ABSTRACT
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.
Subject(s)
Genes, Neoplasm/genetics , Genome, Human/genetics , Host-Pathogen Interactions , Neoplasms/genetics , Neoplasms/metabolism , Oncogenic Viruses/pathogenicity , Viral Proteins/metabolism , Adenoviridae/genetics , Adenoviridae/metabolism , Adenoviridae/pathogenicity , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Herpesvirus 4, Human/genetics , Herpesvirus 4, Human/metabolism , Herpesvirus 4, Human/pathogenicity , Host-Pathogen Interactions/genetics , Humans , Neoplasms/pathology , Oncogenic Viruses/genetics , Oncogenic Viruses/metabolism , Open Reading Frames/genetics , Papillomaviridae/genetics , Papillomaviridae/metabolism , Papillomaviridae/pathogenicity , Polyomavirus/genetics , Polyomavirus/metabolism , Polyomavirus/pathogenicity , Receptors, Notch/metabolism , Signal Transduction , Two-Hybrid System Techniques , Viral Proteins/geneticsABSTRACT
Many human diseases, arising from mutations of disease susceptibility genes (genetic diseases), are also associated with viral infections (virally implicated diseases), either in a directly causal manner or by indirect associations. Here we examine whether viral perturbations of host interactome may underlie such virally implicated disease relationships. Using as models two different human viruses, Epstein-Barr virus (EBV) and human papillomavirus (HPV), we find that host targets of viral proteins reside in network proximity to products of disease susceptibility genes. Expression changes in virally implicated disease tissues and comorbidity patterns cluster significantly in the network vicinity of viral targets. The topological proximity found between cellular targets of viral proteins and disease genes was exploited to uncover a novel pathway linking HPV to Fanconi anemia.
