scholarly journals Identification of Prognostic Biomarkers Originating From the Tumor Stroma of Betel Quid-Associated Oral Cancer Tissues

2021 ◽  
Vol 11 ◽  
Author(s):  
Yi-Hong Liu ◽  
Yu-Lian Chen ◽  
Ting-Yu Lai ◽  
Ying-Chieh Ko ◽  
Yu-Fu Chou ◽  
...  
Keyword(s):  
Overall Survival ◽  
Oral Cancer ◽  
Cancer Progression ◽  
Tumor Stroma ◽  
The Cancer Genome Atlas ◽  
Rna Seq ◽  
Cancer Genome Atlas ◽  
Cancer Types ◽  
Cancer Tissues ◽  
Genome Atlas

BackgroundPartial epithelial-mesenchymal transition (p-EMT) is a distinct clinicopathological feature prevalent in oral cavity tumors of The Cancer Genome Atlas. Located at the invasion front, p-EMT cells require additional support from the tumor stroma for collective cell migration, including track clearing, extracellular matrix remodeling and immune evasion. The pathological roles of otherwise nonmalignant cancer-associated fibroblasts (CAFs) in cancer progression are emerging.MethodsGene set enrichment analysis was used to reveal differentially enriched genes and molecular pathways in OC3 and TW2.6 xenograft tissues, representing mesenchymal and p-EMT tumors, respectively. R packages of genomic data science were executed for statistical evaluations and data visualization. Immunohistochemistry and Alcian blue staining were conducted to validate the bioinformatic results. Univariate and multivariate Cox proportional hazards models were performed to identify covariates significantly associated with overall survival in clinical datasets. Kaplan–Meier curves of estimated overall survival were compared for statistical difference using the log-rank test.ResultsCompared to mesenchymal OC3 cells, tumor stroma derived from p-EMT TW2.6 cells was significantly enriched in microvessel density, tumor-excluded macrophages, inflammatory CAFs, and extracellular hyaluronan deposition. By translating these results to clinical transcriptomic datasets of oral cancer specimens, including the Puram single-cell RNA-seq cohort comprising ~6000 cells, we identified the expression of stromal TGFBI and HYAL1 as independent poor and protective biomarkers, respectively, for 40 Taiwanese oral cancer tissues that were all derived from betel quid users. In The Cancer Genome Atlas, TGFBI was a poor marker not only for head and neck cancer but also for additional six cancer types and HYAL1 was a good indicator for four tumor cohorts, suggesting common stromal effects existing in different cancer types.ConclusionsAs the tumor stroma coevolves with cancer progression, the cellular origins of molecular markers identified from conventional whole tissue mRNA-based analyses should be cautiously interpreted. By incorporating disease-matched xenograft tissue and single-cell RNA-seq results, we suggested that TGFBI and HYAL1, primarily expressed by stromal CAFs and endothelial cells, respectively, could serve as robust prognostic biomarkers for oral cancer control.

scholarly journals PR/SET Domain Family and Cancer: Novel Insights from the Cancer Genome Atlas

2018 ◽  
Vol 19 (10) ◽  
pp. 3250 ◽  
Author(s):  
Anna Sorrentino ◽  
Antonio Federico ◽  
Monica Rienzo ◽  
Patrizia Gazzerro ◽  
Maurizio Bifulco ◽  
...  
Keyword(s):  
Family Members ◽  
Cancer Genome ◽  
The Cancer Genome Atlas ◽  
Driver Gene ◽  
Rna Seq ◽  
Set Domain ◽  
Primary Tumors ◽  
Cancer Genome Atlas ◽  
Pan Cancer ◽  
Genome Atlas

