Objective: DNA damage response(DDR) deficiency has emerged as a prominent determinant of tumor immunogenicity. This study aimed to construct a DDR-related immune activation(DRIA) signature and evaluate the predictive ...Objective: DNA damage response(DDR) deficiency has emerged as a prominent determinant of tumor immunogenicity. This study aimed to construct a DDR-related immune activation(DRIA) signature and evaluate the predictive accuracy of the DRIA signature for response to immune checkpoint inhibitor(ICI) therapy in gastrointestinal(GI) cancer.Methods: A DRIA signature was established based on two previously reported DNA damage immune response assays. Clinical and gene expression data from two published GI cancer cohorts were used to assess and validate the association between the DRIA score and response to ICI therapy. The predictive accuracy of the DRIA score was validated based on one ICI-treated melanoma and three pan-cancer published cohorts.Results: The DRIA signature includes three genes(CXCL10, IDO1, and IFI44L). In the discovery cancer cohort, DRIA-high patients with gastric cancer achieved a higher response rate to ICI therapy than DRIA-low patients(81.8% vs. 8.8%;P < 0.001), and the predictive accuracy of the DRIA score [area under the receiver operating characteristic curve(AUC) = 0.845] was superior to the predictive accuracy of PD-L1 expression, tumor mutational burden, microsatellite instability, and Epstein–Barr virus status. The validation cohort demonstrated that the DRIA score identified responders with microsatellite-stable colorectal and pancreatic adenocarcinoma who received dual PD-1 and CTLA-4 blockade with radiation therapy. Furthermore, the predictive performance of the DRIA score was shown to be robust through an extended validation in melanoma, urothelial cancer, and pan-cancer.Conclusions: The DRIA signature has superior and robust predictive accuracy for the efficacy of ICI therapy in GI cancer and pancancer, indicating that the DRIA signature may serve as a powerful biomarker for guiding ICI therapy decisions.展开更多
The incre asing interest in RNA modifications has signifcantly advanced epigenomic and epitranscriptomic technologies.This study focuses on the immuno oncological impact of ALYREF in human cancer through a pan-cancer ...The incre asing interest in RNA modifications has signifcantly advanced epigenomic and epitranscriptomic technologies.This study focuses on the immuno oncological impact of ALYREF in human cancer through a pan-cancer analysis,enhancing understanding of this gene's role in cancer.We observed differential ALYREF expression between tumor and normal samples,correl ating strongly with prognosis in various cancers,particularly kidney renal papillary cell carcinoma(KIRP)and liver hepatocellular carcinoma(LIHC).ALYREF showed a negative correlation with most tumor-infitrating cells in lung squamous cell carcinoma(LUSC)and lymphoid neoplasm difuse large B-cell lymphoma(DLBC),while positive correlations were noted in IIHC,kidney chromophobe(KICH),mesothelioma(MESO),KIRP,pheochromocytoma and paraganglioma(PARD),and glioma(GBMLGG).Aditionally,ALYREF expression was closely associated with tumor heterogeneity,stemness indices,and a high mutation rate in TP53 across these cancers.In conclusion,ALYREF may serve as an oncogenic biomarker in numerous cancers,meriting further research attention.展开更多
Background:Nuclear receptor binding SET domain protein-3(NSD3)is a histone lysine methyltransferase and a crucial regulator of carcinogenesis in several cancers.We aimed to investigate the prognostic value and potenti...Background:Nuclear receptor binding SET domain protein-3(NSD3)is a histone lysine methyltransferase and a crucial regulator of carcinogenesis in several cancers.We aimed to investigate the prognostic value and potential function of NSD3 in 33 types of human cancer.Methods:The data were obtained from The Cancer Genome Atlas.Kaplan-Meier analysis,CIBERSORT,gene set enrichment analysis,and gene set variation analysis were performed.The expression of NSD3 was measured using quantitative real-time polymerase chain reaction and western blot.Results:The expression of NSD3 was altered in pan-cancer samples.Patients with higher levels of NDS3 generally had shorter overall survival and disease-specific survival.Levels of NSD3 were positively correlated with DNA copy number variation(CNV)in pan-cancer.NSD3 expression was also associated with tumor mutation burden and microsatellite instability.The levels of immune-cell infiltration differed significantly between high and low NSD3 expression.NSD3 negatively correlated with levels of CD8+T cells.Functional enrichment analysis showed that while NSD3 expression was positively associated with several immune cell-related and histone methylation-related pathways,it was negatively correlated with cell metabolism-related,drug transport-related,and drug metabolismrelated pathways.NSD3 levels in the cell lines tested were significantly different.In U251 and NCI-H23 cells,silencing NSD3 inhibited cell proliferation and promoted apoptosis.Conclusions:NSD3 expression was changed in pan-cancer samples that was also verified in cell lines.NSD3 was associated with CNV and immune-cell infiltration.A poor prognosis was predicted in patients with high expression of NSD3.NSD3 might hence be a potential marker for predicting tumor prognosis.展开更多
