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Precision medicine is a paradigm shift in healthcare relying heavily on genomics data. However, the complexity of biological interactions, the large number of genes as well as the lack of comparisons on the analysis of data, remain a tremendous bottleneck regarding clinical adoption. In this paper, we introduce a novel, automatic and unsupervised framework to discover low-dimensional gene biomarkers. Our method is based on the LP-Stability algorithm, a high dimensional center-based unsupervised clustering algorithm, that offers modularity as concerns metric functions and scalability, while being able to automatically determine the best number of clusters. Our evaluation includes both mathematical and biological criteria. The recovered signature is applied to a variety of biological tasks, including screening of biological pathways and functions, and characterization relevance on tumor types and subtypes. Quantitative comparisons among different distance metrics, commonly used clustering methods and a referential gene signature used in the literature, confirm state of the art performance of our approach. In particular, our signature, that is based on 27 genes, reports at least $30$ times better mathematical significance (average Dunns Index) and 25% better biological significance (average Enrichment in Protein-Protein Interaction) than those produced by other referential clustering methods. Finally, our signature reports promising results on distinguishing immune inflammatory and immune desert tumors, while reporting a high balanced accuracy of 92% on tumor types classification and averaged balanced accuracy of 68% on tumor subtypes classification, which represents, respectively 7% and 9% higher performance compared to the referential signature.
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Summary: Interpretation and prioritization of candidate hits from genome-scale screening experiments represent a significant analytical challenge, particularly when it comes to an understanding of cancer relevance. We have developed a flexible tool that substantially refines gene set interpretability in cancer by leveraging a broad scope of prior knowledge unavailable in existing frameworks, including data on target tractabilities, tumor-type association strengths, protein complexes and protein-protein interactions, tissue and cell-type expression specificities, subcellular localizations, prognostic associations, cancer dependency maps, and information on genes of poorly defined or unknown function. Availability: oncoEnrichR is developed in R, and is freely available as a stand-alone R package. A web interface to oncoEnrichR is provided through the Galaxy framework (https://oncotools.elixir.no). All code is open-source under the MIT license, with documentation, example datasets and and instructions for usage available at https://github.com/sigven/oncoEnrichR/ Contact: [email protected]
Linear discrimination, from the point of view of numerical linear algebra, can be treated as solving an ill-posed system of linear equations. In order to generate a solution that is robust in the presence of noise, these problems require regularization. Here, we examine the ill-posedness involved in the linear discrimination of cancer gene expression data with respect to outcome and tumor subclasses. We show that a filter factor representation, based upon Singular Value Decomposition, yields insight into the numerical ill-posedness of the hyperplane-based separation when applied to gene expression data. We also show that this representation yields useful diagnostic tools for guiding the selection of classifier parameters, thus leading to improved performance.
Motivation: Uncovering the genomic causes of cancer, known as cancer driver genes, is a fundamental task in biomedical research. Cancer driver genes drive the development and progression of cancer, thus identifying cancer driver genes and their regulatory mechanism is crucial to the design of cancer treatment and intervention. Many computational methods, which take the advantages of computer science and data science, have been developed to utilise multiple types of genomic data to reveal cancer drivers and their regulatory mechanism behind cancer development and progression. Due to the complexity of the mechanistic insight of cancer genes in driving cancer and the fast development of the field, it is necessary to have a comprehensive review about the current computational methods for discovering different types of cancer drivers. Results: We survey computational methods for identifying cancer drivers from genomic data. We categorise the methods into three groups, methods for single driver identification, methods for driver module identification, and methods for identifying personalised cancer drivers. We also conduct a case study to compare the performance of the current methods. We further analyse the advantages and limitations of the current methods, and discuss the challenges and future directions of the topic. In addition, we investigate the resources for discovering and validating cancer drivers in order to provide a one-stop reference of the tools to facilitate cancer driver discovery. The ultimate goal of the paper is to help those interested in the topic to establish a solid background to carry out further research in the field.
Extracting genetic information from a full range of sequencing data is important for understanding diseases. We propose a novel method to effectively explore the landscape of genetic mutations and aggregate them to predict cancer type. We used multinomial logistic regression, nonsmooth non-negative matrix factorization (nsNMF), and support vector machine (SVM) to utilize the full range of sequencing data, aiming at better aggregating genetic mutations and improving their power in predicting cancer types. Specifically, we introduced a classifier to distinguish cancer types using somatic mutations obtained from whole-exome sequencing data. Mutations were identified from multiple cancers and scored using SIFT, PP2, and CADD, and grouped at the individual gene level. The nsNMF was then applied to reduce dimensionality and to obtain coefficient and basis matrices. A feature matrix was derived from the obtained matrices to train a classifier for cancer type classification with the SVM model. We have demonstrated that the classifier was able to distinguish the cancer types with reasonable accuracy. In five-fold cross-validations using mutation counts as features, the average prediction accuracy was 77.1% (SEM=0.1%), significantly outperforming baselines and outperforming models using mutation scores as features. Using the factor matrices derived from the nsNMF, we identified multiple genes and pathways that are significantly associated with each cancer type. This study presents a generic and complete pipeline to study the associations between somatic mutations and cancers. The discovered genes and pathways associated with each cancer type can lead to biological insights. The proposed method can be adapted to other studies for disease classification and pathway discovery.
Identifying subgroups and properties of cancer biopsy samples is a crucial step towards obtaining precise diagnoses and being able to perform personalized treatment of cancer patients. Recent data collections provide a comprehensive characterization of cancer cell data, including genetic data on copy number alterations (CNAs). We explore the potential to capture information contained in cancer genomic information using a novel topology-based approach that encodes each cancer sample as a persistence diagram of topological features, i.e., high-dimensional voids represented in the data. We find that this technique has the potential to extract meaningful low-dimensional representations in cancer somatic genetic data and demonstrate the viability of some applications on finding substructures in cancer data as well as comparing similarity of cancer types.
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