Human Cancer Subtypes Research Articles

Exploring the Role of CDKN2A in Human Cancers Using an Integrative Pan-Cancer Approach

This study aims to investigate the expression variation, biological significance, and prognostic value of cyclin-dependent kinase inhibitor 2A (CDKN2A) as a common biomarker across 33 malignancies. Various bioinformatics tools, including UALCAN, GEPIA2, OncoDB, cBioPortal, TIMER2, STRING, DAVID, and the GSCA database, were employed for this pan-cancer analysis. The results revealed significant up-regulation of CDKN2A in 24 major human cancer subtypes (P < 0.05). This up-regulation was strongly associated with poor overall survival and tumor dissemination, particularly in uterine corpus endometrial carcinoma (UCEC), colon adenocarcinoma (COAD), and liver hepatocellular carcinoma (LIHC), highlighting its potential as a prognostic biomarker. Moreover, CDKN2A overexpression was linked to diverse clinicopathological characteristics of patients. Genetic alterations recorded via cBioPortal indicated minimal mutation rates in COAD, LIHC, and UCEC. Additionally, promoter methylation, drug sensitivity, and enrichment analyses were performed to explore associations with CDKN2A expression. Overall, the findings emphasize the potential of CDKN2A as a shared diagnostic and prognostic biomarker, as well as a therapeutic target in COAD, LIHC, and UCEC, particularly in patients with varied clinicopathological traits.

Up-regulation of GINS1 highlighted a good diagnostic and prognostic potential of survival in three different subtypes of human cancer.

Cancer is a fatal malignancy and its increasing worldwide prevalence demands the discovery of more sensitive and reliable molecular biomarkers. To investigate the GINS1 expression level and its prognostic value in distinct human cancers using a series of multi-layered in silico approach may help to establish it as a potential shared diagnostic and prognostic biomarker of different cancer subtypes. The GINS1 mRNA, protein expression, and promoter methylation were analyzed using UALCAN and Human Protein Atlas (HPA), while mRNA expression was further validated via GENT2. The potential prognostic values of GINS1 were evaluated through KM plotter. Then, cBioPortal was utilized to examine the GINS1-related genetic mutations and copy number variations (CNVs), while pathway enrichment analysis was performed using DAVID. Moreover, a correlational analysis between GINS1 expression and CD8+ T immune cells and a the construction of gene-drug interaction network was performed using TIMER, CDT, and Cytoscape. The GINS1 was found down-regulated in a single subtypes of human cancer while commonly up-regulated in 23 different other subtypes. The up-regulation of GINS1 was significantly correlated with the poor overall survival (OS) of Liver Hepatocellular Carcinoma (LIHC), Lung Adenocarcinoma (LUAD), and Kidney renal clear cell carcinoma (KIRC). The GINS1 was also found up-regulated in LIHC, LUAD, and KIRC patients of different clinicopathological features. Pathways enrichment analysis revealed the involvement of GINS1 in two diverse pathways, while few interesting correlations were also documented between GINS1 expression and its promoter methylation level, CD8+ T immune cells level, and CNVs. Moreover, we also predicted few drugs that could be used in the treatment of LIHC, LUAD, and KIRC by regulating the GINS1 expression. The expression profiling of GINS1 in the current study has suggested it a novel shared diagnostic and prognostic biomarker of LIHC, LUAD, and KIRC.

Metabolic Lipids in Melanoma Enable Rapid Determination of Actionable BRAF-V600E Mutation with Picosecond Infrared Laser Mass Spectrometry in 10 s.

Rapid molecular profiling of biological tissues with picosecond infrared laser mass spectrometry (PIRL-MS) has enabled the detection of clinically important histologic types and molecular subtypes of human cancers in as little as 10 s of data collection and analysis time. Utilizing an engineered cell line model of actionable BRAF-V600E mutation, we observed statistically significant differences in 10 s PIRL-MS molecular profiles between BRAF-V600E and BRAF-wt cells. Multivariate statistical analyses revealed a list of mass-to-charge (m/z) values most significantly responsible for the identification of BRAF-V600E mutation status in this engineered cell line that provided a highly controlled testbed for this observation. These metabolites predicted BRAF-V600E expression in human melanoma cell lines with greater than 98% accuracy. Through chromatography and tandem mass spectrometry analysis of cell line extracts, a 30-member "metabolite array" was characterized for determination of BRAF-V600E expression levels in subcutaneous melanoma xenografts with an average sensitivity and specificity of 95.6% with 10 s PIRL-MS analysis. This proof-of-principle work warrants a future large-scale study to identify a metabolite array for 10 s determination of actionable BRAF-V600E mutation in human tissue to guide patient care.

Multi-omics analysis of LAMB3 as a potential immunological and biomarker in pan-cancer.