Sterol o-acyltransferase1(SOAT1)is an enzyme that regulates lipid metabolism.Nevertheless,the predictive value of SOAT1 regarding immune responses in cancer is not fully understood.Herein,we aimed to expound the predi...Sterol o-acyltransferase1(SOAT1)is an enzyme that regulates lipid metabolism.Nevertheless,the predictive value of SOAT1 regarding immune responses in cancer is not fully understood.Herein,we aimed to expound the predictive value and the potential biological functions of SOAT1 in pan-cancer.Raw data related to SOAT1 expression in 33 different types of cancer were acquired from The Cancer Genome Atlas(TCGA)and Genotype-Tissue Expression(GTEx)databases.SOAT1 expression was significantly increased in most cancers and showed a distinct correlation with prognosis.This enhanced expression of the SOAT1 gene was confirmed by evaluating SOAT1 protein expression using tissue microarrays.In addition,we found significant positive associations between SOAT1 expression levels and infiltrating immune cells,including T cells,neutrophils,and macrophages.Moreover,the co-expression analysis between SOAT1 and immune genes showed that many immune-related genes were increased with enhanced SOAT1 expression.A gene set enrichment analysis(GSEA)revealed that the expression of SOAT1 correlated with the tumor microenvironment,adaptive immune response,interferon signaling,and cytokine signaling.These findings indicate that SOAT1 is a potential candidate marker for predicting prognosis and a promising target for tumor immunotherapy in cancers.展开更多
B and T-lymphocyte attenuator(BTLA)plays an immunosuppressive role by inhibiting T-and B-cell functions.BTLA is associated with a variety of diseases,especially cancer immunity.However,the function of BTLA in various ...B and T-lymphocyte attenuator(BTLA)plays an immunosuppressive role by inhibiting T-and B-cell functions.BTLA is associated with a variety of diseases,especially cancer immunity.However,the function of BTLA in various cancers and its clinical prognostic value have still not been comprehensively analyzed.This study aimed to identify the relationship between BTLA and cancer from the perspectives of differences in BTLA expression,its clinical value,immune infiltration,and the correlation with immune-related genes in various cancers.Data regarding mRNA expression,miRNA expression,lncRNA expression,and clinical data of patients of 33 existing cancers were collected from the TCGA database.Target miRNA of BTLA and the lncRNA that interacts with the target miRNA were obtained from the StarBase database.Based on bioinformatics analysis methods,the relationship between various types of cancers and BTLA was thoroughly investigated,and a competing endogenous RNA network of BTLA,target miRNA,and interacting lncRNA was constructed.The Kaplan-Meier(KM)prognostic analysis of BTLA and target miRNA(has-miR-137)in various types of cancers was completed using the KM plotter.BTLA expression varied in different cancers,with statistical significance in nine cancer types.KM plotter to analyze the overall survival(OS)and regression-free survival prognosis of cancer patients revealed that the BTLA expression was statistically different in the OS of 11 types of cancers out of 21 types of cancers;the OS of 8 type of cancers was also statistically different.Correlation analysis of tumor immune genes revealed a positive correlation of BTLA expression with immunosuppressive gene(CTLA4 and PDCD1)expression.Gene Set Enrichment Analysis showed that BTLA and its co-expressed genes mainly act through biological processes and pathways,including immune response regulation,cell surface receptor signaling pathway,antigen binding,antigen receptor-mediated signaling pathway,and leukocyte migration.BTLA has the potential as a prognostic marker for CLL,COAD,NSCLC,and OV and a diagnostic marker for CLL,COAD,and KIRC.BTLA has a close and complex relationship with the occurrence and development of tumors,and cancer immunotherapy for BTLA is worthy of further analysis.展开更多
Background:Positive regulatory domain-containing 16(PRDM16)plays a key role in brown adipose transcription,but its function in cancer is unclear.Our research to investigate the potential roles of PRDM16 across multipl...Background:Positive regulatory domain-containing 16(PRDM16)plays a key role in brown adipose transcription,but its function in cancer is unclear.Our research to investigate the potential roles of PRDM16 across multiple types of cancer by pan cancer analyses.Methods:UALCAN and TIMER2 database were utilized to evaluate PRDM16 expression in cancer patients.Gene Expression Profiling Interactive Analysis was employed to analyze the overall survival and disease-free survival across all The Cancer Genome Atlas Program tumors.Using the cBioPortal tool,we analyzed the mutation features of PRDM16 for the The Cancer Genome Atlas Program tumors,then utilized the Encyclopedia of RNA Interactomes database to predict the miRNA-mRNA relationships associated with the PRDM16 for all tumors.Results:The expression level of PRDM16 in the tumor tissues is lower than that in the normal tissues.Interesting,the high expression of PRDM16 has a positive effect on the prognosis of kidney clear cell carcinoma and lung adenocarcinoma,but not conducive to the prognosis of most cancers.In multiple cancer types,the expression of PRDM16 was significantly positively correlated with immune infiltration of cancer-associated fibroblasts.Kyoto Encyclopedia of Genes and Genomes and Gene Ontology analysis indicated that PRDM16 may be related to transcriptional misregulation pathway in cancer.We identified potential miRNAs that play regulatory roles of PRDM16 in kidney clear cell carcinoma and lung adenocarcinoma.Conclusion:PRDM16 is expressed in different cancers,it can be used as a biomarker for prognosis of pan-cancer and is associated with immune infiltration.展开更多
