Expression of HIF-1 alpha in medullary thyroid cancer identifies a subgroup with poor prognosis

Lutske Lodewijk, Paul van Diest, Petra van der Groep, Natalie ter Hoeve, Abbey Schepers, Johannes Morreau, Johannes Bonenkamp, Adriana van Engen-van Grunsven, Schelto Kruijff, Bettien van Hemel, Thera Links, Els Nieveen van Dijkum, Susanne van Eeden, Gerlof Valk, Inne Borel Rinkes, Menno Vriens*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

Background: Medullary thyroid cancer (MTC) comprises only 4% of all thyroid cancers and originates from the parafollicular C-cells. HIF-1 alpha expression has been implied as an indicator of worse prognosis in various solid tumors. However, whether expression of HIF-1 alpha is a prognosticator in MTC remained unclear. Our aim was to evaluate the prognostic value of HIF-1 alpha in patients with MTC.

Methods: All patients with MTC who were operated on between 1988 and 2014 in five tertiary referral centers in The Netherlands were included. A tissue microarray was constructed in which 111 primary tumors could be analyzed for expression of HIF-1 alpha, CAIX, Glut-1, VEGF and CD31 and correlated with clinicopathologic variables and survival.

Results: The mean age of patients was 46.3 years (SD 15.6), 59 (53.2%) were male. Of the 111 primary tumors, 49 (44.1%) were HIF-1 alpha negative and 62 (55.9%) were HIF-1 alpha positive. Positive HIF-1 alpha expression was an independent negative indicator for progression free survival (PFS) in multivariate cox regression analysis (HR 3.1; 95% CI 1.3 - 7.3). Five-years survival decreased from 94.0% to 65.9% for the HIF-1 alpha positive group (p= 0.007). Even within the group of patients with TNM-stage IV disease, HIF-1 alpha positivity was associated with a worse prognosis, shown by a decrease in 5-years survival of 88.0% to 49.3% ( p= 0.020).

Conclusion: Expression of HIF-1 alpha is strongly correlated with adverse prognosis of MTC. This could open up new ways for targeted systemic therapy of MTC.

Original languageEnglish
Pages (from-to)28650-28659
Number of pages10
JournalOncotarget
Volume8
Issue number17
DOIs
Publication statusPublished - 2017

Keywords

  • medullary thyroid cancer
  • hypoxia inducible factor 1 alpha
  • immunohistochemistry
  • tissue microarray
  • oncology
  • HYPOXIA-INDUCIBLE FACTOR-1
  • ANTIGEN DOUBLING-TIMES
  • TISSUE MICROARRAYS
  • CARCINOMA
  • MUTATIONS
  • PROTEIN
  • RET
  • CALCITONIN
  • SURVIVAL
  • MARKER

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