Laminin Subunit Beta 3 (LAMB3) is a transcription factor and participates in the coding of laminin. It plays an important role in cell proliferation, adhesion, and transfer by regulating various target genes and signaling pathways. However, the role of LAMB3 in human pan-cancer immunology and prognosis is still poorly understood. The TCGA, GTEx, CCLE, and HPA databases were utilized for the analysis of LAMB mRNA and protein expression. The expression of LAMB3 in various immune and molecular subtypes of human cancer was examined using the TISIDB database. The prognostic significance of LAMB3 in various cancers and clinical subtypes was investigated using Kaplan-Meier and Cox regression analysis. The relationship between LAMB3 expression, various immune cell infiltration, immune checkpoints, tumor mutational load, microsatellite instability, and DNA methylation was examined using the TCGA database. Clinical samples of four lung cancer cell lines and eight lung cancer cases were collected to confirm the expression of mRNA in lung cancer. In 17 cancers, the mRNA for LAMB3 is expressed differently and has good diagnostic and prognostic value in 22 cancers. Cox regression and Nomogram analysis show that LAMB3 is an independent risk factor for 15 cancers. LAMB3 is implicated in a variety of tumorigenesis and immune-related signaling pathways, according to GO, KEGG, and GSEA results. LAMB3 expression was associated with TMB in 33 cancer types and MSI in 32 cancer types, while in lung cancer LAMB3 expression was strongly associated with immune cell infiltration and negatively correlated with all seven methylated CpG islands. Cellular experiments demonstrated that LAMB3 promotes malignant behavior of tumor cells. Preliminary mechanistic exploration revealed its close association with PD-L1, CTLA4, cell stemness gene CD133 and β-catenin-related signaling pathways. Based on these findings, it appears that LAMB3 could be a potential therapeutic target for immunotherapy and tumor prognosis. Our findings reveal an important role for LAMB3 in different cancer types.

Prognostic and immunological role of FDX1 in pan-cancer: an in-silico analysis

Previous research has demonstrated that ferredoxin 1 (FDX1) contributes to the accumulation of toxic lipoylated dihydrolipoamide S-acetyltransferase (DLAT) and results in cuproptotic cell death. However, the role that FDX1 plays in human cancer prognosis and immunology is still not well understood. The original data was obtained from TCGA and GEO databases and integrated using R 4.1.0. The TIMER2.0, GEPIA, and BioGPS databases were used to explore FDX1 expression. The impact of FDX1 on prognosis was analyzed using the GEPIA and Kaplan–Meier Plotter databases. External validation will be performed using the PrognoScan database. FDX1 expression in different immune and molecular subtypes of human cancers was evaluated using the TISIDB database. The correlation between FDX1 expression and immune checkpoints (ICP), microsatellite instability (MSI), and tumor mutational burden (TMB) in human cancers was analyzed using R 4.1.0. The TIMER2.0 and GEPIA databases were used to study the relationship between FDX1 expression and tumor-infiltrating immune cells. With the c-BioPortal database, we investigated the genomic alterations of FDX1. Pathway analysis and assessment of the sensitivity potential of FDX1-related drugs were also performed. Using the UALCAN database, we analyzed the differential expression of FDX1 in KIRC (kidney renal clear cell carcinoma) with different clinical features. Coexpression networks of FDX1 were analyzed using LinkedOmics. In general, FDX1 was expressed differently in different types of cancer in humans. Expression of FDX1 was strongly correlated with patient prognosis, ICP, MSI, and TMB. FDX1 was also participated in immune regulation and the tumor microenvironment. Coexpression networks of FDX1 were primarily involved in oxidative phosphorylation regulation. Pathway analysis revealed that the expression of FDX1 was correlated to cancer-related and immune-related pathways. FDX1 has the potential to serve as a biomarker for pan-cancer prognosis and immunology, as well as a novel target for tumor therapy.

Whole exome sequencing analysis of canine urothelial carcinomas without BRAF V595E mutation: Short in-frame deletions in BRAF and MAP2K1 suggest alternative mechanisms for MAPK pathway disruption.

Molecular profiling studies have shown that 85% of canine urothelial carcinomas (UC) harbor an activating BRAF V595E mutation, which is orthologous to the V600E variant found in several human cancer subtypes. In dogs, this mutation provides both a powerful diagnostic marker and a potential therapeutic target; however, due to their relative infrequency, the remaining 15% of cases remain understudied at the molecular level. We performed whole exome sequencing analysis of 28 canine urine sediments exhibiting the characteristic DNA copy number signatures of canine UC, in which the BRAF V595E mutation was undetected (UDV595E specimens). Among these we identified 13 specimens (46%) harboring short in-frame deletions within either BRAF exon 12 (7/28 cases) or MAP2K1 exons 2 or 3 (6/28 cases). Orthologous variants occur in several human cancer subtypes and confer structural changes to the protein product that are predictive of response to different classes of small molecule MAPK pathway inhibitors. DNA damage response and repair genes, and chromatin modifiers were also recurrently mutated in UDV595E specimens, as were genes that are positive predictors of immunotherapy response in human cancers. Our findings suggest that short in-frame deletions within BRAF exon 12 and MAP2K1 exons 2 and 3 in UDV595E cases are alternative MAPK-pathway activating events that may have significant therapeutic implications for selecting first-line treatment for canine UC. We developed a simple, cost-effective capillary electrophoresis genotyping assay for detection of these deletions in parallel with the BRAF V595E mutation. The identification of these deletion events in dogs offers a compelling cross-species platform in which to study the relationship between somatic alteration, protein conformation, and therapeutic sensitivity.