Objective:Ankyrin repeat domain-containing protein 6(ANKRD6)is an ankyrin repeat-containing protein which is structurally related to vertebrate inversin and Drosophila Diego.However,the correlations between ANKRD6 and...Objective:Ankyrin repeat domain-containing protein 6(ANKRD6)is an ankyrin repeat-containing protein which is structurally related to vertebrate inversin and Drosophila Diego.However,the correlations between ANKRD6 and tumor-infiltrating immune cells in cancers is not clear.Methods:ANKRD6 expression was analyzed by Oncomine,Tumor Immune Estimation Resource(TIMER)and Gene Expression Profiling Interactive Analysis(GEPIA).PrognoScan and GEPIA were used to evaluate the influence of ANKRD6 on clinical prognosis.TIMER and CIBERSORT were used to analyze correlations between ANKRD6 expression levels and tumor immune cell infiltrates.Immunohistochemical analysis of the relationship between ANKRD6 expression and overall survival,as well as the relationship between ANKRD6 expression and M2 macrophage infiltration,was performed.Results:High level of ANKRD6 expression was associated with poor prognosis of colon cancer.ANKRD6 expression level was positively correlated with infiltrating levels of CD8+T cells,CD4+T cells,macrophages,neutrophils and dendritic cells in colon cancer by using TIMER.Using CIBERSORT,we found that in plasma cells,CD8+T cells,CD4+memory resting T cells,follicular helper T cells and activated natural killer cells were significantly lower in the ANKRD6-high group than in the ANKRD6-low group.M0 and M2 macrophages were significantly higher in the ANKRD6-high group than in the ANKRD6-low group.Immunohistochemistry confirmed that M2 macrophage infiltration in the ANKRD6-high group significantly increased.Conclusions:The high ANKRD6 expression is associated with poor prognosis of colon cancer.ANKRD6 expression is positively correlated with M2 macrophage infiltration in colon cancer.展开更多
Tumor tissues contain both tumor and non-tumor cells,which include infiltrated immune cells and stromal cells,collectively called the tumor microenvironment(TME).Single-cell RNA sequencing(sc RNAseq)enables the examin...Tumor tissues contain both tumor and non-tumor cells,which include infiltrated immune cells and stromal cells,collectively called the tumor microenvironment(TME).Single-cell RNA sequencing(sc RNAseq)enables the examination of heterogeneity of tumor cells and TME.In this review,we examined sc RNAseq datasets for multiple cancer types and evaluated the heterogeneity of major cell type composition in different cancer types.We further showed that endothelial cells and fibroblasts/myofibroblasts in different cancer types can be classified into common subtypes,and the subtype composition is clearly associated with cancer characteristic and therapy response.展开更多
Apolipoprotein E(APOE),a gene identified as one of the strongest genetic factors contributing to the risk determinant of developing late-onset Alzheimer’s disease(AD),may also contribute to the risk of cancer.However,...Apolipoprotein E(APOE),a gene identified as one of the strongest genetic factors contributing to the risk determinant of developing late-onset Alzheimer’s disease(AD),may also contribute to the risk of cancer.However,no pan-cancer analysis has been conducted specifically for the APOE gene.In this study,we investigated the oncogenic role of the APOE gene across cancers by GEO(Gene Expression Omnibus)and TCGA(The Cancer Genome Atlas).Based on the available data,we found that most cancer types overexpress APOE,and clear associations exist between the expression level of APOE and prognosis in tumor patients.The expression of APOE also correlates with certain gender-associated tumors including,ovarian cancer,uterine carcinosarcoma,and breast cancer.However,there is a significant negative association between cancer-associatedfibroblast infiltration levels and the expression level of APOE in testicular germ cell tumors.Moreover,acute inflammatory response and protein-activation cascade-associated functions play an important role in the functional mechanisms of APOE.The present pan-cancer analysis of APOE shows that the protein phosphorylation,DNA methylation,and genetic alterations of APOE have a significant clinical relevance for survival prognosis and immune cell infiltration.This novel pan-cancer study outlines the current understanding of APOE oncogenic roles across thirty-three cancers and highlights the complex association between AD and cancers.展开更多
Objective Glutamine fructose-6-phosphate transaminase 2(GFPT2)is involved in a wide range of biological functions in human cancer.However,few studies have comprehensively analyzed the correlation between GFPT2 and dif...Objective Glutamine fructose-6-phosphate transaminase 2(GFPT2)is involved in a wide range of biological functions in human cancer.However,few studies have comprehensively analyzed the correlation between GFPT2 and different cancer prognoses and tumor microenvironments(TMEs).Methods We evaluated the expression level and prognostic value of GFPT2 using updated public databases and multiple comprehensive bioinformatics analysis methods and explored the relationship between GFPT2 expression and immune infiltration,immune neoantigens,tumor mutational burden(TMB),and microsatellite instability in pan-cancer.Results GFPT2 was highly expressed in five cancers.GFPT2 expression correlates with the prognosis of several cancers from The Cancer Genome Atlas(TCGA)and is significantly associated with stromal and immune scores in pan-cancer.High GFPT2 expression in BLCA,BRCA,and CHOL was positively correlated with the infiltration of immune cells,such as B-cells,CD4+T,CD8+T cells,dendritic cells,neutrophils,and macrophages.Conclusion High GFPT2 expression may modify the outcomes of patients with BLCA,BRCA,or CHOL cancers by increasing immune cell infiltration.These findings may provide insights for further investigation into GFPT2 as a potential target in pan-cancer.展开更多
