Wolfgang Jäger1, Christian Thomas2, Ladan Fazli3, Antonio Hurtado-Coll3, Estelle Li3, Claudia Janssen1, Kilian M Gust3, Alan I So3, Michael Hainz4, Irene Schmidtmann5, Frederik C Roos2, Joachim W Thüroff2, Walburgis Brenner2, Peter C Black6. 1. Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada; Department of Urology, Johannes Gutenberg University, Mainz, Germany. 2. Department of Urology, Johannes Gutenberg University, Mainz, Germany. 3. Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada. 4. Institute of Pathology, Johannes Gutenberg University, Mainz, Germany. 5. Institute of Medical Biostatistics, Epidemiology and Informatics, Johannes Gutenberg University, Mainz, Germany. 6. Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada. Electronic address: pblack@mail.ubc.ca.
Abstract
PURPOSE: Aberrant HH signaling has proved important in the pathogenesis of several solid cancers. Limited in vitro analyses suggested an oncogenic role for HH in renal cell carcinoma. In this explorative study we sought to validate aberrant HH expression in patients with renal cell carcinoma. MATERIALS AND METHODS: A tissue microarray was constructed from 140 radical nephrectomy specimens of patients with clear cell renal cell carcinoma. We performed immunohistochemistry for Ki67 and HH pathway biomarkers, including PTCH1, Smo, SHH, IHH, DHH, Gli1, Gli2 and Gli3. Staining intensity was measured by automated image processing and related to tumor stage and grade. The impact of biomarker expression on cancer specific survival was determined by univariate and multivariate Cox regression analysis. RESULTS: Gli3, PTCH1, DHH and SHH demonstrated markedly higher expression in high than in low grade tumors. Tumor stage was not associated with marker expression. On univariate analysis DHH expression, and tumor grade and stage were associated with cancer specific survival. Multivariate analysis revealed that DHH, grade and stage were independent predictors of cancer specific survival. CONCLUSIONS: To our knowledge we report for the first time that a biomarker of the HH pathway is associated with adverse pathological features and poor disease outcomes in patients with clear cell renal cell carcinoma. DHH may serve as an independent predictor of cancer specific survival in clear cell renal cell carcinoma cases. This supports further evaluation of HH signaling to validate the pathway as a target for novel therapy.
PURPOSE: Aberrant HH signaling has proved important in the pathogenesis of several solid cancers. Limited in vitro analyses suggested an oncogenic role for HH in renal cell carcinoma. In this explorative study we sought to validate aberrant HH expression in patients with renal cell carcinoma. MATERIALS AND METHODS: A tissue microarray was constructed from 140 radical nephrectomy specimens of patients with clear cell renal cell carcinoma. We performed immunohistochemistry for Ki67 and HH pathway biomarkers, including PTCH1, Smo, SHH, IHH, DHH, Gli1, Gli2 and Gli3. Staining intensity was measured by automated image processing and related to tumor stage and grade. The impact of biomarker expression on cancer specific survival was determined by univariate and multivariate Cox regression analysis. RESULTS:Gli3, PTCH1, DHH and SHH demonstrated markedly higher expression in high than in low grade tumors. Tumor stage was not associated with marker expression. On univariate analysis DHH expression, and tumor grade and stage were associated with cancer specific survival. Multivariate analysis revealed that DHH, grade and stage were independent predictors of cancer specific survival. CONCLUSIONS: To our knowledge we report for the first time that a biomarker of the HH pathway is associated with adverse pathological features and poor disease outcomes in patients with clear cell renal cell carcinoma. DHH may serve as an independent predictor of cancer specific survival in clear cell renal cell carcinoma cases. This supports further evaluation of HH signaling to validate the pathway as a target for novel therapy.
Authors: Anna Kotulak-Chrzaszcz; Agnieszka Rybarczyk; Jakub Klacz; Marcin Matuszewski; Zbigniew Kmiec; Piotr M Wierzbicki Journal: Int J Mol Med Date: 2022-03-10 Impact factor: 4.101