Pan-cancer analysis highlights the role of PSENEN in the prognosis and immunology of cancer

BackgroundPresenilin enhancer-2 (PSENEN, PEN-2), one of the four components of the γ-secretase complex, has been increasingly revealed to be significant in cancer types such as pancreatic cancer, gastric cancer, and breast cancer. However, the pan-cancer clinical relevance of PSENEN remains unclear. MethodsRaw data on PSENEN expression in normal and cancer tissues were obtained from The Cancer Genome Atlas (TGCA) database and Genotype-Tissue Expression Project (GTEx). The difference of PSENEN expression was analyzed using data from the TCGA repository and TIMER2 database. Meanwhile, Cox regression analysis and KM plotter were used to analyze the pan-cancer prognostic significance of PSENEN. We also analyzed the correlation between PSENEN expression and tumor immune infiltration using the TIMER and XCELL algorithms. Moreover, we used the TISIDB database to determine PSENEN expression in different immune and molecular subtypes of human cancers. Pan-cancer analysis of genetic alteration of PSENEN was performed using online tools such as cBioPortal and UALCAN. Finally, six Gene Expression Omnibus datasets from the Gene Expression Profiling Interactive Analysis database were used to validate the expression level of PSENEN in lung adenocarcinoma (LUAD). ResultsContrary to nonmalignant tissues, the expression level of PSENEN was significantly upregulated in the cancerous tissues in 22 cancer types. Elevated PSENEN expression was correlated with worse overall survival in 7 cancer types and with worse disease-specific survival in 8 of them. By using xCell algorithm, TIMER algorithm, and Spearman's correlation analysis, we found that PSENEN expression was closely correlated with the infiltration of immune cells across all cancer types. Moreover, aberrant PSENEN expression was associated with 60 immune checkpoint pathway-related genes, microsatellite instability, and tumor mutation burden in various cancer types. Besides, PSENEN expression was significantly associated with different immune subtypes and molecular subtypes of various human cancers. Notably, ovarian epithelial tumor samples demonstrated the highest frequency of PSENEN mutation among all cancer types. ConclusionsOur pan-cancer analysis demonstrated that PSENEN might serve as a prognostic biomarker and revealed the importance of an in-depth understanding of the oncogenic role of PSENEN in various malignancies.

Systematic analysis identifies XRCC4 as a potential immunological and prognostic biomarker associated with pan-cancer

BackgroundXRCC4 is a NHEJ factor identified recently that plays a vital role in repairing DNA double-stranded breaks. Studies have reported the associations between abnormal expression of XRCC4 and tumor susceptibility and radiosensitivity, but the potential biological mechanisms by which XRCC4 exerts effects on tumorigenesis are not fully understood. This study aimed to systematically investigate the role of XRCC4 across cancer types.MethodsThe TIMER, GTEX and Xiantao Academic database were used to interpret the expression of XRCC4. Genomic alterations and protein expression in human organic and tumor tissues were applied in cBioPortal and the Human Protein Atlas databases. Correlations between XRCC4 expression and immune and molecular subtypes were analyzed by using the TISIDB database. Protein–protein interactions, GO and KEGG enrichment were also applied for XRCC4-related genes. The TIMER and the Tumor Immune Single Cell Hub (TISCH) online databases were used to explore the relationship between XRCC4 and tumor immune microenvironment. Drug sensitivity information was acquired from the CellMiner database to analyze the effect of XRCC4 on sensitivity analysis.ResultsThe XRCC4 expression was significantly upregulated in 15 tumor types and downregulated in two tumor types compared with the normal tissues, most of which were validated by the results of Xiantao academic platform. XRCC4 was expressed at intermediate level in malignant cells. The XRCC4 expression was related to the molecular and immune subtypes of human cancers, and the survival outcome of 11 types of cancers, including KIRC, STAD and LIHC. The main type of frequent genetic alteration is amplification. Strong correlations were also found between XRCC4 and immune checkpoint genes in 33 human cancers. Furthermore, the abnormal expression of XRCC4 was related to immune cell infiltration and drug sensitivity. Enrichment analysis showed that XRCC4 was significantly correlated with DNA damage response.ConclusionsThis comprehensive pan-cancer analysis suggested that XRCC4 may play a vital role in the prognosis and immunotherapy response in cancer patients, and it is a promising therapy target in the future.