MYBL2(MYB proto-oncogene like 2)is an emerging prognostic marker for malignant tumors,and its potential role in osteosarcoma and its relationship with immune infiltration in pan-cancer is yet to be elucidated.We const...MYBL2(MYB proto-oncogene like 2)is an emerging prognostic marker for malignant tumors,and its potential role in osteosarcoma and its relationship with immune infiltration in pan-cancer is yet to be elucidated.We constructed a transcription factor activity profile of os-teosarcoma using the single-cell regulatory network inference algorithm based on single-cell RNA sequencing data obtained from the Gene Expression Omnibus.Subsequently,we calcu-lated the extent of MYBL2 activation in malignant proliferative osteoblasts.We also explored the association between MYBL2 and chemotherapy resistance in osteosarcoma.Furthermore,we systematically correlated MYBL2 with immunological signatures in the tumor microenviron-ment in pan-cancer,including immune cell infiltration,immune checkpoints,and tumor immu-notherapy prognosis.Finally,we developed and validated a risk score(MRGS),derived an osteosarcoma risk score nomogram based on MRGS,and tested its ability to predict prognosis.MYBL2 and gene enrichment analyses in osteosarcoma and pan-cancer revealed that MYBL2 was positively correlated with cell proliferation and tumor immune pathways.MYBL2 expres-sion positively correlated with SLC19A1 in pan-cancer and osteosarcoma cell lines.Pan-cancer immune infiltration analysis revealed that MYBL2 was correlated with myeloid-derived sup-pressor cells,Th2 cell infiltration,CD276,RELT gene expression,and tumor mutation burden.展开更多
Background:The molecular mechanisms driving tumorigenesis have continually been the focus of researchers.Cuproplasia is defined as copper-dependent cell growth and proliferation,including its primary and secondary rol...Background:The molecular mechanisms driving tumorigenesis have continually been the focus of researchers.Cuproplasia is defined as copper-dependent cell growth and proliferation,including its primary and secondary roles in tumor formation and proliferation through signaling pathways.In this study,we analyzed the differences in the expression of cuproplasia-associated genes(CAGs)in pan-cancerous tissues and investigated their role in immune-regulation and tumor prognostication.Methods:Raw data from 11,057 cancer samples were acquired from multiple databases.Pan-cancer analysis was conducted to analyze the CAG expression,single-nucleotide variants,copy number variants,methylation signatures,and genomic signatures of micro RNA(miRNA)-messenger RNA(mRNA)interactions.The Genomics of Drug Sensitivity in Cancer and the Cancer Therapeutics Response Portal databases were used to evaluate drug sensitivity and resistance against CAGs.Using single-sample Gene Set Enrichment Analysis(ssGSEA)and Immune Cell Abundance Identifier database,immune cell infiltration was analyzed with the ssGSEA score as the standard.Results:Aberrantly expressed CAGs were found in multiple cancers.The frequency of single-nucleotide variations in CAGs ranged from 1%to 54%among different cancers.Furthermore,the correlation between CAG expression in the tumor microenvironment and immune cell infiltration varied among different cancers.ATP7A and ATP7B were negatively correlated with macrophages in 16 tumors including breast invasive carcinoma and esophageal carcinoma,while the converse was true for MT1A and MT2A.In addition,we established cuproplasia scores and demonstrated their strong correlation with patient prognosis,immunotherapy responsiveness,and disease progression(P<0.05).Finally,we identified potential candidate drugs by matching gene targets with existing drugs.Conclusions:This study reports the genomic characterization and clinical features of CAGs in pan-cancers.It helps clarify the relationship between CAGs and tumorigenesis,and may be helpful in the development of biomarkers and new therapeutic agents.展开更多
Recent studies suggested that cancer was a risk factor for coronavirus disease 2019 (COVID-19). Toll-like receptor 7 (TLR7), a severe acute respiratory syndrome 2 (SARS-CoV-2) virus’’s nucleic acid sensor, was disco...Recent studies suggested that cancer was a risk factor for coronavirus disease 2019 (COVID-19). Toll-like receptor 7 (TLR7), a severe acute respiratory syndrome 2 (SARS-CoV-2) virus’’s nucleic acid sensor, was discovered to be aberrantly expressed in many types of cancers. However, its expression pattern across cancers and association with COVID-19 has not been systematically studied. In this study, we proposed a computational framework to comprehensively study the roles of TLR7 in COVID-19 and pan-cancers at genetic, gene expression, protein, epigenetic, and single-cell levels. We found TLR7 mRNA expression was significantly up-regulated in 6 cancer types and down-regulated in 6 cancer types, further validated in the HPA database at the protein level. The genes significantly co-expressed with TLR7 were mainly enriched in the toll-like receptor signaling pathway, endolysosome, and signaling pattern recognition receptor activity. In addition, the abnormal TLR7 expression was associated with Mismatch repair (MMR), microsatellite instability (MSI), tumor mutational burden (TMB) in various cancers. Mined by the ESTIMATE algorithm, the expression of TLR7 was also closely linked to various immune infiltration patterns in pan-cancer, and TLR7 was mainly enriched in macrophages, as revealed by single-cell RNA sequencing. Finally, TLR7 expressions were very sensitive to a few targeted drugs, such as Alectinib and Imiquimod. In conclusion, TLR7 might be essential in the pathogenesis of COVID-19 and cancers.展开更多
