The genomic complexity of primary human prostate cancer

The Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.
Nature (Impact Factor: 41.46). 02/2011; 470(7333):214-20. DOI: 10.1038/nature09744
Source: PubMed


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.

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Available from: Kyung Park, Jan 13, 2014
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    • "The membrane-associated guanylate kinase, WW and PDZ domain containing 2 (MAGI2) gene and Phosphatidylinositol-4,5- bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) gene potentially also subvert PTEN and therefore PI3K activity. MAGI2 encodes a PTEN scaffolding protein that is recurrently disrupted by balanced re-arrangements without any evidence of copynumber loss (Berger et al, 2011). PIK3CA has been reported to undergo amplifications and activating point mutations in B25% and 5% of prostate cancers, respectively (Barbieri et al, 2012). "
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    ABSTRACT: Prostate cancers are highly prevalent in the developed world, with inheritable risk contributing appreciably to tumour development. Genomic heterogeneity within individual prostate glands and between patients derives predominantly from structural variants and copy-number aberrations. Subtypes of prostate cancers are being delineated through the increasing use of next-generation sequencing, but these subtypes are yet to be used to guide the prognosis or therapeutic strategy. Herein, we review our current knowledge of the mutational landscape of human prostate cancer, describing what is known of the common mutations underpinning its development. We evaluate recurrent prostate-specific mutations prior to discussing the mutational events that are shared both in prostate cancer and across multiple cancer types. From these data, we construct a putative overview of the genomic evolution of human prostate cancer.British Journal of Cancer advance online publication 30 June 2015; doi:10.1038/bjc.2015.234
    Full-text · Article · Jun 2015 · British Journal of Cancer
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    • "These sequence motifs can form slippage structures with extruded singlestrand loops and triple helices, resulting, very likely, in the fragility of these loci (Busch et al., 2007). Furthermore, focusing on BPs within clusters , we found a significantly increased overlap with the H3K27me3 histone modification by in silico analyses, denoting that these BPs tend to occur in correspondence of inactive chromatin and transcriptional repressed regions (Berger et al., 2011). This result could suggest that somatic rearrangements causing genome amplification on RGM in sarcomas might occur more frequently within closed chromatin, or alternatively, that a positive selection acts on BPs arising at inactive loci. "
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    ABSTRACT: Gene amplification is relatively common in tumors. In certain subtypes of sarcoma, it often occurs in the form of ring and/or giant rod-shaped marker (RGM) chromosomes whose mitotic stability is frequently rescued by ectopic novel centromeres (neocentromeres). Little is known about the origin and structure of these RGM chromosomes, including how they arise, their internal organization, and which sequences underlie the neocentromeres. To address these questions, 42 sarcomas with RGM chromosomes were investigated to detect regions prone to double strand breaks and possible functional or structural constraints driving the amplification process. We found nine breakpoint cluster regions potentially involved in the genesis of RGM chromosomes, which turned out to be significantly enriched in poly-pyrimidine traits. Some of the clusters were located close to genes already known to be relevant for sarcomas, thus indicating a potential functional constraint, while others mapped to transcriptionally inactive chromatin domains enriched in heterochromatic sites. Of note, five neocentromeres were identified after analyzing 13 of the cases by fluorescent in situ hybridization. ChIP-on-chip analysis with antibodies against the centromeric protein CENP-A showed that they were a patchwork of small genomic segments derived from different chromosomes, likely joint to form a contiguous sequence during the amplification process. © 2014 Wiley Periodicals, Inc.
    Full-text · Article · Nov 2014 · Genes Chromosomes and Cancer
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    • "Prostate cancer is a leading cause of cancer-related death [14]. Recent whole genome and transcriptome sequencing studies of hundreds of prostate tumors have defined novel molecular subtypes and characterized extensive genomic aberration underlying disease initiation and progression [15], [16], [17]. RNA editing deregulation has begun to be linked to cancer, including in hepatocellular carcinoma, where recurrent editing of AZIN1 promotes pathogenesis [8], [18], [19]. "
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    ABSTRACT: RNA editing modifies the sequence of primary transcripts, potentially resulting in profound effects to RNA structure and protein-coding sequence. Recent analyses of RNA sequence data are beginning to provide insights into the distribution of RNA editing across the entire transcriptome, but there are few published matched whole genome and transcriptome sequence datasets, and designing accurate bioinformatics methodology has proven highly challenging. To further characterize the RNA editome, we analyzed 16 paired DNA-RNA sequence libraries from prostate tumor specimens, employing a comprehensive strategy to rescue low coverage sites and minimize false positives. We identified over a hundred thousand putative RNA editing events, a third of which were recurrent in two or more samples, and systematically characterized their type and distribution across the genome. Within genes the majority of events affect non-coding regions such as introns and untranslated regions (UTRs), but 546 genes had RNA editing events predicted to result in deleterious amino acid alterations. Finally, we report a potential association between RNA editing of microRNA binding sites within 3' UTRs and increased transcript expression. These results provide a systematic characterization of the landscape of RNA editing in low coverage sequence data from prostate tumor specimens. We demonstrate further evidence for RNA editing as an important regulatory mechanism and suggest that the RNA editome should be further studied in cancer.
    Full-text · Article · Jul 2014 · PLoS ONE
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