S E Birch1, J G Kench2, E Takano3, P Chan3, A-L Chan4, K Chiam5, A-S Veillard6, P Stricker7, S Haupt4, Y Haupt8, L Horvath9, S B Fox10. 1. Department of Pathology, Peter MacCallum Cancer, East Melbourne simonebirch@mac.com. 2. Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, Sydney Sydney Medical School, University of Sydney, Sydney The Kinghorn Cancer Centre, Garvan Institute for Medical Research, Sydney. 3. Department of Pathology, Peter MacCallum Cancer, East Melbourne. 4. Department of Pathology, University of Melbourne, Melbourne. 5. The Kinghorn Cancer Centre, Garvan Institute for Medical Research, Sydney. 6. NHMRC Clinical Trial Centre, University of Sydney, Sydney. 7. The Kinghorn Cancer Centre, Garvan Institute for Medical Research, Sydney Department of Urology, St Vincent's Clinic, Sydney. 8. Department of Pathology, Peter MacCallum Cancer, East Melbourne Department of Pathology, University of Melbourne, Melbourne Department of Biochemistry and Molecular Biology, Monash University, Melbourne. 9. Sydney Medical School, University of Sydney, Sydney The Kinghorn Cancer Centre, Garvan Institute for Medical Research, Sydney Department of Medical Oncology, Chris O'Brien Lifehouse, Sydney, Australia. 10. Department of Pathology, Peter MacCallum Cancer, East Melbourne Department of Pathology, University of Melbourne, Melbourne Department of Pathology, University of Melbourne, Melbourne.
Abstract
BACKGROUND: The promyelocytic leukemia (PML) tumor suppressor plays an important role in the response to a variety of cellular stressors and its expression is downregulated or lost in a range of human tumors. We have previously shown that the E3 ligase E6-associated protein (E6AP) is an important regulator of PML protein stability but the relationship and clinical impact of PML and E6AP expression in prostatic carcinoma is unknown. METHODS: E6AP and PML expression was assessed in tissue microarrays from a phase I discovery cohort of 170 patients treated by radical prostatectomy for localized prostate cancer (PC). Correlation analysis was carried out between PML and E6AP expression and clinicopathological variates including PSA as a surrogate of disease recurrence. The results were confirmed in a phase II validation cohort of 318 patients with associated clinical recurrence and survival data. RESULTS: Survival analysis of the phase I cohort revealed that patients whose tumors showed reduced PML and high E6AP expression had reduced time to PSA relapse (P = 0.012). This was confirmed in the phase II validation cohort where the expression profile of high E6AP/low PML was significantly associated with reduced time to PSA relapse (P < 0.001), clinical relapse (P = 0.016) and PC-specific death (P = 0.014). In multivariate analysis, this expression profile was an independent prognostic indicator of PSA relapse and clinical relapse independent of clinicopathologic factors predicting recurrence. CONCLUSION: This study identifies E6AP and PML as potential prognostic markers in localized prostate carcinoma and supports a role for E6AP in driving the downregulation or loss of PML expression in prostate carcinomas.
BACKGROUND: The promyelocytic leukemia (PML) tumor suppressor plays an important role in the response to a variety of cellular stressors and its expression is downregulated or lost in a range of humantumors. We have previously shown that the E3 ligase E6-associated protein (E6AP) is an important regulator of PML protein stability but the relationship and clinical impact of PML and E6AP expression in prostatic carcinoma is unknown. METHODS:E6AP and PML expression was assessed in tissue microarrays from a phase I discovery cohort of 170 patients treated by radical prostatectomy for localized prostate cancer (PC). Correlation analysis was carried out between PML and E6AP expression and clinicopathological variates including PSA as a surrogate of disease recurrence. The results were confirmed in a phase II validation cohort of 318 patients with associated clinical recurrence and survival data. RESULTS: Survival analysis of the phase I cohort revealed that patients whose tumors showed reduced PML and high E6AP expression had reduced time to PSA relapse (P = 0.012). This was confirmed in the phase II validation cohort where the expression profile of high E6AP/low PML was significantly associated with reduced time to PSA relapse (P < 0.001), clinical relapse (P = 0.016) and PC-specific death (P = 0.014). In multivariate analysis, this expression profile was an independent prognostic indicator of PSA relapse and clinical relapse independent of clinicopathologic factors predicting recurrence. CONCLUSION: This study identifies E6AP and PML as potential prognostic markers in localized prostate carcinoma and supports a role for E6AP in driving the downregulation or loss of PML expression in prostate carcinomas.
Authors: Twishi Gulati; Cheng Huang; Franco Caramia; Dinesh Raghu; Piotr J Paul; Robert J A Goode; Simon P Keam; Scott G Williams; Sue Haupt; Oded Kleifeld; Ralf B Schittenhelm; Cristina Gamell; Ygal Haupt Journal: Mol Cell Proteomics Date: 2018-02-20 Impact factor: 5.911
Authors: P J Paul; D Raghu; A-L Chan; T Gulati; L Lambeth; E Takano; M J Herold; J Hagekyriakou; R L Vessella; C Fedele; M Shackleton; E D Williams; S Fox; S Williams; S Haupt; C Gamell; Y Haupt Journal: Oncogene Date: 2016-09-19 Impact factor: 9.867
Authors: Alison Y Zhang; Karen Chiam; Ygal Haupt; Stephen Fox; Simone Birch; Wayne Tilley; Lisa M Butler; Karen Knudsen; Clay Comstock; Krishan Rasiah; Judith Grogan; Kate L Mahon; Tina Bianco-Miotto; Carmela Ricciardelli; Maret Böhm; Susan Henshall; Warick Delprado; Phillip Stricker; Lisa G Horvath; James G Kench Journal: Int J Cancer Date: 2018-12-04 Impact factor: 7.396
Authors: Dinesh Raghu; Piotr Jan Paul; Twishi Gulati; Siddhartha Deb; Christine Khoo; Andrea Russo; Enzo Gallo; Giovanni Blandino; Ai-Leen Chan; Elena Takano; Shahneen K Sandhu; Stephen B Fox; Scott Williams; Sue Haupt; Cristina Gamell; Ygal Haupt Journal: Oncotarget Date: 2017-06-27
Authors: Cristina Gamell; Ivona Bandilovska; Twishi Gulati; Arielle Kogan; Syer Choon Lim; Zaklina Kovacevic; Elena A Takano; Clelia Timpone; Arjelle D Agupitan; Cassandra Litchfield; Giovanni Blandino; Lisa G Horvath; Stephen B Fox; Scott G Williams; Andrea Russo; Enzo Gallo; Piotr J Paul; Catherine Mitchell; Shahneen Sandhu; Simon P Keam; Sue Haupt; Des R Richardson; Ygal Haupt Journal: iScience Date: 2019-11-02
Authors: Ji Young Kim; Kyu Min Kim; Ji Hye Yang; Sam Seok Cho; Seung Jung Kim; Su Jung Park; Sang-Gun Ahn; Gum Hwa Lee; Jin Won Yang; Sung Chul Lim; Keon Wook Kang; Sung Hwan Ki Journal: Sci Rep Date: 2020-01-16 Impact factor: 4.379