Key result
In 7 patients with cyanotic congenital heart disease, EPAS1 mutations were found in 15 of 16 pheochromocytoma/paraganglioma samples, which were also enriched for 11p deletions and 2p amplifications.
Why the study?
To further investigate the role of EPAS1 mutations in the hypoxia-driven pathogenesis of pheochromocytoma and paraganglioma complicating cyanotic congenital heart disease, particularly in metachronous and/or multifocal tumors.
Observational (n=7)
EPAS1 mutations are highly prevalent in PPGL complicating cyanotic congenital heart disease, driven by positive selection under hypoxic environments early in life.
EPAS1 mutations link hypoxia to multifocal CCHD-PPGL; hypothesis-generating, requires prospective validation before clinical use.
CONTEXT: Pheochromocytoma and paraganglioma (PPGL) may appear as a complication of cyanotic congenital heart disease (CCHD-PPGL) with frequent EPAS1 mutations, suggesting a close link between EPAS1 mutations and tissue hypoxia in CCHD-PPGL pathogenesis. OBJECTIVE: Our aim is to further investigate the role of EPAS1 mutations in the hypoxia-driven mechanism of CCHD-PPGL pathogenesis, particularly focusing on metachronous and/or multifocal CCHD-PPGL tumors. METHODS: We performed whole-exome sequencing (WES) for somatic and germline mutations in 15 PPGL samples from 7 CCHD patients, including 3 patients with metachronous and/or multifocal tumors, together with an adrenal medullary hyperplasia (AMH) sample. RESULTS: We detected EPAS1 mutations in 15 out of 16 PPGL/AMH samples from 7 cases. Conspicuously, all EPAS1 mutations in each of 3 cases with multifocal or metachronous tumors were mutually independent and typical examples of parallel evolution, which is suggestive of strong positive selection of EPAS1-mutated clones. Compared to 165 The Cancer Genome Atlas non-CCHD-PPGL samples, CCHD-PPGL/AMH samples were enriched for 11p deletions (13/16) and 2p amplifications (4/16). Of particular note, the multiple metachronous PPGL tumors with additional copy number abnormalities developed 18 to 23 years after the resolution of hypoxemia, suggesting that CCHD-induced hypoxic environments are critical for positive selection of EPAS1 mutants in early life, but may no longer be required for development of PPGL in later life. CONCLUSION: Our results highlight a key role of activated hypoxia-inducible factor 2α due to mutated EPAS1 in positive selection under hypoxic environments, although hypoxemia itself may not necessarily be required for the EPAS1-mutated clones to progress to PPGL.
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Ogasawara et al. (2022) conducted an observational in Pheochromocytoma and paraganglioma complicating cyanotic congenital heart disease (n=7). Cyanotic congenital heart disease (CCHD) vs. Non-CCHD-PPGL (TCGA samples) was evaluated on EPAS1 mutations and copy number abnormalities. In 7 patients with cyanotic congenital heart disease, EPAS1 mutations were found in 15 of 16 pheochromocytoma/paraganglioma samples, which were also enriched for 11p deletions and 2p amplifications.
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