Multi-institutional evaluation of the prognostic significance of EZH2 expression in high-grade upper tract urothelial carcinoma

Nirmish Singla, Laura Maria Krabbe, Ahmet M. Aydin, Vandana Panwar, Solomon L. Woldu, Yuval Freifeld, Christopher G. Wood, Jose A. Karam, Alon Z. Weizer, Jay D. Raman, Mesut Remzi, Nathalie Rioux-Leclercq, Andrea Haitel, Marco Roscigno, Christian Bolenz, Karim Bensalah, Arthur I Sagalowsky, Shahrokh F. Shariat, Yair Lotan, Aditya BagrodiaPayal Kapur, Vitaly Margulis

Research output: Contribution to journalArticle

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Abstract

Purpose: Enhancer of zeste homolog 2 is a methyltransferase encoded by the EZH2 gene, whose role in upper tract urothelial carcinoma (UTUC) is poorly understood. We sought to evaluate the prognostic value of EZH2 expression in UTUC. Methods: We reviewed a multi-institutional cohort of patients who underwent radical nephroureterectomy for high-grade UTUC from 1990 to 2008. Immunohistochemistry for EZH2 was performed on tissue microarrays. Percentage of staining was evaluated, and the discriminative value of EZH2 was tested, with EZH2 positivity defined as>20% staining present. Clinicopathologic characteristics and oncologic outcomes (recurrence-free (RFS), cancer-specific (CSS), and overall survival (OS)) were compared, stratified by EZH2 positivity. The prognostic role of EZH2 was assessed using Kaplan-Meier, univariate (UVA), and multivariate (MVA) Cox regression analyses. Significance was defined for P<0.05. Results: A total of 376 patients were included for analysis, with median follow-up 36.0 months. Overall, 78 (20.7%) were EZH2-positive. EZH2 expression was more often associated with ureteral location, lymphovascular invasion, sessile architecture, necrosis, and concomitant carcinoma in situ. On UVA, increased EZH2 expression was a significant predictor for inferior RFS (HR 1.63, P = 0.033), CSS (HR 2.03, P = 0.003), and OS (HR 2.11, P<0.001). On MVA EZH2 remained a significant predictor of worse CSS (HR 1.99 [95% CI: 1.21–3.27], P = 0.007) and OS (HR 1.54 [95% CI: 1.06–2.24], P = 0.024), while significance was lost for RFS. Conclusion: Increased EZH2 expression is associated with adverse pathologic features and inferior oncologic outcomes in patients with high-grade UTUC. The role of EZH2 biology in UTUC pathogenesis remains to be further elucidated.

Original languageEnglish (US)
JournalUrologic Oncology: Seminars and Original Investigations
DOIs
StateAccepted/In press - Jan 1 2018

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Carcinoma
Survival
Staining and Labeling
Carcinoma in Situ
Methyltransferases
Necrosis
Immunohistochemistry
Regression Analysis
Recurrence
Genes
Neoplasms

Keywords

  • Enhancer of zeste homolog 2
  • Outcomes
  • Prognostic biomarker
  • Upper tract urothelial carcinoma

ASJC Scopus subject areas

  • Oncology
  • Urology

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Multi-institutional evaluation of the prognostic significance of EZH2 expression in high-grade upper tract urothelial carcinoma. / Singla, Nirmish; Krabbe, Laura Maria; Aydin, Ahmet M.; Panwar, Vandana; Woldu, Solomon L.; Freifeld, Yuval; Wood, Christopher G.; Karam, Jose A.; Weizer, Alon Z.; Raman, Jay D.; Remzi, Mesut; Rioux-Leclercq, Nathalie; Haitel, Andrea; Roscigno, Marco; Bolenz, Christian; Bensalah, Karim; Sagalowsky, Arthur I; Shariat, Shahrokh F.; Lotan, Yair; Bagrodia, Aditya; Kapur, Payal; Margulis, Vitaly.

In: Urologic Oncology: Seminars and Original Investigations, 01.01.2018.

