Cytoplasmic HIF-2α correlates to proliferation and predicts worse outcome in sympathetic paraganglioma

Karakaya, S.; Gunnesson, L.; Elias, E.; Martos Salvo, P.; Robledo, M.; Nilsson, O.; Wängberg, B.; Abel, F.; Pahlman, S.; Muth, A.; Mohlin, S.

doi:10.1101/2022.05.27.493680

bioRxiv · 10.1101/2022.05.27.493680

Cytoplasmic HIF-2α correlates to proliferation and predicts worse outcome in sympathetic paraganglioma

Karakaya, S.·Gunnesson, L.·Elias, E.·Martos Salvo, P.·Robledo, M.·Nilsson, O.·Wängberg, B.·Abel, F.·Pahlman, S.·Muth, A.·Mohlin, S.

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Abstract

Pheochromocytomas (PCCs) and paragangliomas (PGLs) are rare neuroendocrine tumors. PGLs can further be divided into sympathetic (sPGLs) and head-and-neck (HN-PGLs). There are virtually no treatment options, and no cure, for metastatic PCCs and PGLs (PPGLs). Here, we composed a tissue microarray (TMA) consisting of 149 PPGLs, reflecting clinical features and presenting as a useful resource. Mutations in the pseudohypoxic marker EPAS1/HIF-2 correlates to an aggressive tumor phenotype. We show that HIF-2 unexpectedly localized to the cytoplasm in PPGLs. This subcompartmentalized protein expression differed between tumor subtypes, and strongly correlated to proliferation. Half of all sPGLs were metastatic at time of diagnosis. Cytoplasmic HIF-2 was strongly expressed in metastatic sPGLs and predicted poor outcome in this subgroup. We propose that cytoplasmic HIF-2 expression serves as a useful clinical marker to differentiate subtypes and predicting outcome, and hence can be used for improved targeted treatment in PPGLs.

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Karakaya, S., Gunnesson, L., Elias, E., Martos Salvo, P., Robledo, M., Nilsson, O., Wängberg, B., Abel, F., Pahlman, S., Muth, A., Mohlin, S.. 2022-05-29. Cytoplasmic HIF-2α correlates to proliferation and predicts worse outcome in sympathetic paraganglioma. https://doi.org/10.1101/2022.05.27.493680

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