A1 Refereed original research article in a scientific journal

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




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

PublisherWiley

Publication year2024

JournalCancer Medicine

Journal name in sourceCancer Medicine

Article numbere6998

Volume13

Issue3

ISSN2045-7634

eISSN2045-7634

DOIhttps://doi.org/10.1002/cam4.6998

Web address https://doi.org/10.1002/cam4.6998

Self-archived copy’s web addresshttps://research.utu.fi/converis/portal/detail/Publication/387280829


Abstract

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.


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Funding information in the publication
This work was supported by Kidney Foundation (Munuaissäätiö), the Finnish Urological Association, Diagnostic Center (Helsinki University hospital) and the Cancer Foundation Finland.


Last updated on 2024-20-12 at 09:26