title: The genomic complexity of primary human prostate cancer.
abstract: Prostate cancer is the second most common cause of male cancer deaths in the United States. However, the full range of prostate cancer genomic alterations is incompletely characterized. Here we present the complete sequence of seven primary human prostate cancers and their paired normal counterparts. Several tumours contained complex chains of balanced (that is, 'copy-neutral') rearrangements that occurred within or adjacent to known cancer genes. Rearrangement breakpoints were enriched near open chromatin, androgen receptor and ERG DNA binding sites in the setting of the ETS gene fusion TMPRSS2-ERG, but inversely correlated with these regions in tumours lacking ETS fusions. This observation suggests a link between chromatin or transcriptional regulation and the genesis of genomic aberrations. Three tumours contained rearrangements that disrupted CADM2, and four harboured events disrupting either PTEN (unbalanced events), a prostate tumour suppressor, or MAGI2 (balanced events), a PTEN interacting protein not previously implicated in prostate tumorigenesis. Thus, genomic rearrangements may arise from transcriptional or chromatin aberrancies and engage prostate tumorigenic mechanisms.
authors.affiliation: The Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Berger
authors.forename: Michael S
authors.initials: MS
authors.lastname: Lawrence
authors.forename: Francesca
authors.initials: F
authors.lastname: Demichelis
authors.forename: Yotam
authors.initials: Y
authors.lastname: Drier
authors.forename: Kristian
authors.initials: K
authors.lastname: Cibulskis
authors.forename: Andrey Y
authors.initials: AY
authors.lastname: Sivachenko
authors.forename: Andrea
authors.initials: A
authors.lastname: Sboner
authors.forename: Raquel
authors.initials: R
authors.lastname: Esgueva
authors.forename: Dorothee
authors.initials: D
authors.lastname: Pflueger
authors.forename: Carrie
authors.initials: C
authors.lastname: Sougnez
authors.forename: Robert
authors.initials: R
authors.lastname: Onofrio
authors.forename: Scott L
authors.initials: SL
authors.lastname: Carter
authors.forename: Kyung
authors.initials: K
authors.lastname: Park
authors.forename: Lukas
authors.initials: L
authors.lastname: Habegger
authors.forename: Lauren
authors.initials: L
authors.lastname: Ambrogio
authors.forename: Timothy
authors.initials: T
authors.lastname: Fennell
authors.forename: Melissa
authors.initials: M
authors.lastname: Parkin
authors.forename: Gordon
authors.initials: G
authors.lastname: Saksena
authors.forename: Douglas
authors.initials: D
authors.lastname: Voet
authors.forename: Alex H
authors.initials: AH
authors.lastname: Ramos
authors.forename: Trevor J
authors.initials: TJ
authors.lastname: Pugh
authors.forename: Jane
authors.initials: J
authors.lastname: Wilkinson
authors.forename: Sheila
authors.initials: S
authors.lastname: Fisher
authors.forename: Wendy
authors.initials: W
authors.lastname: Winckler
authors.forename: Scott
authors.initials: S
authors.lastname: Mahan
authors.forename: Kristin
authors.initials: K
authors.lastname: Ardlie
authors.forename: Jennifer
authors.initials: J
authors.lastname: Baldwin
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Simons
authors.forename: Naoki
authors.initials: N
authors.lastname: Kitabayashi
authors.forename: Theresa Y
authors.initials: TY
authors.lastname: MacDonald
authors.forename: Philip W
authors.initials: PW
authors.lastname: Kantoff
authors.forename: Lynda
authors.initials: L
authors.lastname: Chin
authors.forename: Stacey B
authors.initials: SB
authors.lastname: Gabriel
authors.forename: Mark B
authors.initials: MB
authors.lastname: Gerstein
authors.forename: Todd R
authors.initials: TR
authors.lastname: Golub
authors.forename: Matthew
authors.initials: M
authors.lastname: Meyerson
authors.forename: Ashutosh
authors.initials: A
authors.lastname: Tewari
authors.forename: Eric S
authors.initials: ES
authors.lastname: Lander
authors.forename: Gad
authors.initials: G
authors.lastname: Getz
authors.forename: Mark A
authors.initials: MA
authors.lastname: Rubin
authors.forename: Levi A
authors.initials: LA
authors.lastname: Garraway
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins / Q000235:genetics; D016022:Case-Control Studies; D015815:Cell Adhesion Molecules / Q000235:genetics; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D002869:Chromosome Aberrations; D056905:Chromosome Breakpoints; D044127:Epigenesis, Genetic / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human / Q000235:genetics*; D051528:Guanylate Kinases; D006801:Humans; D008297:Male; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics*; D011995:Recombination, Genetic / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D014158:Transcription, Genetic
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C556123:CADM2 protein, human; D002352:Carrier Proteins; D015815:Cell Adhesion Molecules; D002843:Chromatin; D051528:Guanylate Kinases; C485777:MAGI2 protein, human; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human