A comprehensive characterization of the cell-free transcriptome reveals tissue- and subtype-specific biomarkers for cancer detection.
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ABSTRACT:
SUBMITTER: Larson MH
PROVIDER: S-EPMC8060291 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Cell-free RNA (cfRNA) is a promising analyte for cancer detection. However, a comprehensive assessment of cfRNA in individuals with and without cancer has not been conducted. We performed the first transcriptome-wide characterization of cfRNA in cancer (stage III breast [n=46], lung [n=30]) and non-cancer (n=89) participants from the Circulating Cell-free Genome Atlas (NCT02889978). Of 57,820 annotated genes, 39,564 (68%) were not detected in cfRNA from non-cancer individuals. Within these low-noise regions, we identified tissue- and cancer-specific genes, defined as “dark channel biomarker†(DCB) genes, that were recurrently detected in individuals with cancer. DCB levels in plasma were correlated with tumor shedding rate and RNA expression in matched tissue, suggesting that DCBs with high expression in tumor tissue could enhance cancer detection in patients with low levels of circulating tumor DNA. Overall, cfRNA provides a unique opportunity to detect cancer, predict the tumor tissue of origin, and determine the cancer subtype.
| EGAS00001004704 | EGA
Project description:Triple-negative breast cancer (TNBC) is a highly heterogeneous group of cancers, and molecular subtyping is necessary to better identify molecular-based therapies. While some classifiers have been established, no one has integrated the expression profiles of long noncoding RNAs (lncRNAs) into such subtyping criterions. Considering the emerging important role of lncRNAs in cellular processes, a novel classification integrating transcriptome profiles of both messenger RNA (mRNA) and lncRNA would help us better understand the heterogeneity of TNBC.Using human transcriptome microarrays, we analyzed the transcriptome profiles of 165 TNBC samples. We used k-means clustering and empirical cumulative distribution function to determine optimal number of TNBC subtypes. Gene Ontology (GO) and pathway analyses were applied to determine the main function of the subtype-specific genes and pathways. We conducted co-expression network analyses to identify interactions between mRNAs and lncRNAs.All of the 165 TNBC tumors were classified into four distinct clusters, including an immunomodulatory subtype (IM), a luminal androgen receptor subtype (LAR), a mesenchymal-like subtype (MES) and a basal-like and immune suppressed (BLIS) subtype. The IM subtype had high expressions of immune cell signaling and cytokine signaling genes. The LAR subtype was characterized by androgen receptor signaling. The MES subtype was enriched with growth factor signaling pathways. The BLIS subtype was characterized by down-regulation of immune response genes, activation of cell cycle, and DNA repair. Patients in this subtype experienced worse recurrence-free survival than others (log rank test, P = 0.045). Subtype-specific lncRNAs were identified, and their possible biological functions were predicted using co-expression network analyses.We developed a novel TNBC classification system integrating the expression profiles of both mRNAs and lncRNAs and determined subtype-specific lncRNAs that are potential biomarkers and targets. If further validated in a larger population, our novel classification system could facilitate patient counseling and individualize treatment of TNBC.
| S-EPMC4791797 | biostudies-other
Project description:Major research efforts have focused on defining cell surface marker profiles for characterization and selection of brain tumor stem/progenitor cells. Medulloblastoma is the most common primary malignant pediatric brain cancer and consists of 4 molecular subgroups: WNT, SHH, Group 3 and Group 4. Given the heterogeneity within and between medulloblastoma variants, surface marker profiles may be subtype-specific. Here, we employed a high throughput flow cytometry screen to identify differentially expressed cell surface markers in self-renewing vs. non-self-renewing SHH medulloblastoma cells. The top 25 markers were reduced to 4, CD271/p75NTR/NGFR, CD106/VCAM1, EGFR and CD171/NCAM-L1, by evaluating transcript levels in SHH tumors relative to samples representing the other variants. However, only CD271/p75NTR/NGFR and CD171/NCAM-L1 maintain differential expression between variants at the protein level. Functional characterization of CD271, a low affinity neurotrophin receptor, in cell lines and primary cultures suggested that CD271 selects for lower self-renewing progenitors or stem cells. Moreover, CD271 levels were negatively correlated with expression of SHH pathway genes. Our study reveals a novel role for CD271 in SHH medulloblastoma and suggests that targeting CD271 pathways could lead to the design of more selective therapies that lessen the broad impact of current treatments on developing nervous systems.
