HIF-2α-pVHL complex reveals broad genotype-phenotype correlations in HIF-2α-driven disease

Abstract

It is definitively established that mutations in transcription factor HIF-2α are causative of both neuroendocrine tumors (class 1 disease) and polycythemia (class 2 disease). However, the molecular mechanism that underlies this emergent genotype–phenotype relationship has remained unclear. Here, we report the structure of HIF-2α peptide bound to pVHL-elongin B-elongin C (VBC) heterotrimeric complex, which shows topographical demarcation of class 1 and 2 mutations affecting residues predicted, and demonstrated via biophysical analyses, to differentially impact HIF-2α-pVHL interaction interface stability. Concordantly, biochemical experiments showed that class 1 mutations disrupt pVHL affinity to HIF-2α more adversely than class 2 mutations directly or indirectly via impeding PHD2-mediated hydroxylation. These findings suggest that neuroendocrine tumor pathogenesis requires a higher HIF-2α dose than polycythemia, which requires only a mild increase in HIF-2α activity. These biophysical data reveal a structural basis that underlies, and can be used to predict de novo, broad genotype-phenotype correlations in HIF-2α-driven disease.

Epigenetic crosstalk between hypoxia and tumor driven by HIF regulation

“…HIF signaling directly or indirectly get a tightly command of physiological and pathological functions of numerous genes associated with carcinogenesis mechanisms, which refer to the regulation of proliferation, cell death, radiotherapy and chemotherapy [ 24 , 25 , 27 – 30 ], tumor microenvironment [ 31 – 33 ], metastasis [ 34 – 36 ], angiogenesis [ 37 – 40 ], and metabolic reprogramming [ 41 – 43 ] etc. within solid tumors.…”

Algorithmic evaluation of hereditary erythrocytosis: Pathways and caveats

“…In addition, although lifelong chronicity has been used to favor a heritable cause and the history of a normal phase to favor an acquired condition, the recent link between the oxygen-sensing pathway genes (HIF2/EPAS, PHD2/EGLN1, and VHL) and late-onset erythrocytosis and/or tumor development has widened the phenotypic spectrum of hereditary disorders. 22,25,29,30 Similarly, our experience suggests a normal serum epo level cannot be used to exclude VHL-associated HE and a normal p50 level cannot exclude a BPGM mutation. Due to this overlap, high throughput sequencing modalities will undoubtedly become routine in the diagnosis of these disorders; however, these algorithms and pathways remain useful for straightforward cases and to further characterize the variants of uncertain significance that invariably result from high power genetic testing.…”

“…Interestingly, due to other genes affected, OSP mutations have also been associated with tumor formation, with or without an elevation in hemoglobin. Most commonly neuroendocrine tumors (paraganglioma, pheochromocytoma, somatostatinoma) and rarer cases of vascular neoplasms (hemangioblastoma) have been described in gain of function HIF2α ( EPAS1 ) mutations, as well as, PHD2 ( EGLN1 ) and VHL mutations . Some cases display a wild‐type genotype in peripheral blood, despite showing erythrocytosis at an early age with the EPAS1 mutation detected in tumor tissue .…”

“…Most algorithms stress early exclusion of JAK2 mutations in adult patients, particularly the JAK2 V617F mutation, but many do not mention the practical interpretive difference between results obtained by Sanger sequencing in contrast to more sensitive techniques, such as allele‐specific point mutation detection by quantitative PCR. In addition, although lifelong chronicity has been used to favor a heritable cause and the history of a normal phase to favor an acquired condition, the recent link between the oxygen‐sensing pathway genes ( HIF2/EPAS, PHD2/EGLN1, and VHL) and late‐onset erythrocytosis and/or tumor development has widened the phenotypic spectrum of hereditary disorders . Similarly, our experience suggests a normal serum epo level cannot be used to exclude VHL‐associated HE and a normal p50 level cannot exclude a BPGM mutation.…”

“…neoplasms (hemangioblastoma) have been described in gain of function HIF2α (EPAS1) mutations, as well as, PHD2 (EGLN1) and VHL mutations. [22][23][24] Some cases display a wild-type genotype in peripheral blood, despite showing erythrocytosis at an early age with the EPAS1 mutation detected in tumor tissue. 23,25 OSP pathway abnormalities are associated with normal p50 values and inappropriately normal to increased Epo levels.…”