Research Paper Volume 12, Issue 7 pp 5781—5791

A novel germline gain-of-function HIF2A mutation in hepatocellular carcinoma with polycythemia

Jiong Yu1, *, , Xiaowei Shi1, *, , Chunzhang Yang2, , Petra Bullova3, , Christopher S. Hong2, , Cody L. Nesvick2, , Pauline Dmitriev2, , Karel Pacak3, , Zhengping Zhuang2, , Hongcui Cao1, , Lanjuan Li1, ,

  • 1 State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou City, China
  • 2 Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke (NINDS), National Institute of Health (NIH), Bethesda, MD 20892, USA
  • 3 Department of Molecular Medicine, Institute of Virology, Slovak Academy of Sciences, Bratislava, Slovakia
* Equal contribution

Received: November 16, 2019       Accepted: January 27, 2020       Published: April 1, 2020
How to Cite

Copyright © 2020 Yu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Hypoxia-inducible factors (HIFs) regulate oxygen sensing and expression of genes involved in angiogenesis and erythropoiesis. Polycythemia has been observed in patients with hepatocellular carcinoma (HCC), but the underlying molecular basis remains unknown. Liver tissues from 302 HCC patients, including 104 with polycythemia, were sequenced for HIF2A mutations. A germline HIF2A mutation was detected in one HCC patient with concurrent polycythemia. Three additional family members carried this mutation, but none exhibited polycythemia or were diagnosed with HCC. The gain-of-function mutation resulted in a HIF-2α protein that was transcribed normally but resistant to degradation. HIF-2α target genes EDN1, EPO, GNA14, and VEGF were significantly upregulated in the tumor bed but not in the surrounding liver tissue. Polycythemia resolved upon total resection of the tumor tissue. This newly described HIF2A mutation may promote HCC oncogenesis.


HIF: hypoxia-inducible factor; VHL: Von Hippel-Lindau; EGLN1: Egl-9 homolog 1; PHD2: prolyl hydroxylase domain-containing protein 2; ODD: oxygen-dependent domain; HCC: hepatocellular carcinoma; AASLD: American Association for the Study of Liver Diseases; WHO: World Health Organization; DAB: 3:3’-diaminobenzidine; mRNA: messenger RNA; PCR: polymerase chain reaction; EDN1: endothelin-1; EPO: erythropoietin; GNA14: guanine nucleotide binding protein alpha 14; VEGFA: vascular endothelial growth factor A; ACTB: beta-actin; IP: immunoprecipitation; hemagglutinin: HA; CHX: cycloheximide; CT: computed tomography; HBs: hepatitis B surface antigen; HBc: hepatitis B core antigen; HBe: hepatitis B envelope antigen; HCV: hepatitis C virus; AFP: α-fetoprotein; CBC: complete blood count; HEP: Hep par 1; CK19: cytokeratin 19; pVHL: Von Hippel-Lindau protein; OMIM: Online Mendelian Inheritance in Man; MEN: Multiple Endocrine Neoplasia.