The PR/SET domain gene family (PRDM) encodes 19 different transcription factors that share a subtype of the SET domain [Su(var)3-9, enhancer-of-zeste and trithorax] known as the PRDF1-RIZ (PR) homology domain. This domain, with its potential methyltransferase activity, is followed by a variable number of zinc-finger motifs, which likely mediate protein–protein, protein–RNA, or protein–DNA interactions. Intriguingly, almost all PRDM family members express different isoforms, which likely play opposite roles in oncogenesis. Remarkably, several studies have described alterations in most of the family members in malignancies. Here, to obtain a pan-cancer overview of the genomic and transcriptomic alterations of PRDM genes, we reanalyzed the Exome- and RNA-Seq public datasets available at The Cancer Genome Atlas portal. Overall, PRDM2, PRDM3/MECOM, PRDM9, PRDM16 and ZFPM2/FOG2 were the most mutated genes with pan-cancer frequencies of protein-affecting mutations higher than 1%. Moreover, we observed heterogeneity in the mutation frequencies of these genes across tumors, with cancer types also reaching a value of about 20% of mutated samples for a specific PRDM gene. Of note, ZFPM1/FOG1 mutations occurred in 50% of adrenocortical carcinoma patients and were localized in a hotspot region. These findings, together with OncodriveCLUST results, suggest it could be putatively considered a cancer driver gene in this malignancy. Finally, transcriptome analysis from RNA-Seq data of paired samples revealed that transcription of PRDMs was significantly altered in several tumors. Specifically, PRDM12 and PRDM13 were largely overexpressed in many cancers whereas PRDM16 and ZFPM2/FOG2 were often downregulated. Some of these findings were also confirmed by real-time-PCR on primary tumors.

Identification of Aneuploid Circulating Tumor Cells in Soft-Tissue Sarcoma Patients: A Pilot Study

Oncology ◽  
2020 ◽  
Vol 98 (12) ◽  
pp. 893-896
Author(s):  
Andrea Napolitano ◽  
Alessandro Minelli ◽  
Daniele Santini ◽  
Giuseppe Tonini ◽  
Bruno Vincenzi
Keyword(s):  
Overall Survival ◽  
Pilot Study ◽  
Soft Tissue ◽  
Soft Tissue Sarcoma ◽  
Tumor Cells ◽  
In Silico ◽  
The Cancer Genome Atlas ◽  
Cancer Genome Atlas ◽  
First Time ◽  
Genome Atlas

<b><i>Background:</i></b> Circulating tumor cells (CTCs) have been identified and shown to have prognostic and predictive roles in several types of carcinoma. More recently, aneuploid CTCs have become subject of a growing interest, as aneuploidy is considered a hallmark of cancer often associated with poor prognosis. Here, we aimed to identify for the first time aneuploid CTCs in soft-tissue sarcoma (STS) patients and show supportive in silico evidence on the prognostic role of aneuploidy in mesenchymal cancers. <b><i>Methods:</i></b> In our pilot study, we collected blood from 4 metastatic STS patients and 4 age- and sex-matched healthy controls. After sample processing, cells were cyto-centrifuged onto glass slides and FISH was performed using 5 probes. The in silico analysis was performed using data from The Cancer Genome Atlas cohort of STS patients, using the validated Aneuploidy Score. We divided the patients in two populations (aneuploidy-high, Ane-Hi, and aneuploidy-low, Ane-Lo) using the median value of the Aneuploidy Score as a cutoff. Kaplan-Meier curves associated with log-rank test were used to compare progression-free and overall survival between groups. GraphPad Prism 8.0 (La Jolla, CA, USA) was used for statistical analyses. <b><i>Results:</i></b> Aneuploid CTCs were identified in all 4 STS patients and in none of the controls, with a median value of 4 (range 3–6) per 7 mL of blood. Ane-Hi patients showed a significantly worse progression-free and overall survival compared to Ane-Lo patients. The same trend was maintained when analyzing the data based on the different histologies. <b><i>Conclusions:</i></b> We identified for the first time aneuploid CTCs in STS patients using fluorescence in situ hybridization in a surface marker-independent way. We also showed that the Aneuploidy Score has a prognostic value both in terms of progression-free survival and overall survival in STS patients using The Cancer Genome Atlas data, regardless of the histology.

scholarly journals Putatively cancer-specific exon–exon junctions are shared across patients and present in developmental and other non-cancer cells

