. This information has the potential to be exploited for targeted therapy. Additionally, the observation that SDH loss or inhibition results in blunted retinoic acid response suggests a potential developmental etiology for this tumor subtype.
Methods
We leverage publicly-available human tumor gene expression profiling experiments (N = 179) to reconstruct a PPGL tumor-specific transcriptional network. We subsequently use the inferred transcriptional network to perform master regulator analyses nominating transcription factors predicted to control oncogenic transcription in specific PPGL molecular subtypes.
Results
A small number of master regulator transcription factors are predicted to drive the observed subtype-specific gene expression patterns in SDH loss and MAML3 translocation-positive PPGL. Interestingly, although EPAS1 perturbation is detectible in SDH-loss and VHL-loss tumors, it is by no means the most potent factor driving observed patterns of transcriptional dysregulation. Analysis of conserved SDH-loss master regulators in human tumors and MEFs implicated ZNF423, a known modulator of retinoic acid response in neuroblastoma. Subsequent functional analysis revealed a blunted cell death response to retinoic acid in SDH-loss MEFs and blunted differentiation response in SDH-inhibited SH-SY5Y neuroblastoma cells. Conclusions: The unbiased analyses presented here nominate specific transcription factors that are likely drivers of oncogenic transcription in PPGL tumors. This information has the potential to be exploited for targeted therapy. Additionally, the observation that SDH loss or inhibition results in blunted retinoic acid response suggests a potential developmental etiology for this tumor subtype.