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.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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).
  
  
  METHODS
  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.
  
  
  METHODS
  The incidence of IDC-P and association with overall survival for BRCA2 and BRCAX patients were determined using Kaplan-Meier analysis.
  
  
  CONCLUSIONS
  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).
  
  
  CONCLUSIONS
  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.
  
  
  RESULTS
  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.
authors.affiliation: Prostate Cancer Research Group, Department of Anatomy and Developmental Biology, Monash University, Melbourne, Victoria, Australia.
authors.forename: Gail P
authors.initials: GP
authors.lastname: Risbridger
authors.affiliation: Prostate Cancer Research Group, Department of Anatomy and Developmental Biology, Monash University, Melbourne, Victoria, Australia; Department of Physiology, Monash University, Melbourne, Victoria, Australia.
authors.forename: Renea A
authors.initials: RA
authors.lastname: Taylor
authors.affiliation: Tissupath, Mt. Waverley, Victoria, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Clouston
authors.affiliation: 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.
authors.forename: Ania
authors.initials: A
authors.lastname: Sliwinski
authors.affiliation: 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.
authors.forename: Heather
authors.initials: H
authors.lastname: Thorne
authors.affiliation: 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.
authors.forename: Sally
authors.initials: S
authors.lastname: Hunter
authors.affiliation: 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.
authors.forename: Jason
authors.initials: J
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Gillian
authors.initials: G
authors.lastname: Mitchell
authors.affiliation: Division of Cancer Surgery, Peter MacCallum Cancer Centre, University of Melbourne, East Melbourne, Victoria, Australia; Epworth Research Centre, Epworth Healthcare, Victoria, Australia.
authors.forename: Declan
authors.initials: D
authors.lastname: Murphy
authors.affiliation: 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.
authors.forename: Mark
authors.initials: M
authors.lastname: Frydenberg
authors.affiliation: Prostate Cancer Research Group, Department of Anatomy and Developmental Biology, Monash University, Melbourne, Victoria, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Pook
authors.affiliation: Prostate Cancer Research Group, Department of Anatomy and Developmental Biology, Monash University, Melbourne, Victoria, Australia; Tissupath, Mt. Waverley, Victoria, Australia.
authors.forename: John
authors.initials: J
authors.lastname: Pedersen
authors.affiliation: Prostate Cancer Research Group, Department of Anatomy and Developmental Biology, Monash University, Melbourne, Victoria, Australia.
authors.forename: Roxanne
authors.initials: R
authors.lastname: Toivanen
authors.affiliation: Prostate Cancer Research Group, Department of Anatomy and Developmental Biology, Monash University, Melbourne, Victoria, Australia.
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.affiliation: Prostate Cancer Research Group, Department of Anatomy and Developmental Biology, Monash University, Melbourne, Victoria, Australia.
authors.forename: Melissa
authors.initials: M
authors.lastname: Papargiris
authors.affiliation: Prostate Cancer Research Group, Department of Anatomy and Developmental Biology, Monash University, Melbourne, Victoria, Australia.
authors.forename: Mitchell G
authors.initials: MG
authors.lastname: Lawrence
authors.affiliation: Department of Urology, University of Melbourne, Austin Hospital, Melbourne Heidelberg, Victoria, Australia. Electronic address: damienmb@unimelb.edu.au.
authors.forename: Damien M
authors.initials: DM
authors.lastname: Bolton
mesh_terms: D000368:Aged; D000818:Animals; D024682:BRCA2 Protein / Q000235:genetics*; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000235:genetics* / Q000401:mortality / Q000473:pathology* / Q000601:surgery; D020022:Genetic Predisposition to Disease; D040941:Heredity; D064593:Heterografts; D006801:Humans; D015994:Incidence; D053208:Kaplan-Meier Estimate; D008297:Male; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D009154:Mutation; D009368:Neoplasm Transplantation; D010375:Pedigree; D010641:Phenotype; D016016:Proportional Hazards Models; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology* / Q000601:surgery; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D024682:BRCA2 Protein; C551750:BRCA2 protein, human
keywords: BRCA2 germline mutations; Familial prostate cancer; Intraductal carcinoma; Pathology; Patient-derived xenografts