| S-EPMC4770744 | biostudies-literature
Project description:BackgroundSalivary gland tumors (SGTs) include a large group of rare neoplasms in the head and neck region, and the heterogeneous and overlapping features among the subtypes frequently make diagnostic difficulties. There is an urgent need to understand the cellular mechanisms underlying the heterogeneity and overlap among the subtypes, and explore the subtype-specific diagnostic biomarkers.MethodsThe tumor tissue and the adjacent normal tissue from the 6 most common types of SGTs were processed for organoid culture which only maintained tumor epithelial cells. Organoids were histologically evaluated based on phenotype markers, followed by transcriptional profiling using RNA-sequencing. The transcriptomic similarities and differences among the subtypes were analyzed by subtype consensus clustering and hierarchical clustering. Furthermore, by comparative transcriptional analysis for these 6 types of SGTs and the matched organoids, the potential diagnostic biomarkers from tumor epithelium were identified, in which two selected biomarkers were evaluated by qPCR and confirmed by immunohistochemistry staining using a tissue microarray.ResultsWe generated a biobank of patient-derived organoids (PDOs) with 6 subtypes of SGTs, including 21 benign and 24 malignant SGTs. The PDOs recapitulated the morphological and transcriptional characteristics of the parental tumors. The overlap in the cell types and the heterogenous growth patterns were observed in the different subtypes of organoids. Comparing the bulk tissues, the cluster analysis of the PDOs remarkably revealed the epithelial characteristics, and visualized the intrinsic relationship among these subtypes. Finally, the exclusive biomarkers for the 6 most common types of SGTs were uncovered by comparative analysis, and PTP4A1 was demonstrated as a useful diagnostic biomarker for mucoepidermoid carcinoma.ConclusionsWe established the first organoid biobank with multiple subtypes of SGTs. PDOs of SGTs recapitulate the morphological and transcriptional characteristics of the original tumors, which uncovers subtype-specific biomarkers and reveals the molecular distance among the subtype of SGTs.
| S-EPMC9758872 | biostudies-literature
Project description:BackgroundCell-surface proteins have been widely used as diagnostic and prognostic markers in cancer research and as targets for the development of anticancer agents. So far, very few attempts have been made to characterize the surfaceome of patients with breast cancer, particularly in relation with the current molecular breast cancer (BRCA) classification. In this view, we developed a new computational method to infer cell-surface protein activities from transcriptomics data, termed 'SURFACER'.MethodsGene expression data from GTEx were used to build a normal breast network model as input to infer differential cell-surface proteins activity in BRCA tissue samples retrieved from TCGA versus normal samples. Data were stratified according to the PAM50 transcriptional subtypes (Luminal A, Luminal B, HER2 and Basal), while unsupervised clustering techniques were applied to define BRCA subtypes according to cell-surface proteins activity.ResultsOur approach led to the identification of 213 PAM50 subtypes-specific deregulated surface genes and the definition of five BRCA subtypes, whose prognostic value was assessed by survival analysis, identifying a cell-surface activity configuration at increased risk. The value of the SURFACER method in BRCA genotyping was tested by evaluating the performance of 11 different machine learning classification algorithms.ConclusionsBRCA patients can be stratified into five surface activity-specific groups having the potential to identify subtype-specific actionable targets to design tailored targeted therapies or for diagnostic purposes. SURFACER-defined subtypes show also a prognostic value, identifying surface-activity profiles at higher risk.
| S-EPMC8655506 | biostudies-literature
Project description:Alternative splicing is an important way of regulating gene functions in eukaryotes. Several key genes involved in sex determination and gonadal differentiation, such as nr5a1 and ddx4, have sex-biased transcripts between males and females, suggesting a potential regulatory role of alternative splicing in gonads. Currently, the sex-specific alternative splicing events and genes have not been comprehensively studied at the genome-wide level in zebrafish. In this study, through global splicing analysis on three independent sets of RNA-seq data from matched zebrafish testes and ovaries, we identified 120 differentially spliced genes shared by the three datasets, most of which haven't been reported before. Functional enrichment analysis showed that the GO terms of mRNA processing, mRNA metabolism and microtubule-based process were strongly enriched. The testis- and ovary-biased alternative splicing genes were identified, and part of them (tp53bp1, tpx2, mapre1a, kif2c, and ncoa5) were further validated by RT-PCR. Sequence characteristics analysis suggested that the lengths, GC contents, and splice site strengths of the alternative exons or introns may have different influences in different types of alternative splicing events. Interestingly, we identified an unexpected high proportion (over 70%) of non-frameshift exon-skipping events, suggesting that in these cases the two protein isoforms derived from alternative splicing may both have functions. Furthermore, as a representative example, we found that the alternative splicing of ncoa5 causes the loss of a conserved RRM domain in the short transcript predominantly produced in testes. Our study discovers novel sex-specific alternative splicing events and genes with high reliabilities in zebrafish testes and ovaries, which would provide attractive targets for follow-up studies to reveal the biological significances of alternative splicing events and genes in sex determination and gonadal differentiation.