NAR Cancer ◽  
2020 ◽  
Vol 2 (1) ◽  
Author(s):  
Julianne K David ◽  
Sean K Maden ◽  
Benjamin R Weeder ◽  
Reid F Thompson ◽  
Abhinav Nellore
Keyword(s):  
Rna Splicing ◽  
Tissue Expression ◽  
The Body ◽  
The Cancer Genome Atlas ◽  
Cancer Type ◽  
Rna Seq ◽  
Normal Tissues ◽  
Cancer Types ◽  
Exon Junctions ◽  
Cancer Tissues

Abstract This study probes the distribution of putatively cancer-specific junctions across a broad set of publicly available non-cancer human RNA sequencing (RNA-seq) datasets. We compared cancer and non-cancer RNA-seq data from The Cancer Genome Atlas (TCGA), the Genotype-Tissue Expression (GTEx) Project and the Sequence Read Archive. We found that (i) averaging across cancer types, 80.6% of exon–exon junctions thought to be cancer-specific based on comparison with tissue-matched samples (σ = 13.0%) are in fact present in other adult non-cancer tissues throughout the body; (ii) 30.8% of junctions not present in any GTEx or TCGA normal tissues are shared by multiple samples within at least one cancer type cohort, and 87.4% of these distinguish between different cancer types; and (iii) many of these junctions not found in GTEx or TCGA normal tissues (15.4% on average, σ = 2.4%) are also found in embryological and other developmentally associated cells. These findings refine the meaning of RNA splicing event novelty, particularly with respect to the human neoepitope repertoire. Ultimately, cancer-specific exon–exon junctions may have a substantial causal relationship with the biology of disease.

scholarly journals Epstein-Barr Virus-Positive Cancers Show Altered B-Cell Clonality

mSystems ◽  
2018 ◽  
Vol 3 (5) ◽  
Author(s):  
Sara R. Selitsky ◽  
David Marron ◽  
Lisle E. Mose ◽  
Joel S. Parker ◽  
Dirk P. Dittmer
Keyword(s):  
B Cells ◽  
B Cell ◽  
Epstein Barr Virus ◽  
The Cancer Genome Atlas ◽  
Barr Virus ◽  
Cancer Genome Atlas ◽  
Cancer Types ◽  
Epstein Barr ◽  
Tumor Types ◽  
Genome Atlas

ABSTRACTEpstein-Barr virus (EBV) is convincingly associated with gastric cancer, nasopharyngeal carcinoma, and certain lymphomas, but its role in other cancer types remains controversial. To test the hypothesis that there are additional cancer types with high prevalence of EBV, we determined EBV viral expression in all the Cancer Genome Atlas Project (TCGA) mRNA sequencing (mRNA-seq) samples (n= 10,396) from 32 different tumor types. We found that EBV was present in gastric adenocarcinoma and lymphoma, as expected, and was also present in >5% of samples in 10 additional tumor types. For most samples, EBV transcript levels were low, which suggests that EBV was likely present due to infected infiltrating B cells. In order to determine if there was a difference in the B-cell populations, we assembled B-cell receptors for each sample and found B-cell receptor abundance (P≤ 1.4 × 10−20) and diversity (P≤ 8.3 × 10−27) were significantly higher in EBV-positive samples. Moreover, diversity was independent of B-cell abundance, suggesting that the presence of EBV was associated with an increased and altered B-cell population.IMPORTANCEAround 20% of human cancers are associated with viruses. Epstein-Barr virus (EBV) contributes to gastric cancer, nasopharyngeal carcinoma, and certain lymphomas, but its role in other cancer types remains controversial. We assessed the prevalence of EBV in RNA-seq from 32 tumor types in the Cancer Genome Atlas Project (TCGA) and found EBV to be present in >5% of samples in 12 tumor types. EBV infects epithelial cells and B cells and in B cells causes proliferation. We hypothesized that the low expression of EBV in most of the tumor types was due to infiltration of B cells into the tumor. The increase in B-cell abundance and diversity in subjects where EBV was detected in the tumors strengthens this hypothesis. Overall, we found that EBV was associated with an increased and altered immune response. This result is not evidence of causality, but a potential novel biomarker for tumor immune status.

scholarly journals An R Implementation of Tumor-Stroma-Immune Transcriptome Deconvolution Pipeline using DeMixT