Research output: Contribution to journalArticle

Singla, N, Krabbe, LM, Aydin, AM, Panwar, V, Woldu, SL, Freifeld, Y, Wood, CG, Karam, JA, Weizer, AZ, Raman, JD, Remzi, M, Rioux-Leclercq, N, Haitel, A, Roscigno, M, Bolenz, C, Bensalah, K, Sagalowsky, AI, Shariat, SF, Lotan, Y, Bagrodia, A, Kapur, P & Margulis, V 2018, 'Multi-institutional evaluation of the prognostic significance of EZH2 expression in high-grade upper tract urothelial carcinoma', Urologic Oncology: Seminars and Original Investigations. https://doi.org/10.1016/j.urolonc.2018.04.004
Singla, Nirmish ; Krabbe, Laura Maria ; Aydin, Ahmet M. ; Panwar, Vandana ; Woldu, Solomon L. ; Freifeld, Yuval ; Wood, Christopher G. ; Karam, Jose A. ; Weizer, Alon Z. ; Raman, Jay D. ; Remzi, Mesut ; Rioux-Leclercq, Nathalie ; Haitel, Andrea ; Roscigno, Marco ; Bolenz, Christian ; Bensalah, Karim ; Sagalowsky, Arthur I ; Shariat, Shahrokh F. ; Lotan, Yair ; Bagrodia, Aditya ; Kapur, Payal ; Margulis, Vitaly. / Multi-institutional evaluation of the prognostic significance of EZH2 expression in high-grade upper tract urothelial carcinoma. In: Urologic Oncology: Seminars and Original Investigations. 2018.
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title = "Multi-institutional evaluation of the prognostic significance of EZH2 expression in high-grade upper tract urothelial carcinoma",
abstract = "Purpose: Enhancer of zeste homolog 2 is a methyltransferase encoded by the EZH2 gene, whose role in upper tract urothelial carcinoma (UTUC) is poorly understood. We sought to evaluate the prognostic value of EZH2 expression in UTUC. Methods: We reviewed a multi-institutional cohort of patients who underwent radical nephroureterectomy for high-grade UTUC from 1990 to 2008. Immunohistochemistry for EZH2 was performed on tissue microarrays. Percentage of staining was evaluated, and the discriminative value of EZH2 was tested, with EZH2 positivity defined as>20{\%} staining present. Clinicopathologic characteristics and oncologic outcomes (recurrence-free (RFS), cancer-specific (CSS), and overall survival (OS)) were compared, stratified by EZH2 positivity. The prognostic role of EZH2 was assessed using Kaplan-Meier, univariate (UVA), and multivariate (MVA) Cox regression analyses. Significance was defined for P<0.05. Results: A total of 376 patients were included for analysis, with median follow-up 36.0 months. Overall, 78 (20.7{\%}) were EZH2-positive. EZH2 expression was more often associated with ureteral location, lymphovascular invasion, sessile architecture, necrosis, and concomitant carcinoma in situ. On UVA, increased EZH2 expression was a significant predictor for inferior RFS (HR 1.63, P = 0.033), CSS (HR 2.03, P = 0.003), and OS (HR 2.11, P<0.001). On MVA EZH2 remained a significant predictor of worse CSS (HR 1.99 [95{\%} CI: 1.21–3.27], P = 0.007) and OS (HR 1.54 [95{\%} CI: 1.06–2.24], P = 0.024), while significance was lost for RFS. Conclusion: Increased EZH2 expression is associated with adverse pathologic features and inferior oncologic outcomes in patients with high-grade UTUC. The role of EZH2 biology in UTUC pathogenesis remains to be further elucidated.",
keywords = "Enhancer of zeste homolog 2, Outcomes, Prognostic biomarker, Upper tract urothelial carcinoma",
author = "Nirmish Singla and Krabbe, {Laura Maria} and Aydin, {Ahmet M.} and Vandana Panwar and Woldu, {Solomon L.} and Yuval Freifeld and Wood, {Christopher G.} and Karam, {Jose A.} and Weizer, {Alon Z.} and Raman, {Jay D.} and Mesut Remzi and Nathalie Rioux-Leclercq and Andrea Haitel and Marco Roscigno and Christian Bolenz and Karim Bensalah and Sagalowsky, {Arthur I} and Shariat, {Shahrokh F.} and Yair Lotan and Aditya Bagrodia and Payal Kapur and Vitaly Margulis",
year = "2018",
month = "1",
day = "1",
doi = "10.1016/j.urolonc.2018.04.004",
language = "English (US)",
journal = "Urologic Oncology: Seminars and Original Investigations",
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TY - JOUR

T1 - Multi-institutional evaluation of the prognostic significance of EZH2 expression in high-grade upper tract urothelial carcinoma

AU - Singla, Nirmish

AU - Krabbe, Laura Maria

AU - Aydin, Ahmet M.

AU - Panwar, Vandana

AU - Woldu, Solomon L.

