Please use this identifier to cite or link to this item: http://ahro.austin.org.au/austinjspui/handle/1/12355
Title: Patient-derived xenografts reveal that intraductal carcinoma of the prostate is a prominent pathology in BRCA2 mutation carriers with prostate cancer and correlates with poor prognosis.
Authors: Risbridger, Gail P;Taylor, Renea A;Clouston, David;Sliwinski, Ania;Thorne, Heather;Hunter, Sally;Li, Jason;Mitchell, Gillian;Murphy, Declan;Frydenberg, Mark;Pook, David;Pedersen, John;Toivanen, Roxanne;Wang, Hong;Papargiris, Melissa;Lawrence, Mitchell G;Bolton, Damien M
Affiliation: Prostate Cancer Research Group, Department of Anatomy and Developmental Biology, Monash University, Melbourne, Victoria, Australia; Department of Physiology, Monash University, Melbourne, Victoria, Australia.
Tissupath, Mt. Waverley, Victoria, Australia.
kConFab, Research Department, Peter MacCallum Cancer Centre, University of Melbourne, East Melbourne, Victoria, Australia; Familial Cancer Centre, Peter MacCallum Cancer Centre, University of Melbourne, East Melbourne, Victoria, Australia; Division of Cancer Surgery, Peter MacCallum Cancer Centre, University of Melbourne, East Melbourne, Victoria, Australia.
kConFab, Research Department, Peter MacCallum Cancer Centre, University of Melbourne, East Melbourne, Victoria, Australia; Familial Cancer Centre, Peter MacCallum Cancer Centre, University of Melbourne, East Melbourne, Victoria, Australia; Department of Oncology, Peter MacCallum Cancer Centre, University of Melbourne, East Melbourne, Victoria, Australia.
Department of Oncology, Peter MacCallum Cancer Centre, University of Melbourne, East Melbourne, Victoria, Australia; Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, University of Melbourne, East Melbourne, Victoria, Australia.
Department of Oncology, Peter MacCallum Cancer Centre, University of Melbourne, East Melbourne, Victoria, Australia; Bioinformatics, Peter MacCallum Cancer Centre, University of Melbourne, East Melbourne, Victoria, Australia.
Division of Cancer Surgery, Peter MacCallum Cancer Centre, University of Melbourne, East Melbourne, Victoria, Australia; Epworth Research Centre, Epworth Healthcare, Victoria, Australia.
Prostate Cancer Research Group, Department of Anatomy and Developmental Biology, Monash University, Melbourne, Victoria, Australia; Department of Urology, Monash Medical Centre, Monash University, Melbourne, Victoria, Australia.
Prostate Cancer Research Group, Department of Anatomy and Developmental Biology, Monash University, Melbourne, Victoria, Australia; Tissupath, Mt. Waverley, Victoria, Australia.
Prostate Cancer Research Group, Department of Anatomy and Developmental Biology, Monash University, Melbourne, Victoria, Australia.
Department of Urology, University of Melbourne, Austin Hospital, Melbourne Heidelberg, Victoria, Australia. Electronic address: damienmb@unimelb.edu.au.
Issue Date: 22-Aug-2014
Citation: European Urology 2014; 67(3): 496-503
Abstract: Intraductal carcinoma of the prostate (IDC-P) is a distinct clinicopathologic entity associated with aggressive prostate cancer (PCa). PCa patients carrying a breast cancer 2, early onset (BRCA2) germline mutation exhibit highly aggressive tumours with poor prognosis.To investigate the presence and implications of IDC-P in men with a strong family history of PCa who either carry a BRCA2 pathogenic mutation or do not carry the mutation (BRCAX).Patient-derived xenografts (PDXs) were generated from three germline BRCA2 mutation carriers and one BRCAX patient. Specimens were examined for histologic evidence of IDC-P. Whole-genome copy number analysis (WG-CNA) was performed on IDC-P from a primary and a matched PDX specimen.The incidence of IDC-P and association with overall survival for BRCA2 and BRCAX patients were determined using Kaplan-Meier analysis.PDXs from BRCA2 tumours showed increased incidence of IDC-P compared with sporadic PCa (p=0.015). WG-CNA confirmed that the genetic profile of IDC-P from a matched (primary and PDX) BRCA2 tumour was similar. The incidence of IDC-P was significantly increased in BRCA2 carriers (42%, n=33, p=0.004) but not in BRCAX patients (25.8%, n=62, p=0.102) when both groups were compared with sporadic cases (9%, n=32). BRCA2 carriers and BRCAX patients with IDC-P had significantly worse overall and PCa-specific survival compared with BRCA2 carriers and BRCAX patients without IDC-P (hazard ratio [HR]: 16.9, p=0.0064 and HR: 3.57, p=0.0086, respectively).PDXs revealed IDC-P in patients with germline BRCA2 mutations or BRCAX classification, identifying aggressive tumours with poor survival even when the stage and grade of cancer at diagnosis were similar. Further studies of the prognostic significance of IDC-P in sporadic PCa are warranted.Intraductal carcinoma of the prostate is common in patients with familial prostate cancer and is associated with poor outcomes. This finding affects genetic counselling and identifies patients in whom earlier multimodality treatment may be required.
Internal ID Number: 25154392
URI: http://ahro.austin.org.au/austinjspui/handle/1/12355
DOI: 10.1016/j.eururo.2014.08.007
URL: http://www.ncbi.nlm.nih.gov/pubmed/25154392
Type: Journal Article
Subjects: BRCA2 germline mutations
Familial prostate cancer
Intraductal carcinoma
Pathology
Patient-derived xenografts
Appears in Collections:Journal articles

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