NcR2Met (lncR2metasta v2.0): An updated database for experimentally supported ncRNAs during cancer metastatic events

Non-coding RNAs (ncRNAs) are widely involved in cancer metastatic events (CMEs, e.g., cancer cell invasion, intravasation, extravasation, proliferation), which collaboratively accelerate tumor spread and cause high patient mortality. In early 2020, we developed a manually curated database named ‘lncR2metasta’ to provide a comprehensive repository for long ncRNA (lncRNA) regulation during CMEs. We updated this database by supplementing other two important ncRNA types, microRNAs (miRNAs) and circular RNAs (circRNAs), for their involvement during CMEs after a thorough manual curation from published studies. ncR2metasta documents 1565 lncRNA-associated, 882 miRNA-associated, and 628 circRNA-associated entries for ncRNA-CME associations during 50 CMEs across 63 human cancer subtypes. ncR2Met has a concise web interface for researchers to easily browse, search and download as well as to submit novel ncRNA-CME associations. We anticipated that it could be a valuable resource, which will significantly improve our understanding of ncRNA functions in metastasis. It is freely available at http://ncr2met.wchoda.com.

SHMT2 is Associated with Tumor Purity, CD8+ T Immune Cells Infiltration, and a Novel Therapeutic Target in Four Different Human Cancers.

This study was launched to identify the SHMT2 associated Human Cancer subtypes. Cancer is the 2nd leading cause of death worldwide. Previous reports revealed the limited involvement of SHMT2 in human cancer. In the current study, we comprehensively analyzed the role of SHMT2 in 24 major subtypes of human cancers using in silico approach and identified a few subtypes that are mainly associated with SHMT2. We aim to comprehensively analyze the role of SHMT2 in 24 major subtypes of human cancers using in silico approach and identified a few subtypes that are mainly associated with SHMT2. Earlier, limited knowledge exists in the medical literature regarding the involvement of Serine Hydroxymethyltransferase 2 (SHMT2) in human cancer. In the current study, we comprehensively analyzed the role of SHMT2 in 24 major subtypes of human cancers using in silico approach and identified a few subtypes that are mainly associated with SHMT2. Pan-cancer transcriptional expression profiling of SHMT2 was done using UALCAN while further validation was performed using GENT2. For translational profiling of SHMT2, we utilized Human Protein Atlas (HPA) platform. Promoter methylation, genetic alteration, and copy number variations (CNVs) profiles were analyzed through MEXPRESS and cBioPortal. Survival analysis was carried out through Kaplan-Meier (KM) plotter platform. Pathway enrichment analysis of SHMT2 was performed using DAVID, while the gene-drug network was drawn through CTD and Cytoscape. Furthermore, in the tumor microenvironment, a correlation between tumor purity, CD8+ T immune cells infiltration, and SHMT2 expression was accessed using TIMER. SHMT2 was found overexpressed in 24 different subtypes of human cancers and its overexpression was significantly associated with the reduced Overall survival (OS) and Relapse-free survival durations of Breast cancer (BRCA), Kidney renal papillary cell carcinoma (KIRP), Liver hepatocellular carcinoma (LIHC), and Lung adenocarcinoma (LUAD) patients. This implies that SHMT2 plays a significant role in the development and progression of these cancers. We further noticed that SHMT2 was also up-regulated in BRCA, KIRP, LIHC, and LUAD patients of different clinicopathological features. Pathways enrichment analysis revealed the involvement of SHMT2 enriched genes in five diverse pathways. Furthermore, we also explored some interesting correlations between SHMT2 expression and promoter methylation, genetic alterations, CNVs, tumor purity, and CD8+ T immune cell infiltrates. Our results suggested that overexpressed SHMT2 is correlated with the reduced OS and RFS of the BRCA, KIRP, LIHC, and LUAD patients and can be a potential diagnostic and prognostic biomarker for these cancers.

Pan-Cancer Analysis on the Oncogenic Role of Programmed Cell Death 10.

