In vivo and in vitro oncogenic effects of HIF2A mutations in pheochromocytomas and paragangliomas.
Pheochromocytomas and paragangliomas are highly vascular tumors of the autonomic nervous system. Germline mutations, including those in hypoxia-related genes, occur in one third of the cases, but somatic mutations are infrequent in these tumors. Using exome sequencing of six paired constitutive and tumor DNA from sporadic pheochromocytomas and paragangliomas, we identified a somatic mutation in the HIF2A (EPAS1) gene. Screening of an additional 239 pheochromocytomas/paragangliomas uncovered three other HIF2A variants in sporadic (4/167, 2.3%) but not in hereditary tumors or controls. Three of the mutations involved proline 531, one of the two residues that controls HIF2α stability by hydroxylation. The fourth mutation, on Ser71, was adjacent to the DNA binding domain. No mutations were detected in the homologous regions of the HIF1A gene in 132 tumors. Mutant HIF2A tumors had increased expression of HIF2α target genes, suggesting an activating effect of the mutations. Ectopically expressed HIF2α mutants in HEK293, renal cell carcinoma 786-0, or rat pheochromocytoma PC12 cell lines showed increased stability, resistance to VHL-mediated degradation, target induction, and reduced chromaffin cell differentiation. Furthermore, mice injected with cells expressing mutant HIF2A developed tumors, and those with Pro531Thr and Pro531Ser mutations had shorter latency than tumors from mice with wild-type HIF2A. Our results support a direct oncogenic role for HIF2A in human neoplasia and strengthen the link between hypoxic pathways and pheochromocytomas and paragangliomas.
['Toledo|Rodrigo A|RA|', 'Qin|Yuejuan|Y|', 'Srikantan|Subramanya|S|', 'Morales|Nicole Paes|NP|', 'Li|Qun|Q|', 'Deng|Yilun|Y|', 'Kim|Sang-Woo|SW|', 'Pereira|Maria Adelaide A|MA|', 'Toledo|Sergio P A|SP|', 'Su|Xiaoping|X|', 'Aguiar|Ricardo C T|RC|', 'Dahia|Patricia L M|PL|']
D000310:Adrenal Gland Neoplasms D000368:Aged D000818:Animals D051792:Basic Helix-Loop-Helix Transcription Factors D002648:Child D005260:Female D057809:HEK293 Cells D006801:Humans D008297:Male D051379:Mice D008819:Mice, Nude D008875:Middle Aged D009154:Mutation D016716:PC12 Cells D010235:Paraganglioma D010673:Pheochromocytoma D051381:Rats D047368:Tumor Burden
HIF2A mutations pheochromocytoma paraganglioma somatic EPAS1 cancer hypoxia