2019 ◽  
Author(s):  
Shaolong Cao ◽  
Zeya Wang ◽  
Fan Gao ◽  
Jingxiao Chen ◽  
Feng Zhang ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Expression Profiles ◽  
Progression Free Survival ◽  
Tumor Stroma ◽  
R Package ◽  
The Cancer Genome Atlas ◽  
Biological Information ◽  
Computationally Efficient ◽  
Multiple Cancer ◽  
Cancer Genome Atlas

AbstractThe deconvolution of transcriptomic data from heterogeneous tissues in cancer studies remains challenging. Available software faces difficulties for accurately estimating both component-specific proportions and expression profiles for individual samples. To address these challenges, we present a new R-implementation pipeline for the more accurate and efficient transcriptome deconvolution of high dimensional data from mixtures of more than two components. The pipeline utilizes the computationally efficient DeMixT R-package with OpenMP and additional cancer-specific biological information to perform three-component deconvolution without requiring data from the immune profiles. It enables a wide application of DeMixT to gene expression datasets available from cancer consortium such as the Cancer Genome Atlas (TCGA) projects, where, other than the mixed tumor samples, a handful of normal samples are profiled in multiple cancer types. We have applied this pipeline to two TCGA datasets in colorectal adenocarcinoma (COAD) and prostate adenocarcinoma (PRAD). In COAD, we found varying distributions of immune proportions across the Consensus Molecular Subtypes, from the highest to the lowest being CMS1, CMS3, CMS4 and CMS2. In PRAD, we found the immune proportions are associated with progression-free survival (p<0.01) and negatively correlated with Gleason scores (p<0.001). Our DeMixT-centered analysis protocol opens up new opportunities to investigate the tumor-stroma-immune microenvironment, by providing both proportions and component-specific expressions, and thus better define the underlying biology of cancer progression.Availability and implementation: An R package, scripts and data are available: https://github.com/wwylab/DeMixTallmaterials.

scholarly journals Μελέτη μοριακών σηματοδοτικών μηχανισμών επαγωγής της κυτταρικής επιβίωσης και αποδιαφοροποίησης στον καρκίνο

2019 ◽  
Author(s):  
Ευστάθιος-Ιάσων Βλαχάβας
Keyword(s):  
Cancer Genome ◽  
The Cancer Genome Atlas ◽  
Rna Seq ◽  
Cancer Genome Atlas ◽  
Genome Atlas

