Robustly predicting outcome for cancer patients from gene expression is an important challenge on the road to better personalized treatment. Network-based outcome predictors (NOPs), which considers the cellular wiring diagram in the classification, hold much promise to improve performance, stability and interpretability of identified marker genes. Problematically, reports on the efficacy of NOPs are conflicting and for instance suggest that utilizing random networks performs on par to networks that describe biologically relevant interactions. In this paper we turn the prediction problem around: instead of using a given biological network in the NOP, we aim to identify the network of genes that truly improves outcome prediction. To this end, we propose SyNet, a gene network constructed ab initio from synergistic gene pairs derived from survival-labelled gene expression data. To obtain SyNet, we evaluate synergy for all 69 million pairwise combinations of genes resulting in a network that is specific to the dataset and phenotype under study and can be used to in a NOP model. We evaluated SyNet and 11 other networks on a compendium dataset of >4000 survival-labelled breast cancer samples. For this purpose, we used cross-study validation which more closely emulates real world application of these outcome predictors. We find that SyNet is the only network that truly improves performance, stability and interpretability in several existing NOPs. We show that SyNet overlaps significantly with existing gene networks, and can be confidently predicted (~85% AUC) from graph-topological descriptions of these networks, in particular the breast tissue-specific network. Due to its data-driven nature, SyNet is not biased to well-studied genes and thus facilitates post-hoc interpretation. We find that SyNet is highly enriched for known breast cancer genes and genes related to e.g. histological grade and tamoxifen resistance, suggestive of a role in determining breast cancer outcome.

This Article contains a typographical error in the spelling of the author Wim Verhaegh, which is incorrectly given as Wim Verheagh.

The use of genome-wide data in cancer research, for the identification of groups of patients with similar molecular characteristics, has become a standard approach for applications in therapy-response, prognosis-prediction, and drug-development. To progress in these applications, the trend is to move from single genome-wide measurements in a single cancer-type towards measuring several different molecular characteristics across multiple cancer-types. Although current approaches shed light on molecular characteristics of various cancer-types, detailed relationships between patients within cancer clusters are unclear. We propose a novel multi-omic integration approach that exploits the joint behavior of the different molecular characteristics, supports visual exploration of the data by a two-dimensional landscape, and inspection of the contribution of the different genome-wide data-types. We integrated 4,434 samples across 19 cancer-types, derived from TCGA, containing gene expression, DNA-methylation, copy-number variation and microRNA expression data. Cluster analysis revealed 18 clusters, where three clusters showed a complex collection of cancer-types, squamous-cell-carcinoma, colorectal cancers, and a novel grouping of kidney-cancers. Sixty-four samples were identified outside their tissue-of-origin cluster. Known and novel patient subgroups were detected for Acute Myeloid Leukemia’s, and breast cancers. Quantification of the contributions of the different molecular types showed that substructures are driven by specific (combinations of) molecular characteristics.

Retroviruses have been foundational in cancer research since early studies identified protooncogenes as targets for insertional mutagenesis. Integration of murine gamma-retroviruses into the host genome favours promoters and enhancers and entails interaction of viral integrase with host BET/bromodomain factors. We report that this integration pattern is conserved in feline leukaemia virus (FeLV), a gamma-retrovirus that infects many human cell types. Analysis of FeLV insertion sites in the MCF-7 mammary carcinoma cell line revealed strong bias towards active chromatin marks with no evidence of significant post-integration growth selection. The most prominent FeLV integration targets had little overlap with the most abundantly expressed transcripts, but were strongly enriched for annotated cancer genes. A meta-analysis based on several gamma-retrovirus integration profiling (GRIP) studies in human cells (CD34+, K562, HepG2) revealed a similar cancer gene bias but also remarkable cell-type specificity, with prominent exceptions including a universal integration hotspot at the long non-coding RNA MALAT1. Comparison of GRIP targets with databases of super-enhancers from the same cell lines showed that these have only limited overlap and that GRIP provides unique insights into the upstream drivers of cell growth. These observations elucidate the oncogenic potency of the gamma-retroviruses and support the wider application of GRIP to identify the genes and growth regulatory circuits that drive distinct cancer types.

Summary Understanding the living cell as a system of interconnected components is one of the key contemporary challenges. This is a complex problem, in which different types of functional interactions play a role, each operating across multiple distinct scales. How do functional interactions emerge from the topology of the physical interaction network? To investigate this we explore scale independent descriptions of the topology of the physical protein-protein and protein-DNA interaction networks in yeast.

We introduce a multi-scale kernel diffusion framework and apply it to a large collection of murine retroviral insertional mutagenesis data. The diffusion strength plays the role of scale parameter. As a result, in addition to detecting genes with frequent mutations in their genomic vicinity (red nodes in the interaction graph) we can also find genes that harbor frequent mutations in their interaction network context (white and pink nodes).

In this study, 43 tumors that were induced by retroviral insertional mutagenesis are expression profiled, resulting in a dataset for which both the initiating events (the viral integration sites) as well as the consequent expression profiles are available.
To capture complex associations that arise due to interaction among insertion target genes, we infer small Boolean logic networks that explicitly incorporate operators to model the potential parallel alternatives (‘exclusive-or’ gates) as well as the potential cooperation between mutations (‘and’ gates).

In this study, 43 tumors, that were induced by retroviral insertional mutagenesis, are profiled, resulting in a dataset for which both the initiating events (the viral integration sites) as well as the consequent expression profiles are available. We infer associations between insertion loci and gene expression profiles, while explicitly incorporating simple boolean logic, modelling multiple and parallel oncogenic pathways. We show that this results in the discovery of interesting causal associations between virally inserted loci and differentially expressed genes in tumorigenesis.

Viruses can induce oncogenic mutations when inserted near (or within) proto-oncogenes. Cancer genes can be identified by determining the loci of viral
insertions from tumors induced by retroviruses. Most often, multiple co-occurring mutations are needed for a cell to develop into a tumor. We propose a 2D Gaussian Kernel Convolution method to discover the cooperating oncogenes from publicly available retroviral insertional mutagenesis data.