An Approach for the Identification of Targets Specific to Bone Metastasis Using Cancer Genes Interactome and Gene Ontology Analysis
The strategy that was implemented in this work comprised three tasks, leading to three corresponding gene-sets that were used for obtaining SBC-specific targets of potential therapeutic value. (a) A compilation of cancer genes from CancerGenes database was used to construct a representative cancer genes interactome (Cancer Genes Network; CGN) by mapping them on to a reference human protein interactome (Human Protein Reference Database; HPRD). Using methods of network analysis, proteins that are central to CGN and interaction dynamics were obtained. These set of genes (SET-A; shaded area) was found to be correlating well with genes implicated in generic cancer mechanisms (Figure 6) as well as those annotated as essential using mouse phenotype data (Figure 8). The CGN, comprising of 11602 interactions among 2665 proteins, also serves as a reference set (universe) for gene enrichment studies; (b) A set of genes (Secondary Bone Cancer Genes; SBCGs) that are implicated in metastasis to bone from primary breast and prostate cancer, the most prevalent causes of bone metastasis, was compiled from literature. This set (SET-B) serves as a basis of genes and ontological correlates of secondary bone cancer that characterize the disease phenotype; (c) Significantly enriched GO terms that characterize SBCGs were obtained by overrepresentation analysis against the ‘cancer genes’ universe. SET-C, a subset of CGN, was obtained by segregating cancer genes that were annotated with these SBC-specific ontological terms. Part of SET-C (hatched area; Set-c and Set-bc in Figure 10A) serves as a ‘source set of target cancer genes’ that, both, carry ontological essence of SBCGs and are not involved in generic cancer mechanisms. SBC-specific targets (Figure 3 and Figure 10B), that are annotated with key GO terms (Figure 9) reflecting role in, both, bone processes and metastasis mechanisms, were further obtained from the source set.