Ο όρος καρκίνος χρησιμοποιείται όχι για μια ασθένεια, αλλά για ένα ευρύτερο σύνολο συσχετιζόμενων νοσημάτων, οι οποίες περιγράφονται από ένα κοινό χαρακτηριστικό: την αφύσικη ανάπτυξη κυττάρων που διαιρούνται ανεξέλεγκτα και μπορούν να διηθήσουν παρακείμενους ιστούς. Η μελέτη των μοριακών μηχανισμών που εμπλέκονται στη παθοφυσιολογία των καρκίνου, αποτελεί πεδίο έντονης έρευνας, γιατί η κατανόησή τους συνδέεται άμεσα με την ορθή αντιμετώπιση της νόσου. Στην παρούσα διατριβή, εστιάζουμε στον καρκίνο του παχέος εντέρου. Η πλειοψηφία των όγκων του παχέος εντέρου είναι αδενοκαρκινώματα, τα οποία προκύπτουν από τη δημιουργία πολυπόδων που σχηματίζονται στο εσωτερικό τοίχωμα του παχέος εντέρου και μπορούν να εξελιχθούν σε νεοπλασίες. Ο καρκίνος του παχέος εντέρου είναι μια ιδιαίτερα σύνθετη ασθένεια, με έντονα μεταβλητά μοριακά και γενετικά χαρακτηριστικά και με διαφορική απόκριση σε φαρμακευτικά σχήματα. Περίπου το 40% των περιπτώσεων ανιχνεύονται σε πρώιμο στάδιο με το ποσοστό της πενταετούς επιβίωσης να κυμαίνεται στο 90%. Επιπρόσθετα, αποτελεί μια αιτία θνησιμότητας στις χώρες του ανεπτυγμένου κόσμου, κυρίως λόγω του υψηλού μεταστατικού δυναμικού που παρουσιάζει. Συνολικά, τα παραπάνω στοιχεία καθιστούν επιτακτική την αξιοποίηση όλων των διαθέσιμων μοριακών πληροφοριών αλλά και ιατροβιολογικών δεδομένων για την εφαρμογή εξατομικευμένης θεραπείας στα πλαίσια της μεταφραστικής έρευνας.Την τελευταία δεκαετία, η εκτεταμένη αξιοποίηση των τεχνικών υψηλής απόδοσης, όπως οι μικροσυστοιχίες γονιδίων και οι τεχνολογίες αλληλούχισης νέας γενιάς για την ανάλυση της γονιδιακής έκφρασης σε διάφορους τύπους καρκίνου του παχέος εντέρου, συνέβαλε σημαντικά στην ταυτοποίηση σημαντικών γονιδιακών μεταλλαγών και στον χαρακτηρισμό γονιδίων που εμπλέκονται στην παθοφυσιολογία του συγκεκριμένου καρκίνου. Αν και οι τεχνολογίες αλληλούχισης νέας γενιάς παρουσιάζουν σημαντικές τεχνολογικές βελτιώσεις, οι μικροσυστοιχίες DNA εξακολουθούν να παραμένουν δημοφιλείς για την ανάλυση του μεταγραφώματος, αφενός γιατί παραμένουν πιο οικονομικές και αφετέρου προϋποθέτουν μια λιγότερο σύνθετη προετοιμασία δειγμάτων, συγκριτικά με τις μεθοδολογίες αλληλούχισης. Αντιπροσωπευτικά παραδείγματα για τη συμβολή των τεχνολογιών υψηλής απόδοσης αποτελούν ερευνητικές δημοσιεύσεις από τη διεθνή ερευνητική συνεργασία (The Cancer Genome Atlas) για τον μοριακό χαρακτηρισμού του καρκίνου του παχέος εντέρου, καθώς και τον χαρακτηρισμό συγκεκριμένων μοριακών υποτύπων με βάση γονιδιωματικά δεδομένα από διαφορετικές ερευνητικές ομάδες. Ωστόσο, η ιδιαίτερη ετερογένεια που παρουσιάζει ο συγκεκριμένος καρκίνος αλλά και η δυσκολία της ερμηνείας μοριακών δεδομένων υψηλής διαστασιμότητας που προκύπτουν από την ανάλυση μικροσυστοιχιών αλλά και DNA/RNA-Seq τεχνολογιών, δυσχεραίνουν την αξιοποίηση των διαφόρων γονιδιακών υπογραφών που περιγράφουν ένα συγκεκριμένο καρκινικό φαινότυπο, στην κλινική εφαρμογή.

scholarly journals Pan-cancer analysis reveals complex tumor-specific alternative polyadenylation

2017 ◽  
Author(s):  
Zhuyi Xue ◽  
René L Warren ◽  
Ewan A Gibb ◽  
Daniel MacMillan ◽  
Johnathan Wong ◽  
...  
Keyword(s):  
Alternative Polyadenylation ◽  
Length Change ◽  
The Cancer Genome Atlas ◽  
Cancer Type ◽  
Rna Seq ◽  
Multiple Cancer ◽  
Tissue Samples ◽  
Cancer Genome Atlas ◽  
Specific Alternative ◽  
Cancer Types

AbstractAlternative polyadenylation (APA) of 3’ untranslated regions (3’ UTRs) has been implicated in cancer development. Earlier reports on APA in cancer primarily focused on 3’ UTR length modifications, and the conventional wisdom is that tumor cells preferentially express transcripts with shorter 3’ UTRs. Here, we analyzed the APA patterns of 114 genes, a select list of oncogenes and tumor suppressors, in 9,939 tumor and 729 normal tissue samples across 33 cancer types using RNA-Seq data from The Cancer Genome Atlas, and we found that the APA regulation machinery is much more complicated than what was previously thought. We report 77 cases (gene-cancer type pairs) of differential 3’ UTR cleavage patterns between normal and tumor tissues, involving 33 genes in 13 cancer types. For 15 genes, the tumor-specific cleavage patterns are recurrent across multiple cancer types. While the cleavage patterns in certain genes indicate apparent trends of 3’ UTR shortening in tumor samples, over half of the 77 cases imply 3’ UTR length change trends in cancer that are more complex than simple shortening or lengthening. This work extends the current understanding of APA regulation in cancer, and demonstrates how large volumes of RNA-seq data generated for characterizing cancer cohorts can be mined to investigate this process.

