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HIF2A gain-of-function mutations detected in duodenal gangliocytic paraganglioma

Publication at Faculty of Medicine in Hradec Králové |
2016

Abstract

Somatic hypoxia-inducible factor 2 alpha (HIF2A) mutations are responsible for a newly discovered syndrome of multiple paragangliomas (PGL) and duodenal somatostatinomas associated with polycythemia (Pacak-Zhuang syndrome). Gangliocytic PGL (GPGL), a mixed neuroectodermal-endodermal tumor, is a rare and unique type of PGL Until now, no familial cases of GPGL have been described.

We tested whether duodenal GPGLs share a similar pathogenic mechanism with PGLs associated with somatic HIF2A mutations. Ten GPGL tissues were screened for somatic HIF2A mutations; patient 1 was also tested for a potential germline HIF2A mutation, which included blood leukocytes and gallbladder tissue.

Genomic DNA was extracted from paraffin-embedded tissue and white blood cells. Two female patients were found to have pathogenic somatic HIF2A mutations in their GPGLs.

No HIF2A mutation was found in the blood or gallbladder tissue of patient 1. Whether HIF2A mutations may be associated with the presence of other (neuro)endocrine tumors or health-related abnormalities, especially in tumors that are found in the 2nd portion of the duodenum apart from those associated with MEN1, NF1, and HIF2A-related somatostatinomas, is currently unclear.

If a HIF2A mutation is found, patients may be considered to have personalized clinical and therapeutic management with a HIF2A-targeted drug as for other hereditary neuroendocrine tumors undergoing various genetic screening, including next-generation sequencing.