A gene is considered as essential when it is indispensable for cells to grow and replicate under a certain environment. However, gene essentiality is not a structural property but rather a contextual one, which depends on the specific biological conditions affecting the cell. This circumstantial essentiality of genes is what brings the attention of scientist since we can identify genes essential for cancer cells but not essential for healthy cells. This same contextuality makes their identification extremely challenging. Huge experimental efforts such as Project Achilles where the essentiality of thousands of genes is measured together with a plethora of molecular data (transcriptomics, copy number, mutations, etc.) in over one thousand cell lines can shed light on the causality behind the essentiality of a gene in a given environment. Here, we present an in-silico method for the identification of patient-specific essential genes using constraint-based modelling (CBM). Our method expands the ideas behind traditional CBM to accommodate multisystem networks. In essence, it first calculates the minimum number of non-expressed genes required to be active by the cell to sustain life as defined by a set of requirements; and second, it performs an exhaustive in-silico gene knockout to find those that lead to the need of activating additional non-expressed genes. We validated the proposed methodology using a set of 452 cancer cell lines derived from the Cancer Cell Line Encyclopedia where an exhaustive experimental large-scale gene knockout study using CRISPR (Achilles Project) evaluates the impact of each removal. We also show that the integration of different essentiality predictions per gene, what we called Essentiality Congruity Score, (derived from multiple pathways) reduces the number of false positives. Finally, we explored the gene essentiality predictions for a breast cancer patient dataset, and our results showed high concordance with previous publications. These findings suggest that identifying genes whose activity is fundamental to sustain cellular life in a patient-specific manner is feasible using in-silico methods. The patient-level gene essentiality predictions can pave the way for precision medicine by identifying potential drug targets whose deletion can induce death in tumour cells.
Understanding the cellular composition of tissue samples is crucial for identifying the molecular mechanisms underlying diseases and developing cellular targets for therapeutic interventions. Digital cytometry methods have been developed to predict tissue composition from bulk transcriptomic data, avoiding the high cost associated with single-cell profiling. Here, we present ELITE, a new digital cytometry method that utilizes linear programming to solve the deconvolution problem. ELITE uses as inputs a mixture matrix representing bulk measurements, and a signature matrix representing molecular fingerprints of the cell types to be identified. The signature matrix can be obtained from single-cell datasets or the literature, making ELITE more flexible than other methods that rely solely on single-cell data. We evaluated ELITE on three publicly available single-cell datasets and compared it with five other deconvolution methods, showing superior performance, particularly when there were cell types with similar expression profiles. As a case study, we evaluated the prediction of tumor cellularity using purity estimates from 20 different TCGA carcinoma datasets.
A gene is considered as essential when it is indispensable for cells to grow and replicate in a certain environment. However, gene essentiality is not a structural property but rather a contextual one, which depends on the specific biological conditions affecting the cell. This circumstantial essentiality of genes is what brings the attention of scientist since we can identify genes essential for cancer cells but not essential for healthy cells. This same contextuality makes their identification extremely challenging. Huge experimental efforts such as Project Achilles where the essentiality of thousands of genes is measured together with a plethora of molecular data (transcriptomics, copy number, mutations, etc.) in over one thousand cell lines can shed light on the causality behind the essentiality of a gene in a given environment. Here, we present an in-silico method for the identification of patient-specific essential genes using constraint-based modelling (CBM). Our method expands the ideas behind traditional CBM to accommodate multisystem networks. In essence, it first calculates the minimum number of lowly expressed genes required to be activated by the cell to sustain life as defined by a set of requirements; and second, it performs an exhaustive in-silico gene knockout to find those that lead to the need of activating additional lowly expressed genes. We validated the proposed methodology using a set of 452 cancer cell lines derived from the Cancer Cell Line Encyclopedia where an exhaustive experimental large-scale gene knockout study using CRISPR (Achilles Project) evaluates the impact of each removal. We also show that the integration of different essentiality predictions per gene, what we called Essentiality Congruity Score, reduces the number of false positives. Finally, we explored our method in a breast cancer patient dataset, and our results showed high concordance with previous publications. These findings suggest that identifying genes whose activity is fundamental to sustain cellular life in a patient-specific manner is feasible using in-silico methods. The patient-level gene essentiality predictions can pave the way for precision medicine by identifying potential drug targets whose deletion can induce death in tumour cells.
A gene is considered as essential when it is indispensable for cells to grow and replicate under a certain environment. However, gene essentiality is not a structural property but rather a contextual one, which depends on the specific biological conditions affecting the cell. This circumstantial essentiality of genes is what brings the attention of scientist since we can identify genes essential for cancer cells but not essential for healthy cells. This same contextuality makes their identification extremely challenging. Huge experimental efforts such as Project Achilles where the essentiality of thousands of genes is measured in over one thousand cell lines together with a plethora of molecular data (transcriptomics, copy number, mutations, etc.) can shed light on the causality behind the essentiality of a gene in a given environment by associating the measured essentiality to molecular features of the cell line. Here, we present an in-silico method for the identification of patient-specific essential genes using constraint-based modelling (CBM). Our method expands the ideas behind traditional CBM to accommodate multisystem networks, that is a biological network that focuses on complex interactions within several biological systems. In essence, it first calculates the minimum number of non-expressed genes required to be active by the cell to sustain life as defined by a set of requirements; and second, it performs an exhaustive in-silico gene knockout to find those that lead to the need of activating extra non-expressed genes. We validated the proposed methodology using a set of 452 cancer cell lines derived from the Cancer Cell Line Encyclopedia where an exhaustive experimental large-scale gene knockout study using CRISPR (Achilles Project) evaluates the impact of each removal. We also show that the integration of different essentiality predictions per gene, what we called Essentiality Congruity Score, (derived from multiple pathways) reduces the number of false positives. Finally, we explored the gene essentiality predictions for a breast cancer patient dataset, and our results showed high concordance with previous publications. These findings suggest that identifying genes whose activity are fundamental to sustain cellular life in a patient-specific manner is feasible using in-silico methods. The patient-level gene essentiality predictions can pave the way for precision medicine by identifying potential drug targets whose deletion can induce death in tumour cells.
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