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Exome Sequencing Identifies Recurrent SPOP, FOXA1 and MED12 Mutations in Prostate Cancer

Christopher E Barbieri et al. Nat Genet. .
Free PMC article

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.

Figures

Fig 1
Fig 1. Significantly mutated genes in aggressive primary prostate cancer
(A) (Top) A cohort of 111 primary prostate tumors is ordered by number of mutations per Mb sequenced. (Center) Mutations in significantly mutated genes, colored by the coding consequence of the mutation. Each column represents a tumor and each row a gene. (Left) Number and percentage of tumors with mutations in a given gene. (Right) The negative log of the q-values for the significance level of mutated genes is shown (for all genes with q < 0.1). (B) Net frequency of gene deletion/amplification across 169 copy number-profiled tumors. Significantly mutated genes are indicated. Only autosomal genes with two or more mutations are shown.
Fig 2
Fig 2. Recurrent somatic mutations in FOXA1 and MED12
Mutations detected by exome sequencing are depicted (red), as are variants from non-overlapping transcriptome sequencing data (blue). (A) Structural analysis of mutations in FOXA1. Mutated residues are mapped to the structure of the HNF3γ fork-head domain from coordinate file 1VTN.pdb (www.pdb.org) and highlighted in red. FH, Fork-head domain. (B) Recurrent MED12 mutations in prostate cancer (red, blue) are distinct from those reported in uterine leiomyeoma (shown in black). Domains of MED12 are denoted as in Zhou et al.. Multispecies conservation of the mutated sites is shown below the mutation.
Fig 3
Fig 3. Structural and functional studies of recurrent SPOP mutations in prostate cancer
(A) Positional distribution of somatic mutations in SPOP across the Weill Cornell Medical College (WCMC), University of Michigan (UM), Uropath, and University of Washington (UW) prostate tumor cohorts. (B) Mutated residues in the crystal structure of the SPOP MATH domain bound to substrate (PDB 3IVV). (C) Representative images of invasive 22Rv1 and DU145 cells transfected with control and SPOP siRNA in Matrigel invasion assays. (D) Quantitation of invaded cells transfected with SPOP siRNA. (E) Quantitation of invaded DU145 cells transfected with GFP, SPOP wt, and SPOP F133V. Error bars depict standard deviation.
Fig 4
Fig 4. SPOP mutation defines a distinct genetic subclass of prostate cancer
(Left) Frequency of genomic copy number alterations in SPOP-mutant and SPOP-wildtype tumors. Length of bars reflects the frequency of copy number loss (blue) or gain (red). (Right) Heatmap showing selected recurrent somatic copy number aberrations (SCNA). Each row represents a single prostate cancer sample. Samples are annotated for mutations in SPOP, PTEN, PIK3CA, and TP53, deletions of PTEN, and ERG rearrangements. Deletions positively correlated (5q21, 6q21) or inversely correlated (21q22.3) with SPOP mutation are shown. P-values of peak association with SPOP mutation in both discovery and validation cohorts are displayed at bottom (Fisher’s exact test). Regions are not to scale; full coordinates available in Supplementary Table 8.

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