Purpose Programmed cell death factor 10 (PDCD10) is associated with intercellular junction, cytoskeleton organization, cell proliferation, apoptosis, exocytosis, and angiogenesis. However, the role of PDCD10 in human cancer is unclear. This study aims to explore the role of PDCD10 in various tumors and its possible mechanism through bioinformatics analysis. Methods We verified the expression of the PDCD10 gene based on data from the ONCOMINE, TIMER2.0, and TISDB databases. The correlation of PDCD10 with prognosis of patients with different tumors was analyzed using data from the GEPIA2 database. Proteins bound to PDCD10 were analyzed from the STRING database. PDCD10, PDCD10-binding proteins, and associated candidate genes were analyzed in DAVID for functional and pathway analyses. We also evaluated the immunological, clinical, and genetic aspects of distinct cancers by using TIMER2.0 and the connection between PDCD10 expression and tumor immune subtypes by using TISDB. Single-cell sequencing data from the CancerSEA database were used to characterize cancer cell functional states and generate heat maps. Results PDCD10 overexpression is linked to certain molecular subtypes of human cancer. Low PDCD10 expression in patients with bladder urothelial carcinoma (BLCA), lung adenocarcinoma (LUAD), liver hepatocellular carcinoma (LIHC), adrenocortical carcinoma (ACC), head and neck squamous cell carcinoma (HNSC), kidney chromophobe carcinoma (KICH), brain lower grade glioma (LGG), pancreatic adenocarcinoma (PAAD), uterine corpus endometrial carcinoma (UCEC), oral squamous cell carcinoma (OSCC), and esophageal adenocarcinoma (ESAD) was correlated with favorable OS, whereas high PDCD10 expression in patients with LUSC, KIRC, READ, SKCM, and THYM was correlated with good prognosis. STRING network prediction results showed that 20 proteins, namely, paxillin (PXN), CCM2 scaffold protein (CCM2), TRAF3 interacting protein 3 (TRAF3IP3), FGFR1 oncogene partner 2 (FGFR1OP2), chromosome 4 open reading frame 19 (C4orf19), suppressor of IKBKE 1 (SIKE1), serine/threonine kinase 25 (STK25), striatin (STRN), protein phosphatase 2 catalytic subunit alpha (PPP2CA), mammalian sterile-20-like kinase 4 (MST4), MOB family member 4 (MOB4), protein phosphatase 2 scaffold subunit Abeta (PPP2R1B), sarcolemma-associated protein (SLMAP), serine/threonine kinase 24 (STK24), striatin 4 (STRN4), STRN3, protein phosphatase 2 scaffold subunit A alpha (PPP2R1A), striatin interacting protein 1 (STRIP1), CTTNBP2 N-terminal like (CTTNBP2NL), and cortactin binding protein 2 (CTTNBP2), can bind to PDCD10. Gene enrichment analysis suggested that PDCD10 is involved in the occurrence of different tumors through the Hippo signalling pathway, RNA transport, mRNA monitoring pathway, endocytosis, and T cell receptor signalling pathway. An inverse relationship was found between PDCD10 expression and cancer-associated fibroblasts in LUSC and TGCT, and PDCD10 expression was strongly connected with immunological subtypes, such as C1 (wound healing), C2 (interferon-gamma dominant), C3 (inflammation), C4 (lymphocyte depletion), C5 (immune silenced), and C6 (TGF-beta dominant). Finally, analysis of single-cell sequencing data revealed that PDCD10 expression is linked to epigenetic reprogramming, DNA repair, cell cycle progression, cell differentiation, inflammation, cell proliferation, cell differentiation, cell invasion, and angiogenesis. Conclusion The results of our investigation demonstrate that PDCD10 has an oncogenic function in many cancer types. This study provides a reference for future research on antitumor therapeutic targets.

Noncanonical NF-κB factor p100/p52 regulateshomologous recombination and modulates sensitivity to DNA-damaging therapy.

Homologous recombination (HR) serves multiple roles in DNA repair that are essential for maintaining genomic stability, including double-strand DNA break (DSB) repair. The central HR protein, RAD51, is frequently overexpressed in human malignancies, thereby elevating HR proficiency and promoting resistance to DNA-damaging therapies. Here, we find that the non-canonical NF-κB factors p100/52, but not RelB, control the expression of RAD51 in various human cancer subtypes. While p100/p52 depletion inhibits HR function in human tumor cells, it does not significantly influence the proficiency of non-homologous end joining, the other key mechanism of DSB repair. Clonogenic survival assays were performed using a pair DLD-1 cell lines that differ only in their expression of the key HR protein BRCA2. Targeted silencing of p100/p52 sensitizes the HR-competent cells to camptothecin, while sensitization is absent in HR-deficient control cells. These results suggest that p100/p52-dependent signaling specifically controls HR activity in cancer cells. Since non-canonical NF-κB signaling is known to be activated after various forms of genomic crisis, compensatory HR upregulation may represent a natural consequence of DNA damage. We propose that p100/p52-dependent signaling represents a promising oncologic target in combination with DNA-damaging treatments.

Integrative analysis reveals methylenetetrahydrofolate dehydrogenase 1-like as an independent shared diagnostic and prognostic biomarker in five different human cancers.

