Biology subjects

Hubert, S. M.

Publications and source records attributed to Hubert, S. M..

4 recordsLinked to original sources

bioRxiv2023

A novel Bayesian model for assessing intratumor heterogeneity of tumor infiltrating leukocytes with multi-region gene expression sequencing

Intratumor heterogeneity (ITH) of tumor-infiltrated leukocytes (TILs) is an important phenomenon of cancer biology with potentially profound clinical impacts. Multiregion gene expression sequencing data provide a promising opportunity that allows for explorations of TILs and their intratumor heterogeneity for each subject. Although several existing methods are available to infer the proportions of TILs, considerable methodological gaps exist for evaluating intratumor heterogeneity of TILs with multi-region gene expression data. Here, we develop ICeITH, immune cell estimation reveals intratumor heterogeneity, a Bayesian hierarchical model that borrows cell type profiles as prior knowledge to decompose mixed bulk data while accounting for the within-subject correlations among tumor samples. ICeITH quantifies intratumor heterogeneity by the variability of targeted cellular compositions. Through extensive simulation studies, we demonstrate that ICeITH is more accurate in measuring relative cellular abundance and evaluating intratumor heterogeneity compared with existing methods. We also assess the ability of ICeITH to stratify patients by their intratumor heterogeneity score and associate the estimations with the survival outcomes. Finally, we apply ICeITH to two multi-region gene expression datasets from lung cancer studies to classify patients into different risk groups according to the ITH estimations of targeted TILs that shape either pro- or anti-tumor processes. In conclusion, ICeITH is a useful tool to evaluate intratumor heterogeneity of TILs from multi-region gene expression data.

bioinformatics↗

bioRxiv2020

Differing total mRNA expression shapes the molecular and clinical phenotype of cancer

Cancers can vary greatly in their transcriptomes. In contrast to alterations in specific genes or pathways, differences in tumor cell total mRNA content have not been comprehensively assessed. Technical and analytical challenges have impeded examination of total mRNA expression at scale across cancers. To address this, we developed a model for quantifying tumor-specific total mRNA expression (TmS) from bulk sequencing data, which performs transcriptomic deconvolution while adjusting for mixed genomes. We used single-cell RNA sequencing data to demonstrate total mRNA expression as a feature of tumor phenotype. We estimated and validated TmS in 5,015 patients across 15 cancer types identifying significant inter-individual variability. At a pan-cancer level, high TmS is associated with increased risk of disease progression and death. Cancer type-specific patterns of genetic alterations, intra-tumor genetic heterogeneity, as well as pan-cancer trends in metabolic dysregulation and hypoxia contribute to TmS. Taken together, our results suggest that measuring cell-type specific total mRNA expression offers a broader perspective of tracking cancer transcriptomes, which has important biological and clinical implications.

genomics↗

bioRxiv2020

Genomic and TCR Repertoire Intratumor Heterogeneity of Small-cell Lung Cancer and its Impact on Survival

Small-cell lung cancer (SCLC) is speculated to harbor complex genomic intratumor heterogeneity (ITH) associated with high recurrence rate and suboptimal response to immunotherapy. Here, we revealed a rather homogeneous mutational landscape but extremely suppressed and heterogeneous T cell receptor (TCR) repertoire in SCLCs. Higher mutational burden, lower chromosomal copy number aberration (CNA) burden, less CNA ITH and less TCR ITH were associated with longer overall survival of SCLC patients. Compared to non-small cell lung cancers (NSCLCs), SCLCs had similar predicted neoantigen burden and mutational ITH, but significantly more suppressed and heterogeneous TCR repertoire that may be associated with higher CNA burden and CNA ITH in SCLC. Novel therapeutic strategies targeting CNA could potentially improve the tumor immune microenvironment and response to immunotherapy in SCLC.

genomics↗

bioRxiv2018

Insights into the molecular basis of wooden breast based on comparative analysis of fast- and slow-growth broilers

Wooden breast has emerged as an important condition in the poultry industry and affects the breast muscle of commercial meat-type chickens (broilers). Thus far, the condition has been classified as a myopathy, confirmed to not have an infectious origin, with molecular data showing the muscle to be under oxidative stress. The objective in this study was to query the functional origins of wooden breast and reveal its molecular similarities to known conditions based on pathway analyses. To carry out an in-depth comparative analysis, we generated RNAseq data from wooden breast affected birds and incorporated breast specific transcriptomic data from previously published studies. The comparative datasets were constructed from a range of commercial fast-growth and slow-growth varieties. Analysis of high-impact variants identified from transcriptome data provided a list of genes important in cell signaling, cell proliferation, cytoskeletal development, and calcium metabolism as being affected by nucleotide changes. Overlaying the lists of significantly differentially expressed genes with the list of high-impact variants produced a list of twenty genes that suggest an association of mechanistic and functional causes for woody breast; supporting a polygenic basis for this condition. Our study demonstrates that wooden breast shows an age-dependent gene expression pattern, with pathway analysis showing enrichment of glycolysis, cell differentiation, tumor suppression and inhibition, further indicating a complex condition with few similarities to myopathies. In summary, our results indicate the existence of a mechanistic, heritable basis for wooden breast, the drivers of which deserve more in-depth investigation. Additionally, they also suggest wooden breast to be a more complex condition than previously reported, potentially involving other organ systems.

genomics↗