Accumulating evidence in recent years indicates that DNA methylation(5-methyl-2-deoxycytidine,5-mdC) and hydroxymethylation(5-hydroxymethyl-2-deoxycytidine, 5-hmd C) have been implicated in various biological processe...Accumulating evidence in recent years indicates that DNA methylation(5-methyl-2-deoxycytidine,5-mdC) and hydroxymethylation(5-hydroxymethyl-2-deoxycytidine, 5-hmd C) have been implicated in various biological processes, and the aberrations of these DNA cytosine modifications is tightly associated with cancer. N6-methyl-2-deoxyadenosine(m~6dA), as a newly discovered epigenetic modification in genome of mammals, has been demonstrated to play vital regulatory roles in tumorigenesis. However, the content information of m~6dA in human tumor tissues is still limited and pan-cancer analysis of these DNA epigenetic modifications is lacked. Herein, we developed a sensitive and robust stable isotopediluted hydrophilic interaction liquid chromatography-tandem mass spectrometry(HILIC-MS/MS) method for accurate quantification of m~6dA, 5-mdC and 5-hmdC in genomic DNA from 82 pairs of human tumor tissues and matched tumor-adjacent normal tissues. The types of tumors included esophagus cancer, lung cancer, breast cancer, liver cancer, pancreatic cancer, gastric cancer, stromal tumor and colorectal cancer.Compared to the normal tissues, we revealed the level of m6dA was increased in tumor tissues of esophagus cancer, lung cancer and liver cancer, whereas the level of m~6dA was diminished in tumor tissues of pancreatic cancer and gastric cancer;while the contents of 5-mdC and 5-hmdC exhibited significant decrease in tumor tissues of most types of cancer. It is worth noting that we revealed, for the first time,the content of genomic m~6dA in pancreatic cancer, stromal tumor and colorectal cancer. The significant changes of these DNA epigenetic modifications indicate they may serve as indicators of cancers. In addition, this study will benefit for better understanding of the regulatory roles of these DNA epigenetic modifications in cancers.展开更多
Background:Cancer cells reprogram metabolism for proliferation.Phosphoglycerate kinase 1(PGK1),as a glycolytic enzyme and newly identified protein kinase,coordinates glycolysis and mitochondrial metabolism.However,the...Background:Cancer cells reprogram metabolism for proliferation.Phosphoglycerate kinase 1(PGK1),as a glycolytic enzyme and newly identified protein kinase,coordinates glycolysis and mitochondrial metabolism.However,the clini-cal significance of PGK1 expression and function in cancer progression is unclear.Here,we investigated the relation-ship between the progression and prognosis of multiple cancer types and PGK1 expression and its function in the mitochondrial metabolism regulation.Methods:We performed pan-cancer analyses of PGK1 mRNA level and DNA methylation in 11,908 tumor tissues and 1582 paired normal tissues across 34 cancer types in The Cancer Genome Atlas datasets.Using specific antibodies against PGK1 S203 and PDHK1 T338 phosphorylation,we performed immunohistochemistry with tissue microarray assay in additional 818 cancer cases with 619 paired normal tissues from five cancer types.Results:The PGK1 mRNA level was significantly elevated with hypomethylation in promotor regions and associated with advanced TNM stage in 15 and four cancer types,respectively.In breast carcinoma,elevated PGK1 mRNA level and promoter hypomethylation were associated with poor prognosis.Positively correlated PGK1 S203 and PDHK1 T338 phosphorylation levels were significantly associated with short overall survival(OS)in cancers of the breast,liver,lung,stomach,and esophagus and with advanced TNM stage in breast and esophageal cancers.PGK1 pS203 and PDHK1 pT338 were also independent predictors of short OS in liver,lung,and stomach cancer.Conclusions:The elevated expression,promoter hypomethylation,and phosphorylation of PGK1 and PDHK1 were related with disease progression and short OS in diverse types of cancer.PGK1 and PDHK1 phosphorylation may be potential prognostic biomarkers.展开更多
Changes in the abundance and activity of long non-coding RNAs(lncRNAs)have an important impact on the development of cancer.The nuclear paraspeckle assembly transcript 1(NEAT1)has been reported to be overexpressed in ...Changes in the abundance and activity of long non-coding RNAs(lncRNAs)have an important impact on the development of cancer.The nuclear paraspeckle assembly transcript 1(NEAT1)has been reported to be overexpressed in many types of cancer since its discovery.However,inconsistencies exist as NEAT1 can also function as a tumor suppressor in certain types of cancer,such as acute promyelocytic leukemia.Here we systematically describe our current understanding of NEAT1 in tumor initiation and progression.First,we analyzed the expression patterns of NEAT1 in various normal tissues and malignant cancers using data from public data portals,the Genotype-Tissue Expression Project(GTEx)and the Cancer Genome Atlas(TCGA),together with recent progress in the study of NEAT1 in various types of cancer.Second,we discussed the functions and mechanisms of NEAT1 in modulating tumor activity.Then,the upstream transcription factors and downstream microRNA targets of NEAT1 in the transcription cascade of cancers were also summarized.These data highlight the emerging role of NEAT1 in tumorigenesis,and present promising targetable pathways and clinical opportunities for tumor prevention and classifications.展开更多
