RESUMEN
Precision oncology has primarily relied on coding mutations as biomarkers of response to therapies. While transcriptome analysis can provide valuable information, incorporation into workflows has been difficult. For example, the relative rather than absolute gene expression level needs to be considered, requiring differential expression analysis across samples. However, expression programs related to the cell-of-origin and tumor microenvironment effects confound the search for cancer-specific expression changes. To address these challenges, we developed an unsupervised clustering approach for discovering differential pathway expression within cancer cohorts using gene expression measurements. The hydra approach uses a Dirichlet process mixture model to automatically detect multimodally distributed genes and expression signatures without the need for matched normal tissue. We demonstrate that the hydra approach is more sensitive than widely-used gene set enrichment approaches for detecting multimodal expression signatures. Application of the hydra analysis framework to small blue round cell tumors (including rhabdomyosarcoma, synovial sarcoma, neuroblastoma, Ewing sarcoma, and osteosarcoma) identified expression signatures associated with changes in the tumor microenvironment. The hydra approach also identified an association between ATRX deletions and elevated immune marker expression in high-risk neuroblastoma. Notably, hydra analysis of all small blue round cell tumors revealed similar subtypes, characterized by changes to infiltrating immune and stromal expression signatures.
Asunto(s)
Perfilación de la Expresión Génica/métodos , Neoplasias/genética , Transcriptoma/genética , Biomarcadores de Tumor , Niño , Análisis por Conglomerados , Biología Computacional/métodos , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Modelos Estadísticos , Neuroblastoma/genética , Medicina de Precisión/métodos , Microambiente Tumoral/genéticaRESUMEN
The cellular components of tumors and their microenvironment play pivotal roles in tumor progression, patient survival, and the response to cancer treatments. Unveiling a comprehensive cellular profile within bulk tumors via single-cell RNA sequencing (scRNA-seq) data is crucial, as it unveils intrinsic tumor cellular traits that elude identification through conventional cancer subtyping methods. Our contribution, scBeacon, is a tool that derives cell-type signatures by integrating and clustering multiple scRNA-seq datasets to extract signatures for deconvolving unrelated tumor datasets on bulk samples. Through the employment of scBeacon on the The Cancer Genome Atlas (TCGA) cohort, we find cellular and molecular attributes within specific tumor categories, many with patient outcome relevance. We developed a tumor cell-type map to visually depict the relationships among TCGA samples based on the cell-type inferences.
Asunto(s)
Neoplasias , Análisis de la Célula Individual , Microambiente Tumoral , Humanos , Microambiente Tumoral/genética , Análisis de la Célula Individual/métodos , Neoplasias/genética , Neoplasias/patología , Análisis de Secuencia de ARN , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Análisis por ConglomeradosRESUMEN
Biological states are controlled by orchestrated transcriptional factors (TFs) within gene regulatory networks. Here we show TFs responsible for the dynamic changes of biological states can be prioritized with temporal PageRank. We further show such TF prioritization can be extended by integrating gene regulatory networks reverse engineered from multi-omics profiles, e.g. gene expression, chromatin accessibility, and chromosome conformation assays, using multiplex PageRank.