Spatial and temporal intra-tumoral heterogeneity in advanced HGSOC: Implications for surgical and clinical outcomes.

Limited evidence exists on the impact of spatial and temporal heterogeneity of high-grade serous ovarian cancer (HGSOC) on tumor evolution, clinical outcomes, and surgical operability. We perform systematic multi-site tumor mapping at presentation and matched relapse from 49 high-tumor-burden patients, operated up front. From SNP array-derived copy-number data, we categorize dendrograms representing tumor clonal evolution as sympodial or dichotomous, noting most chemo-resistant patients favor simpler sympodial evolution. Three distinct tumor evolutionary patterns from primary to relapse are identified, demonstrating recurrent disease may emerge from pre-existing or newly detected clones. Crucially, we identify spatial heterogeneity for clinically actionable homologous recombination deficiency scores and for poor prognosis biomarkers CCNE1 and MYC. Copy-number signature, phenotypic, proteomic, and proliferative-index heterogeneity further highlight HGSOC complexity. This study explores HGSOC evolution and dissemination across space and time, its impact on optimal surgical cytoreductive effort and clinical outcomes, and its consequences for clinical decision-making.

Dynamic CpG methylation delineates subregions within super-enhancers selectively decommissioned at the exit from naive pluripotency.

Clusters of enhancers, referred as to super-enhancers (SEs), control the expression of cell identity genes. The organisation of these clusters, and how they are remodelled upon developmental transitions remain poorly understood. Here, we report the existence of two types of enhancer units within SEs typified by distinctive CpG methylation dynamics in embryonic stem cells (ESCs). We find that these units are either prone for decommissioning or remain constitutively active in epiblast stem cells (EpiSCs), as further established in the peri-implantation epiblast in vivo. Mechanistically, we show a pivotal role for ESRRB in regulating the activity of ESC-specific enhancer units and propose that the developmentally regulated silencing of ESRRB triggers the selective inactivation of these units within SEs. Our study provides insights into the molecular events that follow the loss of ESRRB binding, and offers a mechanism by which the naive pluripotency transcriptional programme can be partially reset upon embryo implantation.

A framework for generalized subspace pattern mining in high-dimensional datasets.

BACKGROUND: A generalized notion of biclustering involves the identification of patterns across subspaces within a data matrix. This approach is particularly well-suited to analysis of heterogeneous molecular biology datasets, such as those collected from populations of cancer patients. Different definitions of biclusters will offer different opportunities to discover information from datasets, making it pertinent to tailor the desired patterns to the intended application. This paper introduces 'GABi', a customizable framework for subspace pattern mining suited to large heterogeneous datasets. Most existing biclustering algorithms discover biclusters of only a few distinct structures. However, by enabling definition of arbitrary bicluster models, the GABi framework enables the application of biclustering to tasks for which no existing algorithm could be used. RESULTS: First, a series of artificial datasets were constructed to represent three clearly distinct scenarios for applying biclustering. With a bicluster model created for each distinct scenario, GABi is shown to recover the correct solutions more effectively than a panel of alternative approaches, where the bicluster model may not reflect the structure of the desired solution. Secondly, the GABi framework is used to integrate clinical outcome data with an ovarian cancer DNA methylation dataset, leading to the discovery that widespread dysregulation of DNA methylation associates with poor patient prognosis, a result that has not previously been reported. This illustrates a further benefit of the flexible bicluster definition of GABi, which is that it enables incorporation of multiple sources of data, with each data source treated in a specific manner, leading to a means of intelligent integrated subspace pattern mining across multiple datasets. CONCLUSIONS: The GABi framework enables discovery of biologically relevant patterns of any specified structure from large collections of genomic data. An R implementation of the GABi framework is available through CRAN (http://cran.r-project.org/web/packages/GABi/index.html).

Molecular subtypes of serous borderline ovarian tumor show distinct expression patterns of benign tumor and malignant tumor-associated signatures.

Borderline ovarian tumors show heterogeneity in clinical behavior. Most have excellent prognosis, although a small percentage show recurrence or progressive disease, usually to low-grade serous carcinoma. The aim of this study was to understand the molecular relationship between these entities and identify potential markers of tumor progression and therapeutic targets. We studied gene expression using Affymetrix HGU133plus2 GeneChip microarrays in 3 low-grade serous carcinomas, 13 serous borderline tumors and 8 serous cystadenomas. An independent data set of 18 serous borderline tumors and 3 low-grade serous carcinomas was used for validation. Unsupervised clustering revealed clear separation of benign and malignant tumors, whereas borderline tumors showed two distinct groups, one clustering with benign and the other with malignant tumors. The segregation into benign- and malignant-like borderline molecular subtypes was reproducible on applying the same analysis to an independent publicly available data set. We identified 50 genes that separate borderline tumors into their subgroups. Functional enrichment analysis of genes that separate borderline tumors to the two subgroups highlights a cell adhesion signature for the malignant-like subset, with Claudins particularly prominent. This is the first report of molecular subtypes of borderline tumors based on gene expression profiling. Our results provide the basis for identification of biomarkers for the malignant potential of borderline ovarian tumor and potential therapeutic targets for low-grade serous carcinoma.