Background:Human epidermal growth factor receptor(EGFR)is an oncogenic gene and one of top targets of precision therapy in lung cancer with EGFR mutations.Although there are many reports for some individual cancers,co...Background:Human epidermal growth factor receptor(EGFR)is an oncogenic gene and one of top targets of precision therapy in lung cancer with EGFR mutations.Although there are many reports for some individual cancers,comprehensive profiling of EGFR mutations,overexpression,amplification,DNA methylation,and their clinical associations across many different cancers simultaneously was not available.This study aimed to fill the gap and provide insights to the alteration spectrum of EGFR and its therapeutic and prognostic implications.Methods:The Cancer Genome Atlas(TCGA)datasets for 32 cancer types involving 11,314 patients were analyzed for alterations(mutations and amplification/deletion),abnormal expression and DNA methylation in EGFR gene.Mutation frequency,genomic location distribution,functional impact,and clinical targeted therapy implication were compared among different cancer types,and their associations with patient survival were analyzed.Results:EGFR alteration frequency,mutation sites across functional domains,amplification,overexpression,and DNA methylation patterns differed greatly among different cancer types.The overall mutation frequency in all cancers combined was relatively low.Targetable mutations,mainly in lung cancer,were primarily found in the Pkinase_Tyr domain.Glioblastoma multiforme had the highest rate of alterations,but it was dominated by gene amplification and most mutations were in the Furin-like domain where targeted therapy was less effective.Low-grade glioma often had gene amplification and increased EGFR expression which was associated with poor outcome.Colon and pancreatic adenocarcinoma had very few EGFR mutations;however,high EGFR expression was significantly associated with short patient survival.Squamous cell carcinoma regardless of their sites(the head and neck,lung,or esophagus)exhibited similar characteristics with an alteration frequency of about 5.0%,was dominated by gene amplification,and had increased EGFR expression generally associated with short patient survival.DNA methylation was highly associated with EGFR expression and patient outcomes in some cancers.Conclusions:EGFR aberration type,frequency,distribution in functional domains,and expression vary from cancer to cancer.While mutations in the Pkinase_Tyr domain are more important for treatment selection,increased expression from amplification or deregulation affects more tumor types and leads to worse outcome,which calls for new treatment strategies for these EGFR-driven tumors.展开更多
Tumor development is a process involving loss of the differentiation phenotype and acquisition of stem-like characteristics,which is driven by intracellular rewiring of signaling network.The measurement of network rep...Tumor development is a process involving loss of the differentiation phenotype and acquisition of stem-like characteristics,which is driven by intracellular rewiring of signaling network.The measurement of network reprogramming and disorder would be challenging due to the complexity and heterogeneity of tumors.Here,we proposed signaling entropy(SR)to assess the degree of tumor network disorder.We calculated SR for 33 tumor types in The Cancer Genome Atlas database based on transcrip-tomic and proteomic data.The SR of tumors was significantly higher than that of normal samples and was highly correlated with cell sternness,cancer type,tumor grade,and metastasis.We further demonstrated the sensitivity and accuracy of using local SR in prognosis prediction and drug response evaluation.Overall,SR could reveal cancer network disorders related to tumor malignant potency,clinical prognosis,and drug response.展开更多
The DEAD-box RNA helicase(DDX)family plays a critical role in the growth and development of multiple organisms.DDX1 is involved in mRNA/rRNA processing and mature,virus replication and transcription,hormone metabolism...The DEAD-box RNA helicase(DDX)family plays a critical role in the growth and development of multiple organisms.DDX1 is involved in mRNA/rRNA processing and mature,virus replication and transcription,hormone metabolism,tumo-rigenesis,and tumor development.However,how DDX1 functions in various cancers remains unclear.Here,we explored the potential oncogenic roles of DDX1 across 33 tumors with The Cancer Genome Atlas(TCGA)and the Genotype-Tissue Expression(GTEx)databases.DDX1 is highly expressed in breast cancer(BRCA),cholangiocarcinoma(CHOL),and colon adenocarcinoma(COAD),but it is lowly expressed in renal cancers,including kidney renal clear cell carcinoma(KIRC),kidney chromophobe(KICH),and kidney renal papillary cell carcinoma(KIRP).Low expression of DDX1 in KIRC is cor-related with a good prognosis of overall survival(OS)and disease-free survival(DFS).Highly expressed DDX1 is linked to a poor prognosis of OS for adrenocortical carcinoma(ACC),bladder urothelial carcinoma(BLCA),KICH,and liver hepatocellular carcinoma(LIHC).Also,the residue Ser481 of DDX1 had an enhanced phosphorylation level in BRCA and ovarian cancer(OV)but decreased in KIRC.Immune infiltration analysis exhibited that DDX1 expression affected CD8+T cells,and it was significantly associated with MSI(microsatellite instability),TMB(tumor mutational burden),and ICT(immune checkpoint blockade therapy)in tumors.In addition,the depletion of DDX1 dramatically affected the cell viability of human tumor-derived cell lines.DDX1 could affect the DNA repair pathway and the RNA transport/DNA replication processes during tumorigenesis by analyzing the CancerSEA database.Thus,our pan-cancer analysis revealed that DDX1 had complicated impacts on different cancers and might act as a prognostic marker for cancers such as renal cancer.展开更多