| S-EPMC9501657 | biostudies-literature
Project description:Emerging evidence has been experimentally confirmed the tissue-specific expression of circRNAs (circRNAs). Global identification of human tissue-specific circRNAs is crucial for the functionality study, which facilitates the discovery of circRNAs for potential diagnostic biomarkers.In this study, circRNA back-splicing junctions were identified from 465 publicly available transcriptome sequencing samples. The number of reads aligned to these identified junctions was normalized with the read length and sequence depth for each sample. We generated 66 models representing enriched circRNAs among human tissue transcriptome through biclustering algorithm. The result provides thousands of newly identified human tissue-specific circRNAs.This result suggests that expression of circRNAs is not prompted by random splicing error but serving molecular functional roles. We also identified circRNAs enriched within circulating system, which, along with identified tissue-specific circRNAs, can serve as potential diagnostic biomarkers.
| S-EPMC5780853 | biostudies-literature
Project description:Epigenetic machinery contributes to gene regulation in eukaryotic species. However, the machinery including more than 600 epigenetic regulator (ER) genes responsible for reading, writing, and erasing histone modifications and DNA modifications remains largely uncharacterized across species. We compile a comprehensive list of ERs based on an evolutionary analysis across 23 species, which is the most comprehensive ER list in various species until recently. We further perform comparative transcriptomic analyses across different tissues in humans, mice, as well as other amniote species. We observe a consistent tissue-of-origin expression specificity pattern of duplicated ER genes across species and suggest links between expression specificity and ER gene evolution as well as ER function. Additional analyses further suggest that ER duplication can generate tissue-specific ER genes with the same epigenetic substrates, which may be closely related to their regulatory specificity in tissue development. Our work can serve as a foundation to better comprehend the tissue-specific expression patterns of ER genes from an evolutionary perspective and also the functional implications of ERs in tissue-specific epigenetic regulation.
| S-EPMC9980636 | biostudies-literature
Project description:Recent efforts on genome wide profiling of muscle invasive bladder cancer (MIBC) have led to its classification into distinct genomic and transcriptomic molecular subtypes that exhibit variability in prognosis. Evolving evidence from recent immunotherapy trials has demonstrated the significance of pre-existing tumour immune profiles that could guide treatment decisions. To identify immune gene expression patterns associated with the molecular subtypes, we performed a comprehensive in silico immune transcriptomic profiling, utilizing transcriptomic data from 347 MIBC cases from The Cancer Genome Atlas (TCGA). To investigate subtype-associated immune gene expression patterns, we assembled 924 immune response genes and specifically those involved in T-cell cytotoxicity and the Type I/II interferon pathways. A set of 157 ranked genes was able to distinguish the four subtypes in an unsupervised analysis in an original training cohort (n=122) and an expanded, validation cohort (n=225). The most common overrepresented pathways distinguishing the four molecular subtypes, included JAK/STAT signaling, Toll-like receptor signaling, interleukin signaling, and T-cell activation. Some of the most enriched biological processes were responses to IFN-γ, antigen processing and presentation, cytokine mediated signaling, hemopoeisis, cell proliferation and cellular defense response in the TCGA cluster IV. Our novel findings provide further insights into the association between genomic subtypes and immune activation in MIBC and may open novel opportunities for their exploitation towards precise treatment with immunotherapy.
| S-EPMC5642612 | biostudies-literature
Project description:Endemic Burkitt lymphoma (eBL) is the most common pediatric cancer in malaria-endemic equatorial Africa and nearly always contains Epstein-Barr virus (EBV), unlike sporadic Burkitt lymphoma (sBL) that occurs with a lower incidence in developed countries. Given these differences and the variable clinical presentation and outcomes, we sought to further understand pathogenesis by investigating transcriptomes using RNA sequencing (RNAseq) from multiple primary eBL tumors compared with sBL tumors. Within eBL tumors, minimal expression differences were found based on: anatomical presentation site, in-hospital survival rates, and EBV genome type, suggesting that eBL tumors are homogeneous without marked subtypes. The outstanding difference detected using surrogate variable analysis was the significantly decreased expression of key genes in the immunoproteasome complex (PSMB9/?1i, PSMB10/?2i, PSMB8/?5i, and PSME2/PA28?) in eBL tumors carrying type 2 EBV compared with type 1 EBV. Second, in comparison with previously published pediatric sBL specimens, the majority of the expression and pathway differences was related to the PTEN/PI3K/mTOR signaling pathway and was correlated most strongly with EBV status rather than geographic designation. Third, common mutations were observed significantly less frequently in eBL tumors harboring EBV type 1, with mutation frequencies similar between tumors with EBV type 2 and without EBV. In addition to the previously reported genes, a set of new genes mutated in BL, including TFAP4, MSH6, PRRC2C, BCL7A, FOXO1, PLCG2, PRKDC, RAD50, and RPRD2, were identified. Overall, these data establish that EBV, particularly EBV type 1, supports BL oncogenesis, alleviating the need for certain driver mutations in the human genome. IMPLICATIONS:Genomic and mutational analyses of Burkitt lymphoma tumors identify key differences based on viral content and clinical outcomes suggesting new avenues for the development of prognostic molecular biomarkers and therapeutic interventions.
| S-EPMC5471630 | biostudies-literature