Trends in Genetics
UpdateGenome AnalysisLow duplicability and network fragility of cancer genes
Section snippets
Functional heterogeneity of genes mutated in cancer
Recent systematic and unbiased screenings of cancer genomes revealed a significant number of functionally heterogeneous genes to be mutated in tumors 1, 2, 3, 4. These studies described each tumor as a distinct disease with specific, and partly unrelated, genetic determinants. However, high heterogeneity does not necessarily imply that these genes lack common properties. Modifications of cancer genes, although functionally different, lead to the same outcome: uncontrolled cell proliferation.
Genes mutated in cancer duplicate less than other human genes
We measured gene duplicability by aligning the corresponding protein sequences directly to the human genome (see Supplementary Section 1.1 and Figure S1). We defined as ‘duplicates’ all additional genomic matches covering at least 60% of the query length. This threshold of coverage allowed us to detect duplicates that were at least 70% identical to more than one half of the query sequence (Figure S2). A gene was considered a ‘singleton’ if the corresponding protein matched only to one genomic
Cancer proteins are central hubs of interconnected modules of the human protein–protein interaction network
We derived the human protein–protein interaction network (PIN) from the Human Protein Reference Database (HPRD), which consists of a manually curated collection of in vivo, in vitro and high-throughput data [13]. After removing self-interactions, we obtained a graph composed of 9264 nodes (proteins) and 34 564 edges (protein–protein interactions). It contains information on 304 cancer and 154 CAN-proteins and has the features of a scale-free network [14] (see Supplementary Section 2). Although
Biological implications of systems-level properties of cancer genes
Our analysis showed that genes mutated in cancer are characterized by systems-level properties independent of their molecular function. They are significantly enriched in a special group of human singletons encoding proteins in central positions of highly interconnected clusters of the human PIN. These properties suggest an intrinsic fragility of cancer genes toward perturbations: gene dosage modifications of highly interconnected hubs (but, arguably, also sequence mutations) are likely to
Identification of novel candidate cancer genes
Only a small proportion of the human PIN is composed of highly clustered hubs that, unlike most human hubs, are preferentially encoded by singletons (Supplementary Section 5). This is consistent with the hypothesis that such positions constitute general weak points for the system, probably sensitive to dosage effect. Resembling the same system-level properties of cancer genes, they are likely to bear novel candidate cancer genes. We therefore focused on 101 singleton genes encoding highly
Concluding remarks
Our analysis provided evidence for the existence of shared properties of human genes involved in cancer that can explain their role in terms of system perturbations rather than modifications of single components. This finding offers a novel paradigm to interpret the heterogeneous mutational landscape of cancer genomes. It also provides the starting platform for measuring the actual effects of each gene modification on network stability. Future efforts in this direction will help not only to
Acknowledgements
The authors thank Lars Jensen (EMBL-Heidelberg) for the list of gene-associated abstracts and Giovanni D’Ario (IFOM) and Lara Lusa (Istituto Tumori, Milan) for help with statistics. This work was supported by an AIRC Start-Up grant to F.D.C.
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Systematic identification of molecular links between core and candidate genes in breast cancer
2015, Journal of Molecular BiologyCitation Excerpt :A complete list of the selected core BC genes is given in Supplemental Table 1a. It has been reported that disease genes, including human cancers, tend to be highly interconnected [20], even in unbiased interactomes [21]. We first checked the closeness between these 59 well-known genes to verify whether this tendency is also true for BC.
Recessive cancer genes engage in negative genetic interactions with their functional paralogs
2013, Cell ReportsCitation Excerpt :Of 99 genes, 23 were duplicated (23.2% of the total, Table S1). This was a significantly lower fraction compared to other human genes (38.5%; p = 0.002, Fisher’s exact test) and confirmed the tendency of cancer genes, and in particular of recessive genes, to retain only one gene copy (D’Antonio and Ciccarelli, 2011; Rambaldi et al., 2008). Interestingly, in more than 65% of cases, we found support from the literature for functional compensation between recessive genes and their paralogs (Table S1).
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