BACKGROUND The pyruvate dehydrogenase E1 subunitβ(PDHB)gene which regulates energy metabolism is located in mitochondria.However,few studies have elucidated the role and mechanism of PDHB in different cancers.AIM To ...BACKGROUND The pyruvate dehydrogenase E1 subunitβ(PDHB)gene which regulates energy metabolism is located in mitochondria.However,few studies have elucidated the role and mechanism of PDHB in different cancers.AIM To comprehensive pan-cancer analysis of PDHB was performed based on bioinformatics approaches to explore its tumor diagnostic and prognostic value and tumor immune relevance in cancer.In vitro experiments were performed to examine the biological regulation of PDHB in liver cancer.METHODS Pan-cancer data related to PDHB were obtained from the Cancer Genome Atlas(TCGA)database.Analysis of the gene expression profiles of PDHB was based on TCGA and Genotype Tissue Expression Dataset databases.Cox regression analysis and Kaplan-Meier methods were used to assess the correlation between PDHB expression and survival prognosis in cancer patients.The correlation between PDHB and receiver operating characteristic diagnostic curve,clinicopathological staging,somatic mutation,tumor mutation burden(TMB),microsatellite instability(MSI),DNA methylation,and drug susceptibility in pan-cancer was also analyzed.Various algorithms were used to analyze the correlation between PDHB and immune cell infiltration and tumor chemotaxis environment,as well as the co-expression analysis of PDHB and immune checkpoint(ICP)genes.The expression and functional phenotype of PDHB in single tumor cells were studied by single-cell sequencing,and the functional enrichment analysis of PDHB-related genes was performed.The study also validated the level of mRNA or protein expression of PDHB in several cancers.Finally,in vitro experiments verified the regulatory effect of PDHB on the proliferation,migration,and invasion of liver cancer.RESULTS PDHB was significantly and differently expressed in most cancers.PDHB was significantly associated with prognosis in patients with a wide range of cancers,including kidney renal clear cell carcinoma,kidney renal papillary cell carcinoma,breast invasive carcinoma,and brain lower grade glioma.In some cancers,PDHB expression was clearly associated with gene mutations,clinicopathological stages,and expression of TMB,MSI,and ICP genes.The expression of PDHB was closely related to the infiltration of multiple immune cells in the immune microenvironment and the regulation of tumor chemotaxis environment.In addition,single-cell sequencing results showed that PDHB correlated with different biological phenotypes of multiple cancer single cells.This study further demonstrated that down-regulation of PDHB expression inhibited the proliferation,migration,and invasion functions of hepatoma cells.CONCLUSION As a member of pan-cancer,PDHB may be a novel cancer marker with potential value in diagnosing cancer,predicting prognosis,and in targeted therapy.展开更多
基金supported by the National Natural Science Foundation of China (Grant Nos. 81972761 and 82202837)the National Key R&D Program of China (Grant Nos. 2016YFC1303200 and 2022YFC2505100)。
文摘Objective: DNA damage response(DDR) deficiency has emerged as a prominent determinant of tumor immunogenicity. This study aimed to construct a DDR-related immune activation(DRIA) signature and evaluate the predictive accuracy of the DRIA signature for response to immune checkpoint inhibitor(ICI) therapy in gastrointestinal(GI) cancer.Methods: A DRIA signature was established based on two previously reported DNA damage immune response assays. Clinical and gene expression data from two published GI cancer cohorts were used to assess and validate the association between the DRIA score and response to ICI therapy. The predictive accuracy of the DRIA score was validated based on one ICI-treated melanoma and three pan-cancer published cohorts.Results: The DRIA signature includes three genes(CXCL10, IDO1, and IFI44L). In the discovery cancer cohort, DRIA-high patients with gastric cancer achieved a higher response rate to ICI therapy than DRIA-low patients(81.8% vs. 8.8%;P < 0.001), and the predictive accuracy of the DRIA score [area under the receiver operating characteristic curve(AUC) = 0.845] was superior to the predictive accuracy of PD-L1 expression, tumor mutational burden, microsatellite instability, and Epstein–Barr virus status. The validation cohort demonstrated that the DRIA score identified responders with microsatellite-stable colorectal and pancreatic adenocarcinoma who received dual PD-1 and CTLA-4 blockade with radiation therapy. Furthermore, the predictive performance of the DRIA score was shown to be robust through an extended validation in melanoma, urothelial cancer, and pan-cancer.Conclusions: The DRIA signature has superior and robust predictive accuracy for the efficacy of ICI therapy in GI cancer and pancancer, indicating that the DRIA signature may serve as a powerful biomarker for guiding ICI therapy decisions.
基金the Chinese Scholarship Council(Grant No.202206240086)the National Natural Science Foundation of China(Grant No.82170432)programs from Science and Technology Department of Sichuan Province(Grant No.2020YFSY0024).
文摘The incre asing interest in RNA modifications has signifcantly advanced epigenomic and epitranscriptomic technologies.This study focuses on the immuno oncological impact of ALYREF in human cancer through a pan-cancer analysis,enhancing understanding of this gene's role in cancer.We observed differential ALYREF expression between tumor and normal samples,correl ating strongly with prognosis in various cancers,particularly kidney renal papillary cell carcinoma(KIRP)and liver hepatocellular carcinoma(LIHC).ALYREF showed a negative correlation with most tumor-infitrating cells in lung squamous cell carcinoma(LUSC)and lymphoid neoplasm difuse large B-cell lymphoma(DLBC),while positive correlations were noted in IIHC,kidney chromophobe(KICH),mesothelioma(MESO),KIRP,pheochromocytoma and paraganglioma(PARD),and glioma(GBMLGG).Aditionally,ALYREF expression was closely associated with tumor heterogeneity,stemness indices,and a high mutation rate in TP53 across these cancers.In conclusion,ALYREF may serve as an oncogenic biomarker in numerous cancers,meriting further research attention.
基金supported in part by the National Natural Science Foundation of China(Grant No.81703005)the Natural Science Foundation of Hunan Province(Grant Nos.2017JJ3195,2018JJ3317)the Key Research and Development Projects of Hunan Province(Grant No.2018SK2120).