Background: Defects in methylenetetrahydrofolate dehydrogenase 1-like (MTHFD1L) expression have earlier been examined in only a few human cancers. Objectives: Multi-omics profiling of MTHFD1L as a shared biomarker in distinct subtypes of human cancers. Methods: In the current study, for the multi-omics analysis of MTHFD1L in 24 major subtypes of human cancers, a comprehensive in silico approach was adopted to mine different open access online databases including UALCAN, Kaplan–Meier (KM) plotter, LOGpc, GEPIA, Human Protein Atlas (HPA), Gene Expression across Normal and Tumor tissue (GENT2), MEXPRESS, cBioportal, STRING, DAVID, TIMER, and Comparative Toxicogenomics Database (CTD). Results: We noticed that the expression of MTHFD1L was significantly higher in all the analyzed 24 subtypes of human cancers as compared with the normal controls. Moreover, MTHDF1L overexpression was also found to be significantly associated with the reduced overall survival (OS) duration of Bladder urothelial cancer (BLCA), Head and neck cancer (HNSC), Kidney renal papillary cell carcinoma (KIRP), Lung adenocarcinoma (LUAD), and Uterine corpus endometrial carcinoma (UCEC). This implies that MTHFD1L plays a significant role in the development and progression of these cancers. We further noticed that MTHFD1L was also overexpressed in BLCA, HNSC, KIRP, LUAD, and UCEC patients of different clinicopathological features. Pathways enrichment analysis revealed the involvement of MTHFD1L-associated genes in five diverse pathways. We also explored few interesting correlations between MTHFD1L expression and its promoter methylation, genetic alterations, CNVs, and between CD8+ T immune cells level. Conclusion: In conclusion, our results elucidated that MTHFD1L can serve as a shared diagnostic and prognostic biomarker in BLCA, HNSC, KIRP, LUAD, and UCEC patients of different clinicopathological features.

GNB1, a novel diagnostic and prognostic potential biomarker of head and neck and liver hepatocellular carcinoma

Background: Nucleotide-binding protein beta 1 (GNB1) encodes for heterotrimeric G-protein subunit beta (β) that is involved in various transmembrane signaling systems. A little has been reported earlier regarding GNB1 dysregulation in human cancers. Therefore, we carried out this study to investigate GNB1 expression levels and explore its prognostic values in distinct human cancers through a multi-layered bioinformatics approach. Methods: GNB1 expression and promoter methylation levels across distinct cancers were analyzed using UALCAN, GENT2, and MEXPRESS databases, whereas its potential prognostic values were evaluated through Kaplan–Meier plotter. Then, cBioPortal was utilized to analyze the GNB1-related genetic mutations and copy number variations (CNVs). However, GNB1-related pathways were explored using DAVID. Moreover, the correlational analysis between GNB1 expression and CD8+ T immune cell infiltration and a gene–drug interaction network analysis were performed using TIMER, CDT, and Cytoscape. Results: GNB1 was found commonly upregulated in 23 major subtypes of human cancers and its upregulation was significantly correlated with the reduced overall survival of only head and neck squamous cell carcinoma (HNSC) and liver hepatocellular carcinoma (LIHC). This implies that GNB1 plays a significant role in the development and progression of these cancers. The GNB1 was also found to be upregulated in HNSC and LIHC patients of different clinicopathological features. Pathways enrichment analysis revealed the involvement of GNB1-enriched genes in several diverse pathways, whereas a few interesting correlations were also documented between GNB1 expression and promoter methylation level, CD8+ T immune cell infiltration, and CNVs. In addition, we have also predicted few drugs that could regulate the GNB1 expression. Conclusions: Our findings suggested GNB1 as a potential diagnostic and prognostic biomarker of HNSC and LIHC.

Angiotensinogen - A Potential Diagnostic and Prognostic Candidate Gene  for Adenocarcinomas of Rectum and Stomach

<p>The Angiotensinogen (AGT) gene encodes for angiotensinogen protein that mainly regulates blood pressure and maintains the fluid and salt balance in the body. AGT expression variations have been documented earlier in only a few subtypes of human cancers, the multi-omics profiling of AGT as a shared biomarker in different other subtypes of human cancers remains to be uncovered. In the current study, AGT multi-omics analysis in 24 major subtypes of human cancer were performed using different authentic online databases and bioinformatics analysis including UALCAN, Kaplan Meier (KM) plotter, Human protein Atlas (HPA), GENT2, MEXPRESS, cBioportal, STRING, DAVID, TIMER., and CTD database. AGT is found commonly up-regulated in most human cancers. Overexpression of AGT is significantly correlated with the poor overall survival (OS) of only rectum adenocarcinoma (READ) and Stomach Adenocarcinoma (STAD). This implies that AGT plays a significant role in the development and progression of these cancers. We further noticed that AGT is also overexpressed in READ and STAD patients of different clinicopathological features. Pathways enrichment analysis revealed that AGT is involved in various diverse pathways. While, a few interesting correlations were also documented between AGT expression and its promoter methylation level, CD8+ T immune cells level, and CNVs. Moreover, we also predicted a few drugs through gene-drug interaction analysis that could be used in the treatment of READ and STAD by regulating the AGT expression. Our findings suggest that AGT alone might be helpful in predicting the diagnosis and prognosis of READ and STAD patients commonly.</p>

