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Background Genes implicated in tumorigenesis often exhibit diverse sets of genomic variants in the tumor cohorts within which they are frequently mutated. For many genes, neither the transcriptomic effects of these variants nor their relationship to one another in cancer processes have been well-characterized. We sought to identify the downstream expression effects of these mutations and to determine whether this heterogeneity at the genomic level is reflected in a corresponding heterogeneity at the transcriptomic level. Results By applying a novel hierarchical framework for organizing the mutations present in a cohort along with machine learning pipelines trained on samples’ expression profiles we systematically interrogated the signatures associated with combinations of mutations recurrent in cancer. This allowed us to catalogue the mutations with discernible downstream expression effects across a number of tumor cohorts as well as to uncover and characterize over a hundred cases where subsets of a gene’s mutations are clearly divergent in their function from the remaining mutations of the gene. These findings successfully replicated across a number of disease contexts and were found to have clear implications for the delineation of cancer processes and for clinical decisions. Conclusions The results of cataloguing the downstream effects of mutation subgroupings across cancer cohorts underline the importance of incorporating the diversity present within oncogenes in models designed to capture the downstream effects of their mutations.

Background The development of clinical -omic biomarkers for predicting patient prognosis has mostly focused on multi-gene models. However, several studies have described significant weaknesses of multi-gene biomarkers. Indeed, some high-profile reports have even indicated that multi-gene biomarkers fail to consistently outperform simple single-gene ones. Given the continual improvements in -omics technologies and the availability of larger, better-powered datasets, we revisited this “single-gene hypothesis” using new techniques and datasets. Results By deeply sampling the population of available gene sets, we compare the intrinsic properties of single-gene biomarkers to multi-gene biomarkers in twelve different partitions of a large breast cancer meta-dataset. We show that simple multi-gene models consistently outperformed single-gene biomarkers in all twelve partitions. We found 270 multi-gene biomarkers (one per ~11,111 sampled) that always made better predictions than the best single-gene model. Conclusions The single-gene hypothesis for breast cancer does not appear to retain its validity in the face of improved statistical models, lower-noise genomic technology and better-powered patient cohorts. These results highlight that it is critical to revisit older hypotheses in the light of newer techniques and datasets.

Acute Myeloid Leukemia (AML) develops due to the acquisition of mutations from multiple functional classes. Here, we demonstrate that activating mutations in the granulocyte colony stimulating factor receptor (CSF3R), cooperate with loss of function mutations in the transcription factor CEBPA to promote acute leukemia development. The interaction between these distinct classes of mutations occurs at the level of myeloid lineage enhancers where mutant CEBPA prevents activation of a subset of differentiation associated enhancers. To confirm this enhancer-dependent mechanism, we demonstrate that CEBPA mutations must occur as the initial event in AML initiation. This improved mechanistic understanding will facilitate therapeutic development targeting the intersection of oncogene cooperativity. Acute Myeloid Leukemia (AML) develops following multiple mutations of differing impact. Here, the authors show that activating mutations of CSF3R co-operate with loss-of-function mutations of CEBPA to promote AML development through an enhancer-dependent mechanism.

Background We introduce BPG, a framework for generating publication-quality, highly-customizable plots in the R statistical environment. Results This open-source package includes multiple methods of displaying high-dimensional datasets and facilitates generation of complex multi-panel figures, making it suitable for complex datasets. A web-based interactive tool allows online figure customization, from which R code can be downloaded for integration with computational pipelines. Conclusion BPG provides a new approach for linking interactive and scripted data visualization and is available at http://labs.oicr.on.ca/boutros-lab/software/bpg or via CRAN at https://cran.r-project.org/web/packages/BoutrosLab.plotting.general

Background: Effective classification of cancer patients into groups with differential survival remains an important and unsolved challenge. Biomarkers have been developed based on mRNA abundance data, but their replicability and clinical utility is modest. Integrating functional information, such as pathway data, has been suggested to improve biomarker performance. To date, however, the advantages of subnetwork-based biomarkers have not been quantified. Results: We deeply sampled the population of prognostic gene-based and subnetwork-based biomarkers in a breast cancer meta-dataset of 4,960 patients. Analysing the performance and robustness of 22,000,000 gene biomarkers and 6,250,000 subnetwork biomarkers across twenty different training:testing cohort partitions of the meta-dataset revealed that subnetwork biomarkers exhibit superior overall performance and higher concordance across partitions. We find evidence of an upper bound for optimal biomarker size of ~200 genes or ~100 subnetworks. Additionally, with both biomarker feature types, larger biomarkers tend to show less consistency in performance across partitions, suggestive of over-fitting. Finally, an evaluation of varying training cohort sizes quantifies the effects of training cohort size. Conclusions: Many groups are developing techniques for exploiting network-based representations of biological pathways to characterize cancer and other diseases. By considering the distribution of gene- and subnetwork-based biomarkers, we show that pathway data improves performance and replicability, and that smaller biomarkers are more robust across patient cohorts. These insights may facilitate development of clinically useful biomarkers.

We introduce BPG, an easy-to-use framework for generating publication-quality, highly-customizable plots in the R statistical environment. This open-source package includes novel methods of displaying high-dimensional datasets and facilitates generation of complex multi-panel figures, making it ideal for complex datasets. A web-based interactive tool allows online figure customization, from which R code can be downloaded for seamless integration with computational pipelines. BPG is available at http://labs.oicr.on.ca/boutros-lab/software/bpg.

Genes implicated in tumorigenesis often exhibit diverse sets of genomic variants in the tumor cohorts within which they are frequently mutated. We sought to identify the downstream expression effects of these perturbations and to find whether or not this heterogeneity at the genomic level is reflected in a corresponding heterogeneity at the transcriptomic level. Applying a novel hierarchical framework for organizing the mutations present in a cohort along with machine learning pipelines trained on sample expression profiles we systematically interrogated the signatures associated with combinations of perturbations recurrent in cancer. This allowed us to catalogue the mutations with discernible downstream expression effects across a number of tumor cohorts as well as to uncover and characterize a multitude of cases where subsets of a genes mutations are clearly divergent in their function from the remaining mutations of the gene. Competing Interest Statement The authors have declared no competing interest. Footnotes * Adding line numbers; shortening abstract; cleaning up references; adding graphical abstract.

Acute Myeloid Leukemia (AML) develops due to the acquisition of mutations from multiple functional classes. Here, we demonstrate that activating mutations in the granulocyte colony stimulating factor receptor (CSF3R), cooperate with loss of function mutations in the transcription factor CEBPA to promote acute leukemia development. This finding of mutation-synergy is broadly applicable other mutations that activate the JAK/STAT pathway or disrupt CEBPA function (i.e. activating mutations in JAK3 and Core Binding Factor translocations). The interaction between these distinct classes of mutations occurs at the level of myeloid lineage enhancers where mutant CEBPA prevents activation of subset of differentiation associated enhancers. To confirm this enhancer-dependent mechanism, we demonstrate that CEBPA mutations must occur as the initial event in AML initiation, confirming predictions from clinical sequencing data. This improved mechanistic understanding will facilitate therapeutic development targeting the intersection of oncogene cooperativity.