title: Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer.
abstract: Prostate cancer is the second most common cancer in men worldwide and causes over 250,000 deaths each year. Overtreatment of indolent disease also results in significant morbidity. Common genetic alterations in prostate cancer include losses of NKX3.1 (8p21) and PTEN (10q23), gains of AR (the androgen receptor gene) and fusion of ETS family transcription factor genes with androgen-responsive promoters. Recurrent somatic base-pair substitutions are believed to be less contributory in prostate tumorigenesis but have not been systematically analyzed in large cohorts. Here, we sequenced the exomes of 112 prostate tumor and normal tissue pairs. New recurrent mutations were identified in multiple genes, including MED12 and FOXA1. SPOP was the most frequently mutated gene, with mutations involving the SPOP substrate-binding cleft in 6-15% of tumors across multiple independent cohorts. Prostate cancers with mutant SPOP lacked ETS family gene rearrangements and showed a distinct pattern of genomic alterations. Thus, SPOP mutations may define a new molecular subtype of prostate cancer.
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Barbieri
authors.forename: Sylvan C
authors.initials: SC
authors.lastname: Baca
authors.forename: Michael S
authors.initials: MS
authors.lastname: Lawrence
authors.forename: Francesca
authors.initials: F
authors.lastname: Demichelis
authors.forename: Mirjam
authors.initials: M
authors.lastname: Blattner
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Theurillat
authors.forename: Thomas A
authors.initials: TA
authors.lastname: White
authors.forename: Petar
authors.initials: P
authors.lastname: Stojanov
authors.forename: Eliezer
authors.initials: E
authors.lastname: Van Allen
authors.forename: Nicolas
authors.initials: N
authors.lastname: Stransky
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Nickerson
authors.forename: Sung-Suk
authors.initials: SS
authors.lastname: Chae
authors.forename: Gunther
authors.initials: G
authors.lastname: Boysen
authors.forename: Daniel
authors.initials: D
authors.lastname: Auclair
authors.forename: Robert C
authors.initials: RC
authors.lastname: Onofrio
authors.forename: Kyung
authors.initials: K
authors.lastname: Park
authors.forename: Naoki
authors.initials: N
authors.lastname: Kitabayashi
authors.forename: Theresa Y
authors.initials: TY
authors.lastname: MacDonald
authors.forename: Karen
authors.initials: K
authors.lastname: Sheikh
authors.forename: Terry
authors.initials: T
authors.lastname: Vuong
authors.forename: Candace
authors.initials: C
authors.lastname: Guiducci
authors.forename: Kristian
authors.initials: K
authors.lastname: Cibulskis
authors.forename: Andrey
authors.initials: A
authors.lastname: Sivachenko
authors.forename: Scott L
authors.initials: SL
authors.lastname: Carter
authors.forename: Gordon
authors.initials: G
authors.lastname: Saksena
authors.forename: Douglas
authors.initials: D
authors.lastname: Voet
authors.forename: Wasay M
authors.initials: WM
authors.lastname: Hussain
authors.forename: Alex H
authors.initials: AH
authors.lastname: Ramos
authors.forename: Wendy
authors.initials: W
authors.lastname: Winckler
authors.forename: Michelle C
authors.initials: MC
authors.lastname: Redman
authors.forename: Kristin
authors.initials: K
authors.lastname: Ardlie
authors.forename: Ashutosh K
authors.initials: AK
authors.lastname: Tewari
authors.forename: Juan Miguel
authors.initials: JM
authors.lastname: Mosquera
authors.forename: Niels
authors.initials: N
authors.lastname: Rupp
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Wild
authors.forename: Holger
authors.initials: H
authors.lastname: Moch
authors.forename: Colm
authors.initials: C
authors.lastname: Morrissey
authors.forename: Peter S
authors.initials: PS
authors.lastname: Nelson
authors.forename: Philip W
authors.initials: PW
authors.lastname: Kantoff
authors.forename: Stacey B
authors.initials: SB
authors.lastname: Gabriel
authors.forename: Todd R
authors.initials: TR
authors.lastname: Golub
authors.forename: Matthew
authors.initials: M
authors.lastname: Meyerson
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: D059472:Exome; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000235:genetics*; D006801:Humans; D008297:Male; D056892:Mediator Complex / Q000235:genetics*; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D009154:Mutation; D011471:Prostatic Neoplasms / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: C496499:FOXA1 protein, human; D051541:Hepatocyte Nuclear Factor 3-alpha; C491894:MAP6 protein, human; C460107:MED12 protein, human; D056892:Mediator Complex; D008869:Microtubule-Associated Proteins