CTHRC1 expression is a novel shared diagnostic and prognostic biomarker of survival in six different human cancer subtypes

According to the previous reports, the collagen triple helix repeat containing 1 (CTHRC1) causes tumorigenesis by modulating the tumor microenvironment, however, the evidence is limited to a few human cancer subtypes. In the current study, we analyzed and validated the CTHRC1 expression variations in 24 different human cancer tissues paired with normal tissues using publically available databases. We observed that CTHRC1 was overexpressed in all the 24 major subtypes of human cancers and its overexpression was significantly associated with the reduced overall survival (OS) duration of head and neck squamous cell carcinoma (HNSC), kidney renal clear cell carcinoma (KIRC), liver hepatocellular carcinoma (LIHC), Lung adenocarcinoma (LUAD), stomach adenocarcinoma (STAD), and Uterine corpus endometrial carcinoma (UCEC). This implies that CTHRC1 plays a significant role in the development and progression of these cancers. We further noticed that CTHRC1 was also overexpressed in HNSC, KIRC, LIHC, LUAD, STAD, and UCEC patients of different clinicopathological features. Pathways enrichment analysis revealed the involvement of CTHRC1 associated genes in seven diverse pathways. We also explored few interesting correlations between CTHRC1 expression and promoter methylation, genetic alterations, CNVs, CD8+ T immune cells infiltration, and tumor purity. In conclusion, CTHRC1 can serve as a shared diagnostic and prognostic biomarker in HNSC, KIRC, LIHC, LUAD, STAD, and UCEC patients of different clinicopathological features.

Multi-Omics Analysis Identified TMED2 as a Shared Potential Biomarker in Six Subtypes of Human Cancer.

IntroductionCancer is one of the most common malignancies and the leading cause of death worldwide. As a member of the transmembrane emp24 domain (Tmed)/p24 family of proteins, TMED2 expression variations have been documented earlier in only a few subtypes of human cancers, and the multi-omics profiling of TMED2 as a shared biomarker in different other subtypes of human cancers remains to be uncovered.MethodsIn the current study, TMED2 multi-omics analysis in 24 major subtypes of human cancer was performed using different authentic online databases and bioinformatics analysis including UALCAN, Kaplan–Meier (KM) plotter, Human Protein Atlas (HPA), GENT2, MEXPRESS, cBioportal, STRING, DAVID, TIMER, and CTD.ResultsIn general, the TMED2 expression in 24 major subtypes of human cancers was higher relative to normal controls and was also strongly associated with the lower overall survival (OS) and relapse-free survival (RFS) duration of CESC, ESCA, HNSC, KIRC, LIHC, and LUAD patients. This implies that TMED2 plays a significant role in the development and progression of these cancers. Furthermore, the TMED2 overexpression was also correlated with different clinicopathological features of CESC, ESCA, HNSC, KIRC, LIHC, and LUAD patients. TMED2-associated genes network was involved in 3 diverse pathways, and finally, few stronger correlations were also explored between TMED2 expression and its promoter methylation level, genetic alterations, and CD8+ T immune cells level.ConclusionIn conclusion, via this in silico study, we have elucidated that TMED2 can serve as a shared diagnostic and prognostic biomarker in CESC, ESCA, HNSC, KIRC, LIHC, and LUAD patients of different clinicopathological features but, further in vitro and in vivo research should be carried out to confirm these findings.

Abstract 2765: The indoleamine 2,3 dioxygenase-1 pathway drives intratumoral B cell maintenance

Abstract Immunotherapy has revolutionized cancer treatment by improving survival in many cancer subtypes. While tumor infiltrating B (TIL-B) cells correlate with response to immunotherapy in selected solid tumors, they portend resistance to BRAF inhibitors in BRAF mutant melanoma. Thus, the mechanisms underlying TIL-B cell function within the tumor microenvironment have remained elusive. Here, we discovered that inhibition of the indoleamine 2,3 dioxygenase-1 (IDO1) pathway with D-1-methyl-tryptophan (D-1MT) markedly decreases TIL-B cells in a preclinical model of melanoma. Single cell RNA sequencing (scRNAseq) of murine melanoma demonstrate TIL-B cells are heterogeneous: while some B cells express markers consistent with an immune stimulatory phenotype, others express markers consistent with immune inhibitory function. D-1MT decreased splenic B cells and bone marrow derived B cell precursors in tumor bearing mice, suggesting that IDO1 pathway inhibition impedes B cell maturation. In four distinct human cancer subtypes, intratumoral IDO1 expression consistently correlates with high expression of a pan-B cell gene signature. Further, analysis of scRNAseq data from a cohort of patients with melanoma revealed that most TIL-B cells express IDO1. In mice, D-1MT also decreases intratumoral myeloid derived suppressor cells (MDSCs), which are essential for maintenance of TIL-B cells. Surprisingly, we found that D-1MT enhanced anti-tumor effects of the BRAF inhibitor, vemurafenib, in a preclinical model of BRAF mutant melanoma, suggesting that targeting B cells in this setting may be beneficial. Together, our data reveal a novel paradigm for the IDO1 pathway in regulating TIL-B cells, and uncovered IDO1 as a potential targetable mechanism of resistance to BRAF inhibition in melanoma. Citation Format: Burles Avner Johnson, Adam K. Aragaki, Donna M. Williams, Ophelia Rogers, Li Luo, Lingling Xian, Lionel Chia, Noah M. Hahn, Stephen Desiderio, Theodore S. Johnson, David J. McConkey, Linda M.S. Resar. The indoleamine 2,3 dioxygenase-1 pathway drives intratumoral B cell maintenance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2765.

