Low nuclear expression of HIF-hydroxylases PHD2/EGLN1 and PHD3/EGLN3 are associated with poor recurrence-free survival in clear cell renal cell carcinoma

Lassi Luomala, Kalle Mattila, Paula Vainio, Harry Nisén, Teijo Pellinen, Jouni Lohi, Teemu D. Laajala, Petrus Järvinen, Anna-Riina Koskenniemi, Panu Jaakkola, Tuomas Mirtti

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Background: Hypoxia inducible factors, HIF-1α and HIF-2α, and their main regulators, the prolyl hydroxylase domain proteins (PHDs), mediate cellular response to hypoxia and contribute to tumor progression in clear cell renal cell carcinoma (ccRCC). These biomarkers may improve the value of traditional histopathological features in predicting disease progression after nephrectomy for localized ccRCC and guide patient selection for adjuvant treatments. Patients and Methods: In this study, we analyzed the associations of PHD2 and PHD3 with histopathological tumor features and recurrence-free survival (RFS) in a retrospective cohort of 173 patients who had undergone surgery for localized ccRCC at Helsinki University Hospital (HUH), Finland. An external validation cohort of 191 patients was obtained from Turku University Hospital (TUH), Finland. Tissue-microarrays (TMA) were constructed using the primary tumor samples. Clinical parameters and follow-up information from 2006 to 2019 were obtained from electronic medical records. The cytoplasmic and nuclear expression of PHD2, and PHD3 were scored based on immunohistochemical staining and their associations with histopathological features and RFS were evaluated. Results: Nuclear PHD2 and PHD3 expression in cancer cells were associated with lower pT-stage and Fuhrman grade compared with negative nuclei. Patients with positive nuclear expression of PHD2 and PHD3 in cancer cells had favorable RFS compared with patients having negative tumors. The nuclear expression of PHD2 was independently associated with a decreased risk of disease recurrence or death from RCC in multivariable analysis. These results were observed in both cohorts. Conclusions: The absence of nuclear PHD2 and PHD3 expression in ccRCC was associated with poor RFS and the nuclear expression of PHD2 predicted RFS regardless of other known histopathological prognostic factors. Nuclear PHD2 and PHD3 are potential prognostic biomarkers in patients with localized ccRCC and should be further investigated and validated in prospective studies.

Original languageEnglish
Article numbere6998
JournalCancer medicine
Issue number3
Publication statusPublished - Feb 2024
MoE publication typeA1 Journal article-refereed

Bibliographical note

Publisher Copyright:
© 2024 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Fields of Science

  • biomarker
  • hydroxylase-domain proteins (PHD)
  • hypoxia inducible factors (HIF)
  • recurrence-free survival
  • renal cell carcinoma (RCC)
  • 3122 Cancers

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