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. 2010 Jul 13;18(1):11-22.
doi: 10.1016/j.ccr.2010.05.026. Epub 2010 Jun 24.

Integrative genomic profiling of human prostate cancer

Barry S Taylor  1 , Nikolaus Schultz, Haley Hieronymus, Anuradha Gopalan, Yonghong Xiao, Brett S Carver, Vivek K Arora, Poorvi Kaushik, Ethan Cerami, Boris Reva, Yevgeniy Antipin, Nicholas Mitsiades, Thomas Landers, Igor Dolgalev, John E Major, Manda Wilson, Nicholas D Socci, Alex E Lash, Adriana Heguy, James A Eastham, Howard I Scher, Victor E Reuter, Peter T Scardino, Chris Sander, Charles L Sawyers, William L Gerald
Affiliations

Integrative genomic profiling of human prostate cancer

Barry S Taylor et al. Cancer Cell. .

Abstract

Annotation of prostate cancer genomes provides a foundation for discoveries that can impact disease understanding and treatment. Concordant assessment of DNA copy number, mRNA expression, and focused exon resequencing in 218 prostate cancer tumors identified the nuclear receptor coactivator NCOA2 as an oncogene in approximately 11% of tumors. Additionally, the androgen-driven TMPRSS2-ERG fusion was associated with a previously unrecognized, prostate-specific deletion at chromosome 3p14 that implicates FOXP1, RYBP, and SHQ1 as potential cooperative tumor suppressors. DNA copy-number data from primary tumors revealed that copy-number alterations robustly define clusters of low- and high-risk disease beyond that achieved by Gleason score. The genomic and clinical outcome data from these patients are now made available as a public resource.

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Figures

Figure 1
Figure 1. A global view of the prostate cancer genome
A. Significant genomic aberrations in the prostate oncogenome. Regions of amplification (red) or deletion (blue) with FDR≤10% are plotted, with chromosomes indicated at the center and centromeres in red. Genes in which we detected somatic non-synonymous mutations are listed on top (black). Additional genes of interest targeted by copy-number alterations alone are also indicated (gray). B. Three of the most commonly altered pathways in both primary and metastatic prostate cancers: RB, PI3K, and RAS/RAF signaling. Alteration frequencies are shown for individual genes and for the entire pathway in primary and metastatic tumors. Alterations are defined as those having outlier expression (significant up- or down-regulation) compared to the distribution of expression in normal prostate samples (outlier analysis described in further detail in Experimental Procedures), or by somatic mutations, and are interpreted as activation (red) or inactivation (blue) of protein function. See also Figure S1 and Tables S3 and S6.
Figure 2
Figure 2. Diversity of androgen signaling pathway alterations in primary and metastatic prostate cancers
A. Alterations in androgen signaling components where frequencies are shown for AR and selected activators in primary and metastatic tumors. Alterations are defined as those having outlier expression (as described in Figure 1B and Experimental Procedures), or by somatic mutations, and interpreted as activation (red) or inactivation (blue). B. Overall genomic alteration rates in androgen signaling genes. The eleven genes in the AR pathway (panel A) had somatic mutations (black, red) and/or outlier expression (over- or under-expression, see Experimental Procedures), a subset of which was the result of copy-number alterations (gray, broad and focal gain or loss of one or more copies, see Supplementary Information). Primary tumors show moderate levels of alteration in at least one of these eleven AR pathway genes (left), preceding the generally higher alteration rates in metastatic tumors (right). C. The steroid receptor co-activator NCOA2 had two novel somatic point mutations in primary tumors. These clustered near sites of known NCOA2 point mutations in melanoma [G435S in the serine/threonine-rich (S/T) regulatory domain] and lung cancer [S1024N in the transcriptional activation domain 1 (AD1)]. D. Increasing levels of NCOA2 induce increasing androgen-dependent AR transcriptional activity. Increasing amounts of NCOA2 plasmid were transfected into LNCaP cells, resulting in NCOA2 protein expression (inset western blot) and ARE-luciferase reporter activity. Error bars representing the S.E.M (standard error of the mean) are displayed, but represent a very small portion of the signal, and are therefore not visible. E. Non-castrate primary tumors with NCOA2 gain (defined as copy-number amplification greater than single-copy gain, outlier over-expression, or mutation) have higher androgen signaling (student’s t-test, P<0.0001), as assessed by an independent signature of 29 androgen-responsive genes (Hieronymus et al., 2006). See also Figure S2.
Figure 3
Figure 3. TMPRSS2-ERG-associated deletion of 3p14.1-p13
A. TMPRSS2-ERG gene fusion co-occurs with genomic aberrations in the prostate cancer genome including deletions of loci encoding TP53 (17p13.1) and PTEN (10q23.31), as well as focal deletion of 3p14.1-p13 (genes listed in genomic order; green lines represent statistically significant associations, FDR ≤ 1%). Chromosomes are shown around the ring. B. Diverse genomic deletions (heterozygous and homozygous deletions, light and dark blue respectively) target a ~2.2mb region of 3p14.1-p13 encoding 8 genes (indicated at bottom). Tumors are rows and those harboring TMPRSS2-ERG fusion or PTEN/TP53 deletion (heterozygous and homozygous deletions are black and grey respectively) are identified at right. Tumors are sorted according to their locus of deletion with focal losses preferentially affecting FOXP1 (top), RYBP and the adjacent gene SHQ1 (bottom), or both loci simultaneously (middle). Inset indicates the pattern of significance of total genomic deletion juxtaposed to the significance of TMPRSS2-ERG-associated deletion (black and dotted blue respectively). C. Transcript expression according to copy-number status for the three genes targeted by the 3p14.1-p13 deletion: FOXP1, RYBP, and SHQ1, all three of which are correlated (p-values as indicated, Anova). EIF4E3 and PPP4R2 expression and copy-number loss were also correlated, but neither of these two genes was focally targeted by 3p14.1-p13 deletion. D. Along with whole-gene deletions of SHQ1 (panel b), we detected a single tumor with a P22S somatic mutation of the CS domain, indicated in red in the three-dimensional structure of the SHQ1 yeast homolog (3eud) and in linear representation of the protein (top right). Also, intragenic deletions (shown here in metastatic sample PCA0187) confer exon-specific loss of expression indicating a truncation event (bottom right).
Figure 4
Figure 4. Genomic aberrations identify clinically distinct subtypes of prostate cancer
A. Unsupervised hierarchical clustering of copy-number alterations (heatmap; red is amplification, white is copy-neutral, blue is deletion) indicates six groups of prostate cancers exist. Samples are ordered based on their group membership (dendrogram, groups are colored, metastatic samples are indicated by hashes). Selected genomic regions indicative of group membership are labeled (right). B. There exist significant differences in the risk of biochemical recurrence among the groups of tumors determined by patterns of genomic aberrations (left; p-values as indicated, log-rank test). C. Differences in the risk of biochemical relapse (panel B) were independent of Gleason grade (≤6) in the most diploid clusters (1–4) (no statistically significant association of Gleason grade in clusters 1–4). See also Figure S3 and Table S4.
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