Two competing mechanisms of DNMT3A recruitment regulate the dynamics of de novo DNA methylation at PRC1-targeted CpG islands.

Precise deposition of CpG methylation is critical for mammalian development and tissue homeostasis and is often dysregulated in human diseases. The localization of de novo DNA methyltransferase DNMT3A is facilitated by its PWWP domain recognizing histone H3 lysine 36 (H3K36) methylation1,2 and is normally depleted at CpG islands (CGIs)3. However, methylation of CGIs regulated by Polycomb repressive complexes (PRCs) has also been observed4-8. Here, we report that DNMT3A PWWP domain mutations identified in paragangliomas9 and microcephalic dwarfism10 promote aberrant localization of DNMT3A to CGIs in a PRC1-dependent manner. DNMT3A PWWP mutants accumulate at regions containing PRC1-mediated formation of monoubiquitylated histone H2A lysine 119 (H2AK119ub), irrespective of the amounts of PRC2-catalyzed formation of trimethylated histone H3 lysine 27 (H3K27me3). DNMT3A interacts with H2AK119ub-modified nucleosomes through a putative amino-terminal ubiquitin-dependent recruitment region, providing an alternative form of DNMT3A genomic targeting that is augmented by the loss of PWWP reader function. Ablation of PRC1 abrogates localization of DNMT3A PWWP mutants to CGIs and prevents aberrant DNA hypermethylation. Our study implies that a balance between DNMT3A recruitment by distinct reader domains guides de novo CpG methylation and may underlie the abnormal DNA methylation landscapes observed in select human cancer subtypes and developmental disorders.

YTHDF1 Is a Potential Pan-Cancer Biomarker for Prognosis and Immunotherapy.

BackgroundYTH N6-methyladenosine RNA binding protein 1 (YTHDF1) has been indicated proven to participate in the cross-presentation of tumor antigens in dendritic cells and the cross-priming of CD8+ T cells. However, the role of YTHDF1 in prognosis and immunology in human cancers remains largely unknown.MethodsAll original data were downloaded from TCGA and GEO databases and integrated via R 3.2.2. YTHDF1 expression was explored with the Oncomine, TIMER, GEPIA, and BioGPS databases. The effect of YTHDF1 on prognosis was analyzed via GEPIA, Kaplan-Meier plotter, and the PrognoScan database. The TISIDB database was used to determine YTHDF1 expression in different immune and molecular subtypes of human cancers. The correlations between YTHDF1 expression and immune checkpoints (ICP), tumor mutational burden (TMB), microsatellite instability (MSI), and neoantigens in human cancers were analyzed via the SangerBox database. The relationships between YTHDF1 expression and tumor-infiltrated immune cells were analyzed via the TIMER and GEPIA databases. The relationships between YTHDF1 and marker genes of tumor-infiltrated immune cells in urogenital cancers were analyzed for confirmation. The genomic alterations of YTHDF1 were investigated with the c-BioPortal database. The differential expression of YTHDF1 in urogenital cancers with different clinical characteristics was analyzed with the UALCAN database. YTHDF1 coexpression networks were studied by the LinkedOmics database.ResultsIn general, YTHDF1 expression was higher in tumors than in paired normal tissue in human cancers. YTHDF1 expression had strong relationships with prognosis, ICP, TMB, MSI, and neoantigens. YTHDF1 plays an essential role in the tumor microenvironment (TME) and participates in immune regulation. Furthermore, significant strong correlations between YTHDF1 expression and tumor immune-infiltrated cells (TILs) existed in human cancers, and marker genes of TILs were significantly related to YTHDF expression in urogenital cancers. TYHDF1 coexpression networks mostly participated in the regulation of immune response and antigen processing and presentation.ConclusionYTHDF1 may serve as a potential prognostic and immunological pan-cancer biomarker. Moreover, YTHDF1 could be a novel target for tumor immunotherapy.