Interpreting cancer genomes using systematic host perturbations by tumour virus proteins

Genomic Analysis of Network Perturbations Center of Excellence in Genomic Science, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
Nature (Impact Factor: 41.46). 07/2012; 487(7408):491-5. DOI: 10.1038/nature11288
Source: PubMed


Genotypic differences greatly influence susceptibility and resistance to disease. Understanding genotype-phenotype relationships requires that phenotypes be viewed as manifestations of network properties, rather than simply as the result of individual genomic variations. Genome sequencing efforts have identified numerous germline mutations, and large numbers of somatic genomic alterations, associated with a predisposition to cancer. However, it remains difficult to distinguish background, or 'passenger', cancer mutations from causal, or 'driver', mutations in these data sets. Human viruses intrinsically depend on their host cell during the course of infection and can elicit pathological phenotypes similar to those arising from mutations. Here we test the hypothesis that genomic variations and tumour viruses may cause cancer through related mechanisms, by systematically examining host interactome and transcriptome network perturbations caused by DNA tumour virus proteins. The resulting integrated viral perturbation data reflects rewiring of the host cell networks, and highlights pathways, such as Notch signalling and apoptosis, that go awry in cancer. We show that systematic analyses of host targets of viral proteins can identify cancer genes with a success rate on a par with their identification through functional genomics and large-scale cataloguing of tumour mutations. Together, these complementary approaches increase the specificity of cancer gene identification. Combining systems-level studies of pathogen-encoded gene products with genomic approaches will facilitate the prioritization of cancer-causing driver genes to advance the understanding of the genetic basis of human cancer.

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Available from: Eric Johannsen
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    • "The following example illustrates the power of our combined approach. C-terminal Binding Protein 2 (CTBP2) is encoded at a locus associated with prostate cancer susceptibility (Thomas et al., 2008) and belongs to both SB and VT gene lists (Mann et al., 2012; Rozenblatt-Rosen et al., 2012). Two Cancer Census genes, IKZF1 and FLI1, encode interacting partners of Cell 159, 1212–1226, November 20, 2014 ª2014 Elsevier Inc. 1219 A mRNA abundance in HEK cells "
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    ABSTRACT: Just as reference genome sequences revolutionized human genetics, reference maps of interactome networks will be critical to fully understand genotype-phenotype relationships. Here, we describe a systematic map of ∼14,000 high-quality human binary protein-protein interactions. At equal quality, this map is ∼30% larger than what is available from small-scale studies published in the literature in the last few decades. While currently available information is highly biased and only covers a relatively small portion of the proteome, our systematic map appears strikingly more homogeneous, revealing a “broader” human interactome network than currently appreciated. The map also uncovers significant interconnectivity between known and candidate cancer gene products, providing unbiased evidence for an expanded functional cancer landscape, while demonstrating how high-quality interactome models will help “connect the dots” of the genomic revolution.
    Full-text · Article · Nov 2014 · Cell
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    • "The list of potential binding partners was filtered to remove proteins identified with a frequency>1% across a large set of negative control TAPs. In addition, we required that at least one peptide of the reported protein partner could be matched unambiguously to a single gene [25]. "
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    ABSTRACT: Loss of the chromatin remodeling ATPase CHD5 has been linked to the progression of neuroblastoma tumors, yet the underlying mechanisms behind the tumor suppressor role of CHD5 are unknown. In this study, we purified the human CHD5 complex and found that CHD5 is a component of the full NuRD transcriptional repressor complex, which also contains methyl-CpG binding proteins and histone deacetylases. The CHD5/NuRD complex appears mutually exclusive with the related CHD4/NuRD complex as overexpression of CHD5 results in loss of the CHD4 protein in cells. Following a search for genes that are regulated by CHD5 in neuroblastoma cells, we found that CHD5 binds to and represses the G2/M checkpoint gene WEE1. Reintroduction of CHD5 into neuroblastoma cells represses WEE1 expression, demonstrating that CHD5 can function as a repressor in cells. A catalytically inactive mutant version of CHD5 is able to associate with a NuRD cofactor but fails to repress transcription. Our study shows that CHD5 is a NuRD-associated transcriptional repressor and identifies WEE1 as one of the CHD5-regulated genes that may link CHD5 to tumor suppression.
    Full-text · Article · Sep 2014 · PLoS ONE
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    • "The other 122 were novel. In addition, 47 of the hits were identified as potential cancer genes in systematic cancer gene screening efforts (Beroukhim et al. 2010; Rozenblatt-Rosen et al. 2012; T Rolland, M Tas xan, B Charloteaux, SJ Pevzner, N Sahni, Q Zhong, S Yi, I Lemmens, C Fontanillo, R Mosca, et al., in prep.), and 12 are present in two large cancer gene lists (the overlap between our 147 hits and these two cancer gene lists was significant; P < 0.001) (Fig. 1B; Supplemental Fig. S1B; Supplemental Table S5; Futreal et al. 2004; Vogelstein et al. 2013). We queried the gene ontology (GO) term (Ashburner et al. 2000) association of these interactors and found an enrichment (47 of the 147 hits) for proteins involved in DNA damage repair, replication, and transcription among other functions (all highlighted in the network, with the gene symbol being selectively colored to reflect various GO term associations as indicated in the key in Fig. 1B; Supplemental Fig. S1B; Supplemental Table S5). "
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    ABSTRACT: BRCA1 is a breast and ovarian tumor suppressor. Given its numerous incompletely understood functions and the possibility that more exist, we performed complementary systematic screens in search of new BRCA1 protein-interacting partners. New BRCA1 functions and/or a better understanding of existing ones were sought. Among the new interacting proteins identified, genetic interactions were detected between BRCA1 and four of the interactors: TONSL, SETX, TCEANC, and TCEA2. Genetic interactions were also detected between BRCA1 and certain interactors of TONSL, including both members of the FACT complex. From these results, a new BRCA1 function in the response to transcription-associated DNA damage was detected. Specifically, new roles for BRCA1 in the restart of transcription after UV damage and in preventing or repairing damage caused by stabilized R loops were identified. These roles are likely carried out together with some of the newly identified interactors. This new function may be important in BRCA1 tumor suppression, since the expression of several interactors, including some of the above-noted transcription proteins, is repeatedly aberrant in both breast and ovarian cancers.
    Full-text · Article · Sep 2014 · Genes & Development
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