title: Opposite prognostic roles of HIF1α and HIF2α expressions in bone metastatic clear cell renal cell cancer.
abstract: BACKGROUND
  Prognostic markers of bone metastatic clear cell renal cell cancer (ccRCC) are poorly established. We tested prognostic value of HIF1α/HIF2α and their selected target genes in primary tumors and corresponding bone metastases.
  
  
  RESULTS
  Expression of HIF2α was lower in mRCC both at mRNA and protein levels (p/mRNA/=0.011, p/protein/=0.001) while HIF1α was similar to nmRCC. At the protein level, CAIX, GAPDH and GLUT1 were increased in mRCC. In all primary RCCs, low HIF2α and high HIF1α as well as CAIX, GAPDH and GLUT1 expressions correlated with adverse prognosis, while VEGFR2 and EPOR gene expressions were associated with favorable prognosis. Multivariate analysis confirmed high HIF2α protein expression as an independent risk factor. Prognostic validation of HIFs, LDH, EPOR and VEGFR2 in RNA-Seq data confirmed higher HIF1α gene expression in primary RCC as an adverse (p=0.07), whereas higher HIF2α and VEGFR2 expressions as favorable prognostic factors. HIF1α/HIF2α-index (HIF-index) proved to be an independent prognostic factor in both the discovery and the TCGA cohort.
  
  
  METHODS
  Expressions of HIF1α and HIF2α as well as their 7 target genes were analysed on the mRNA and protein level in 59 non-metastatic ccRCCs (nmRCC), 40 bone metastatic primary ccRCCs (mRCC) and 55 corresponding bone metastases. Results were validated in 399 ccRCCs from the TCGA project.
  
  
  CONCLUSIONS
  We identified HIF2α protein as an independent marker of the metastatic potential of ccRCC, however, unlike HIF1α, increased HIF2α expression is a favorable prognostic factor. The HIF-index incorporated these two markers into a strong prognostic biomarker of ccRCC.
authors.affiliation: Department of Urology, Semmelweis University, Budapest 1082, Hungary.
authors.forename: Attila
authors.initials: A
authors.lastname: Szendrői
authors.affiliation: 2nd Department of Pathology, Semmelweis University, Budapest 1091, Hungary.
authors.forename: A Marcell
authors.initials: AM
authors.lastname: Szász
authors.affiliation: 2nd Department of Pathology, Semmelweis University, Budapest 1091, Hungary.
authors.forename: Magdolna
authors.initials: M
authors.lastname: Kardos
authors.affiliation: 2nd Department of Pathology, Semmelweis University, Budapest 1091, Hungary.|Molecular Oncology Research Group, Hungarian Academy of Sciences and Semmelweis University, Budapest 1091, Hungary.
authors.forename: Anna-Mária
authors.initials: AM
authors.lastname: Tőkés
authors.affiliation: 2nd Department of Pathology, Semmelweis University, Budapest 1091, Hungary.
authors.forename: Roni
authors.initials: R
authors.lastname: Idan
authors.affiliation: Department of Urology, Semmelweis University, Budapest 1082, Hungary.
authors.forename: Miklós
authors.initials: M
authors.lastname: Szűcs
authors.affiliation: 2nd Department of Pathology, Semmelweis University, Budapest 1091, Hungary.
authors.forename: Janina
authors.initials: J
authors.lastname: Kulka
authors.affiliation: Department of Urology, Semmelweis University, Budapest 1082, Hungary.
authors.forename: Péter
authors.initials: P
authors.lastname: Nyirády
authors.affiliation: Department of Orthopedics, Semmelweis University, Budapest 1113, Hungary.
authors.forename: Miklós
authors.initials: M
authors.lastname: Szendrői
authors.affiliation: Children's Hospital Informatics Program at the Harvard-MIT Division of Health Sciences and Technology, Harvard Medical School, Boston, MA 02115, USA.|Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Lyngby 2800, Denmark.
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Szállási
authors.affiliation: MTA-TTK Lendület Cancer Biomarker Research Group, Budapest 1117, Hungary.|2nd Department of Pediatrics, Semmelweis University, Budapest 1082, Hungary.
authors.forename: Balázs
authors.initials: B
authors.lastname: Győrffy
authors.affiliation: 2nd Department of Pathology, Semmelweis University, Budapest 1091, Hungary.|Molecular Oncology Research Group, Hungarian Academy of Sciences and Semmelweis University, Budapest 1091, Hungary.
authors.forename: József
authors.initials: J
authors.lastname: Tímár
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000378:metabolism; D001859:Bone Neoplasms / Q000175:diagnosis / Q000556:secondary*; D002292:Carcinoma, Renal Cell / Q000175:diagnosis / Q000378:metabolism*; D018572:Disease-Free Survival; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007680:Kidney Neoplasms / Q000175:diagnosis / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011379:Prognosis; D012333:RNA, Messenger / Q000378:metabolism; D012306:Risk; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D014408:Biomarkers, Tumor; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human
keywords: bone metastasis; hypoxia inducible factor; prognosis; renal cell cancer