AU - Freifeld, Yuval

AU - Wood, Christopher G.

AU - Karam, Jose A.

AU - Weizer, Alon Z.

AU - Raman, Jay D.

AU - Remzi, Mesut

AU - Rioux-Leclercq, Nathalie

AU - Haitel, Andrea

AU - Roscigno, Marco

AU - Bolenz, Christian

AU - Bensalah, Karim

AU - Sagalowsky, Arthur I

AU - Shariat, Shahrokh F.

AU - Lotan, Yair

AU - Bagrodia, Aditya

AU - Kapur, Payal

AU - Margulis, Vitaly

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Purpose: Enhancer of zeste homolog 2 is a methyltransferase encoded by the EZH2 gene, whose role in upper tract urothelial carcinoma (UTUC) is poorly understood. We sought to evaluate the prognostic value of EZH2 expression in UTUC. Methods: We reviewed a multi-institutional cohort of patients who underwent radical nephroureterectomy for high-grade UTUC from 1990 to 2008. Immunohistochemistry for EZH2 was performed on tissue microarrays. Percentage of staining was evaluated, and the discriminative value of EZH2 was tested, with EZH2 positivity defined as>20% staining present. Clinicopathologic characteristics and oncologic outcomes (recurrence-free (RFS), cancer-specific (CSS), and overall survival (OS)) were compared, stratified by EZH2 positivity. The prognostic role of EZH2 was assessed using Kaplan-Meier, univariate (UVA), and multivariate (MVA) Cox regression analyses. Significance was defined for P<0.05. Results: A total of 376 patients were included for analysis, with median follow-up 36.0 months. Overall, 78 (20.7%) were EZH2-positive. EZH2 expression was more often associated with ureteral location, lymphovascular invasion, sessile architecture, necrosis, and concomitant carcinoma in situ. On UVA, increased EZH2 expression was a significant predictor for inferior RFS (HR 1.63, P = 0.033), CSS (HR 2.03, P = 0.003), and OS (HR 2.11, P<0.001). On MVA EZH2 remained a significant predictor of worse CSS (HR 1.99 [95% CI: 1.21–3.27], P = 0.007) and OS (HR 1.54 [95% CI: 1.06–2.24], P = 0.024), while significance was lost for RFS. Conclusion: Increased EZH2 expression is associated with adverse pathologic features and inferior oncologic outcomes in patients with high-grade UTUC. The role of EZH2 biology in UTUC pathogenesis remains to be further elucidated.

AB - Purpose: Enhancer of zeste homolog 2 is a methyltransferase encoded by the EZH2 gene, whose role in upper tract urothelial carcinoma (UTUC) is poorly understood. We sought to evaluate the prognostic value of EZH2 expression in UTUC. Methods: We reviewed a multi-institutional cohort of patients who underwent radical nephroureterectomy for high-grade UTUC from 1990 to 2008. Immunohistochemistry for EZH2 was performed on tissue microarrays. Percentage of staining was evaluated, and the discriminative value of EZH2 was tested, with EZH2 positivity defined as>20% staining present. Clinicopathologic characteristics and oncologic outcomes (recurrence-free (RFS), cancer-specific (CSS), and overall survival (OS)) were compared, stratified by EZH2 positivity. The prognostic role of EZH2 was assessed using Kaplan-Meier, univariate (UVA), and multivariate (MVA) Cox regression analyses. Significance was defined for P<0.05. Results: A total of 376 patients were included for analysis, with median follow-up 36.0 months. Overall, 78 (20.7%) were EZH2-positive. EZH2 expression was more often associated with ureteral location, lymphovascular invasion, sessile architecture, necrosis, and concomitant carcinoma in situ. On UVA, increased EZH2 expression was a significant predictor for inferior RFS (HR 1.63, P = 0.033), CSS (HR 2.03, P = 0.003), and OS (HR 2.11, P<0.001). On MVA EZH2 remained a significant predictor of worse CSS (HR 1.99 [95% CI: 1.21–3.27], P = 0.007) and OS (HR 1.54 [95% CI: 1.06–2.24], P = 0.024), while significance was lost for RFS. Conclusion: Increased EZH2 expression is associated with adverse pathologic features and inferior oncologic outcomes in patients with high-grade UTUC. The role of EZH2 biology in UTUC pathogenesis remains to be further elucidated.

KW - Enhancer of zeste homolog 2

KW - Outcomes

KW - Prognostic biomarker

KW - Upper tract urothelial carcinoma

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