scholarly journals The role of miR-92b in cholangiocarcinoma patients

2018 ◽  
Vol 33 (3) ◽  
pp. 293-300 ◽  
Author(s):  
Min-hang Zhou ◽  
Hong-wei Zhou ◽  
Mo Liu ◽  
Jun-zhong Sun
Keyword(s):  
Gene Expression ◽  
Overall Survival ◽  
Gene Expression Omnibus ◽  
Cancer Genome ◽  
The Cancer Genome Atlas ◽  
Positive Regulation ◽  
Cancer Genome Atlas ◽  
High Level ◽  
Genome Atlas

Purpose: The role of microRNA (miRNA) in cholangiocarcinoma was not clear. The aim of this study was to find the potential diagnostic and prognostic miRNA in cholangiocarcinoma patients. Methods: The miRNA expression profiles in cholangiocarcinoma patients from The Cancer Genome Atlas and Gene Expression Omnibus (GSE53870) were analyzed. The comparison of overall survival was performed using the Kaplan–Meier method. The targeted genes of prognostic miRNA were identified in miRanda, PicTar, or TargetScan, and their cell signaling pathways were analyzed by the Database for Annotation, Visualization and Integrated Discovery. Results: In The Cancer Genome Atlas and the Gene Expression Omnibus miRNA dataset, miR-92b and miR-99a were found with concordant directionality, up-regulated and down-regulated, respectively. In The Cancer Genome Atlas survival data, patients with the high level of miR-99b had obviously shorter overall survival time ( P=0.038). However, the level of miR-99a was not found to be significant. The 17 shared target genes of miR-92b were identified, such as DAB21IP, BCL21L11, SPHK2, PER2, and TSC1. The related pathways included positive regulation of transcription, positive regulation of cellular biosynthetic process, regulation of programmed cell death, etc. Conclusion: miR-92b was up-regulated in cholangiocarcinoma compared with normal controls. The high level of miR-92b was associated with adverse outcomes in cholangiocarcinoma patients, which might be partly explained by the targeted genes of miR-92b and their signaling pathways.

scholarly journals A pan-cancer analysis of prognostic genes

PeerJ ◽  
2016 ◽  
Vol 3 ◽  
pp. e1499 ◽  
Author(s):  
Jordan Anaya ◽  
Brian Reon ◽  
Wei-Min Chen ◽  
Stefan Bekiranov ◽  
Anindya Dutta
Keyword(s):  
Microarray Data ◽  
The Cancer Genome Atlas ◽  
Rna Seq ◽  
Cancer Pathogenesis ◽  
Gene Sets ◽  
Protective Genes ◽  
Cancer Genome Atlas ◽  
Cancer Types ◽  
Measure Of Association ◽  
Pan Cancer

Numerous studies have identified prognostic genes in individual cancers, but a thorough pan-cancer analysis has not been performed. In addition, previous studies have mostly used microarray data instead of RNA-SEQ, and have not published comprehensive lists of associations with survival. Using recently available RNA-SEQ and clinical data from The Cancer Genome Atlas for 6,495 patients, we have investigated every annotated and expressed gene’s association with survival across 16 cancer types. The most statistically significant harmful and protective genes were not shared across cancers, but were enriched in distinct gene sets which were shared across certain groups of cancers. These groups of cancers were independently recapitulated by both unsupervised clustering of Cox coefficients (a measure of association with survival) for individual genes, and for gene programs. This analysis has revealed unappreciated commonalities among cancers which may provide insights into cancer pathogenesis and rationales for co-opting treatments between cancers.

Sign in / Sign up

Export Citation Format

Share Document