title: Germline BRCA2 mutations drive prostate cancers with distinct evolutionary trajectories.
abstract: Germline mutations in the BRCA2 tumour suppressor are associated with both an increased lifetime risk of developing prostate cancer (PCa) and increased risk of aggressive disease. To understand this aggression, here we profile the genomes and methylomes of localized PCa from 14 carriers of deleterious germline BRCA2 mutations (BRCA2-mutant PCa). We show that BRCA2-mutant PCa harbour increased genomic instability and a mutational profile that more closely resembles metastastic than localized disease. BRCA2-mutant PCa shows genomic and epigenomic dysregulation of the MED12L/MED12 axis, which is frequently dysregulated in metastatic castration-resistant prostate cancer (mCRPC). This dysregulation is enriched in BRCA2-mutant PCa harbouring intraductal carcinoma (IDC). Microdissection and sequencing of IDC and juxtaposed adjacent non-IDC invasive carcinoma in 10 patients demonstrates a common ancestor to both histopathologies. Overall we show that localized castration-sensitive BRCA2-mutant tumours are uniquely aggressive, due to de novo aberration in genes usually associated with metastatic disease, justifying aggressive initial treatment.
authors.affiliation: Monash Partners Comprehensive Cancer Consortium and Cancer Program, Biomedicine Discovery Institute, Department of Physiology, Monash University, Melbourne, Victoria 3800, Australia.
authors.forename: Renea A
authors.initials: RA
authors.lastname: Taylor
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada M5G 1L7.
authors.forename: Michael
authors.initials: M
authors.lastname: Fraser
authors.affiliation: Informatics &Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada M5G 0A3.
authors.forename: Julie
authors.identifier: 0000-0002-8424-3768
authors.initials: J
authors.lastname: Livingstone
authors.affiliation: Informatics &Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada M5G 0A3.
authors.forename: Shadrielle Melijah G
authors.initials: SM
authors.lastname: Espiritu
authors.affiliation: kConFab, Research Department, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia.|The Sir Peter MacCallum Department of Oncology University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Heather
authors.initials: H
authors.lastname: Thorne
authors.affiliation: Informatics &Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada M5G 0A3.
authors.forename: Vincent
authors.identifier: 0000-0002-6504-179X
authors.initials: V
authors.lastname: Huang
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada M5G 1L7.
authors.forename: Winnie
authors.initials: W
authors.lastname: Lo
authors.affiliation: Informatics &Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada M5G 0A3.
authors.forename: Yu-Jia
authors.initials: YJ
authors.lastname: Shiah
authors.affiliation: Informatics &Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada M5G 0A3.
authors.forename: Takafumi N
authors.identifier: 0000-0003-1082-3871
authors.initials: TN
authors.lastname: Yamaguchi
authors.affiliation: The Sir Peter MacCallum Department of Oncology University of Melbourne, Parkville, Victoria 3010, Australia.|Department of Urology, University of Melbourne, Austin Hospital, Heidelberg, Victoria 3084, Australia.
authors.forename: Ania
authors.initials: A
authors.lastname: Sliwinski
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada M5G 1L7.
authors.forename: Sheri
authors.initials: S
authors.lastname: Horsburgh
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada M5G 1L7.
authors.forename: Alice
authors.initials: A
authors.lastname: Meng
authors.affiliation: Informatics &Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada M5G 0A3.
authors.forename: Lawrence E
authors.initials: LE
authors.lastname: Heisler
authors.affiliation: Informatics &Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada M5G 0A3.
authors.forename: Nancy
authors.initials: N
authors.lastname: Yu
authors.affiliation: Informatics &Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada M5G 0A3.
authors.forename: Fouad
authors.initials: F
authors.lastname: Yousif
authors.affiliation: Monash Partners Comprehensive Cancer Consortium and Cancer Program Biomedicine Discovery Institute, Department of Anatomy and Developmental Biology, Monash University, Melbourne, Victoria 3800, Australia.
authors.forename: Melissa
authors.initials: M
authors.lastname: Papargiris
authors.affiliation: Monash Partners Comprehensive Cancer Consortium and Cancer Program Biomedicine Discovery Institute, Department of Anatomy and Developmental Biology, Monash University, Melbourne, Victoria 3800, Australia.
authors.forename: Mitchell G
authors.initials: MG
authors.lastname: Lawrence
authors.affiliation: Genome Technologies Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada M5G 0A3.
authors.forename: Lee
authors.initials: L
authors.lastname: Timms
authors.affiliation: Department of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia.
authors.forename: Declan G
authors.initials: DG
authors.lastname: Murphy
authors.affiliation: Monash Partners Comprehensive Cancer Consortium and Cancer Program Biomedicine Discovery Institute, Department of Anatomy and Developmental Biology, Monash University, Melbourne, Victoria 3800, Australia.
authors.forename: Mark
authors.initials: M
authors.lastname: Frydenberg
authors.affiliation: Informatics &Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada M5G 0A3.
authors.forename: Julia F
authors.initials: JF
authors.lastname: Hopkins
authors.affiliation: Monash Partners Comprehensive Cancer Consortium and Cancer Program Biomedicine Discovery Institute, Department of Anatomy and Developmental Biology, Monash University, Melbourne, Victoria 3800, Australia.
authors.forename: Damien
authors.initials: D
authors.lastname: Bolton
authors.affiliation: Urological Pathology, Tissupath, Mt Waverley, Victoria 3149, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Clouston
authors.affiliation: Genome Technologies Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada M5G 0A3.
authors.forename: John D
authors.initials: JD
authors.lastname: McPherson
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada M5G 1L7.
authors.forename: Theodorus
authors.initials: T
authors.lastname: van der Kwast
authors.affiliation: Informatics &Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada M5G 0A3.|Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada M5G 1L7.|Department of Pharmacology &Toxicology, University of Toronto, Toronto, Ontario, Canada M5S 1A8.
authors.forename: Paul C
authors.identifier: 0000-0003-0553-7520
authors.initials: PC
authors.lastname: Boutros
authors.affiliation: Monash Partners Comprehensive Cancer Consortium and Cancer Program Biomedicine Discovery Institute, Department of Anatomy and Developmental Biology, Monash University, Melbourne, Victoria 3800, Australia.
authors.forename: Gail P
authors.initials: GP
authors.lastname: Risbridger
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada M5G 1L7.|Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada M5G 1L7.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Bristow
mesh_terms: D000368:Aged; D024682:BRCA2 Protein / Q000172:deficiency / Q000235:genetics*; D044584:Carcinoma, Ductal / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D004252:DNA Mutational Analysis; D044127:Epigenesis, Genetic; D019143:Evolution, Molecular; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D042822:Genomic Instability; D018095:Germ-Line Mutation; D006579:Heterozygote; D006801:Humans; D008297:Male; D056892:Mediator Complex / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D011467:Prostate / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012189:Retrospective Studies; D000073336:Whole Genome Sequencing
chemical_list: D024682:BRCA2 Protein; C551750:BRCA2 protein, human; C460107:MED12 protein, human; D056892:Mediator Complex; D020033:Protein Isoforms