Exome sequencing identifies a spectrum of mutation frequencies in advanced and lethal prostate cancers

Department of Genome Sciences, University of Washington, Seattle, WA 98105, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 09/2011; 108(41):17087-92. DOI: 10.1073/pnas.1108745108
Source: PubMed


To catalog protein-altering mutations that may drive the development of prostate cancers and their progression to metastatic disease systematically, we performed whole-exome sequencing of 23 prostate cancers derived from 16 different lethal metastatic tumors and three high-grade primary carcinomas. All tumors were propagated in mice as xenografts, designated the LuCaP series, to model phenotypic variation, such as responses to cancer-directed therapeutics. Although corresponding normal tissue was not available for most tumors, we were able to take advantage of increasingly deep catalogs of human genetic variation to remove most germline variants. On average, each tumor genome contained ~200 novel nonsynonymous variants, of which the vast majority was specific to individual carcinomas. A subset of genes was recurrently altered across tumors derived from different individuals, including TP53, DLK2, GPC6, and SDF4. Unexpectedly, three prostate cancer genomes exhibited substantially higher mutation frequencies, with 2,000-4,000 novel coding variants per exome. A comparison of castration-resistant and castration-sensitive pairs of tumor lines derived from the same prostate cancer highlights mutations in the Wnt pathway as potentially contributing to the development of castration resistance. Collectively, our results indicate that point mutations arising in coding regions of advanced prostate cancers are common but, with notable exceptions, very few genes are mutated in a substantial fraction of tumors. We also report a previously undescribed subtype of prostate cancers exhibiting "hypermutated" genomes, with potential implications for resistance to cancer therapeutics. Our results also suggest that increasingly deep catalogs of human germline variation may challenge the necessity of sequencing matched tumor-normal pairs.

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Available from: Eva Corey, Sep 30, 2015
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    • "Genes with expression trends peaking at 12 weeks (n = 384) included several anti-apoptotic genes (e.g., BIRC3, OLFM4, and REG4) and genes involved in Wnt/b-catenin signaling (e.g., LEF1, FZD7, and WNT2B) (Figure 1F). Components of the Wnt pathway are frequently deregulated through genomic aberration in CRPC, but not treatment-naive tumors (Grasso et al., 2012; Kumar et al., 2011), and stromal Wnt signaling contributes to therapy resistance in tumor cells (Li et al., 2008; Sun et al., 2012). It is probable that several of the genes upregulated by 12 weeks are critical for cell survival in androgen-deprived conditions. "
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    ABSTRACT: More potent targeting of the androgen receptor (AR) in advanced prostate cancer is driving an increased incidence of neuroendocrine prostate cancer (NEPC), an aggressive and treatment-resistant AR-negative variant. Its molecular pathogenesis remains poorly understood but appears to require TP53 and RB1 aberration. We modeled the development of NEPC from conventional prostatic adenocarcinoma using a patient-derived xenograft and found that the placental gene PEG10 is de-repressed during the adaptive response to AR interference and subsequently highly upregulated in clinical NEPC. We found that the AR and the E2F/RB pathway dynamically regulate distinct post-transcriptional and post-translational isoforms of PEG10 at distinct stages of NEPC development. In vitro, PEG10 promoted cell-cycle progression from G0/G1 in the context of TP53 loss and regulated Snail expression via TGF-β signaling to promote invasion. Taken together, these findings show the mechanistic relevance of RB1 and TP53 loss in NEPC and suggest PEG10 as a NEPC-specific target. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 07/2015; 12(6). DOI:10.1016/j.celrep.2015.07.012 · 8.36 Impact Factor
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    • "The number of somatic nonsynonymous single-nucleotide variations (SNV) and indels ranged from 29 in MSK-PCa1 to 75 in MSK-PCa4 with a mean of 45.4 per sample, consistent with reported mutation frequency in CRPC tissue (Baca et al., 2013; Barbieri et al., 2012; Grasso et al., 2012) (Figure 2A, Table S2), and the specific genes are similar to those reported in metastatic CRPC (Figure 2B, Table S3). TP53, the most commonly mutated gene in CRPC (Grasso et al., 2012; Kumar et al., 2011), was mutant in four organoid samples (Figure 2C). In all cases, only the mutant allele was detected by RNA-seq, with complete loss of p53 function through either single-copy loss or copy-neutral loss of heterozygosity (Figure S2A). "
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    ABSTRACT: The lack of in vitro prostate cancer models that recapitulate the diversity of human prostate cancer has hampered progress in understanding disease pathogenesis and therapy response. Using a 3D organoid system, we report success in long-term culture of prostate cancer from biopsy specimens and circulating tumor cells. The first seven fully characterized organoid lines recapitulate the molecular diversity of prostate cancer subtypes, including TMPRSS2-ERG fusion, SPOP mutation, SPINK1 overexpression, and CHD1 loss. Whole-exome sequencing shows a low mutational burden, consistent with genomics studies, but with mutations in FOXA1 and PIK3R1, as well as in DNA repair and chromatin modifier pathways that have been reported in advanced disease. Loss of p53 and RB tumor suppressor pathway function are the most common feature shared across the organoid lines. The methodology described here should enable the generation of a large repertoire of patient-derived prostate cancer lines amenable to genetic and pharmacologic studies.
    Cell 09/2014; 159(1). DOI:10.1016/j.cell.2014.08.016 · 32.24 Impact Factor
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    • "Range: 0.3–2 mutations/Mb Kumar et al. [12]; 23 prostate cancers including metastatic and high-grade primary prostate cancers "
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    ABSTRACT: Objectives: In this review, we will discuss the latest advances in our understanding of the relationship between the cellular DNA damage response and genomic instability in prostate cancer and the emerging possibilities to exploit these aberrations as prognostic biomarkers and guides for personalized patient management. Methods: Important findings related to genomic instability in prostate cancer were retrieved from the literature and combined with our own results and a translational perspective. Results: Prostate cancer is characterized by a highly altered genomic landscape with a wide spectrum of genomic alterations, including somatic mutations, copy number alterations (CNAs), gene fusions, complex chromosomal rearrangements, and aneuploidy. In addition, massive DNA damaging events, including chromothripsis and chromoplexy, which can lead to extensive genomic insults in a single step, have been identified. A number of these genomic aberrations have been found to provide prognostic information and can therefore help to identify high-risk patients. In addition, defects in the DNA damage checkpoint and repair machinery can potentially be harnessed for therapeutic purposes. Conclusions: Genomic instability plays a crucial role in the malignant progression of prostate cancer and can be exploited for the development of novel prognostic biomarkers and innovative therapies.
    Urologic Oncology 06/2014; 32(8). DOI:10.1016/j.urolonc.2014.02.005 · 2.77 Impact Factor
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