文摘Background:Nuclear receptor binding SET domain protein-3(NSD3)is a histone lysine methyltransferase and a crucial regulator of carcinogenesis in several cancers.We aimed to investigate the prognostic value and potential function of NSD3 in 33 types of human cancer.Methods:The data were obtained from The Cancer Genome Atlas.Kaplan-Meier analysis,CIBERSORT,gene set enrichment analysis,and gene set variation analysis were performed.The expression of NSD3 was measured using quantitative real-time polymerase chain reaction and western blot.Results:The expression of NSD3 was altered in pan-cancer samples.Patients with higher levels of NDS3 generally had shorter overall survival and disease-specific survival.Levels of NSD3 were positively correlated with DNA copy number variation(CNV)in pan-cancer.NSD3 expression was also associated with tumor mutation burden and microsatellite instability.The levels of immune-cell infiltration differed significantly between high and low NSD3 expression.NSD3 negatively correlated with levels of CD8+T cells.Functional enrichment analysis showed that while NSD3 expression was positively associated with several immune cell-related and histone methylation-related pathways,it was negatively correlated with cell metabolism-related,drug transport-related,and drug metabolismrelated pathways.NSD3 levels in the cell lines tested were significantly different.In U251 and NCI-H23 cells,silencing NSD3 inhibited cell proliferation and promoted apoptosis.Conclusions:NSD3 expression was changed in pan-cancer samples that was also verified in cell lines.NSD3 was associated with CNV and immune-cell infiltration.A poor prognosis was predicted in patients with high expression of NSD3.NSD3 might hence be a potential marker for predicting tumor prognosis.
基金This work was mainly supported by the Science and Technology Innovation Fund Project of Shanghai Jinshan District Science and Technology Commission(No.2021-3-55)All sponsors or funders played no roles in the study design,data collection and analysis,decision to publish,or preparation of the manuscript.
文摘Sterol o-acyltransferase1(SOAT1)is an enzyme that regulates lipid metabolism.Nevertheless,the predictive value of SOAT1 regarding immune responses in cancer is not fully understood.Herein,we aimed to expound the predictive value and the potential biological functions of SOAT1 in pan-cancer.Raw data related to SOAT1 expression in 33 different types of cancer were acquired from The Cancer Genome Atlas(TCGA)and Genotype-Tissue Expression(GTEx)databases.SOAT1 expression was significantly increased in most cancers and showed a distinct correlation with prognosis.This enhanced expression of the SOAT1 gene was confirmed by evaluating SOAT1 protein expression using tissue microarrays.In addition,we found significant positive associations between SOAT1 expression levels and infiltrating immune cells,including T cells,neutrophils,and macrophages.Moreover,the co-expression analysis between SOAT1 and immune genes showed that many immune-related genes were increased with enhanced SOAT1 expression.A gene set enrichment analysis(GSEA)revealed that the expression of SOAT1 correlated with the tumor microenvironment,adaptive immune response,interferon signaling,and cytokine signaling.These findings indicate that SOAT1 is a potential candidate marker for predicting prognosis and a promising target for tumor immunotherapy in cancers.
基金funded by the Central to guide local scientific and Technological Development(ZYYDDFFZZJ-1)Natural Science Foundation of Gansu Province,China(No.18JR3RA052)+2 种基金Lanzhou Talent Innovation and Entrepreneurship Project Task Contract(No.2016-RC-56)Gansu Da Vinci Robot High-End Diagnosis and Treatment Team Construction Project,and Gansu Provincial Youth Science and Technology Fund Program(20JR10RA415)National Key Research and Development Program(No.2018YFC1311500).
文摘B and T-lymphocyte attenuator(BTLA)plays an immunosuppressive role by inhibiting T-and B-cell functions.BTLA is associated with a variety of diseases,especially cancer immunity.However,the function of BTLA in various cancers and its clinical prognostic value have still not been comprehensively analyzed.This study aimed to identify the relationship between BTLA and cancer from the perspectives of differences in BTLA expression,its clinical value,immune infiltration,and the correlation with immune-related genes in various cancers.Data regarding mRNA expression,miRNA expression,lncRNA expression,and clinical data of patients of 33 existing cancers were collected from the TCGA database.Target miRNA of BTLA and the lncRNA that interacts with the target miRNA were obtained from the StarBase database.Based on bioinformatics analysis methods,the relationship between various types of cancers and BTLA was thoroughly investigated,and a competing endogenous RNA network of BTLA,target miRNA,and interacting lncRNA was constructed.The Kaplan-Meier(KM)prognostic analysis of BTLA and target miRNA(has-miR-137)in various types of cancers was completed using the KM plotter.BTLA expression varied in different cancers,with statistical significance in nine cancer types.KM plotter to analyze the overall survival(OS)and regression-free survival prognosis of cancer patients revealed that the BTLA expression was statistically different in the OS of 11 types of cancers out of 21 types of cancers;the OS of 8 type of cancers was also statistically different.Correlation analysis of tumor immune genes revealed a positive correlation of BTLA expression with immunosuppressive gene(CTLA4 and PDCD1)expression.Gene Set Enrichment Analysis showed that BTLA and its co-expressed genes mainly act through biological processes and pathways,including immune response regulation,cell surface receptor signaling pathway,antigen binding,antigen receptor-mediated signaling pathway,and leukocyte migration.BTLA has the potential as a prognostic marker for CLL,COAD,NSCLC,and OV and a diagnostic marker for CLL,COAD,and KIRC.BTLA has a close and complex relationship with the occurrence and development of tumors,and cancer immunotherapy for BTLA is worthy of further analysis.
基金This study was financially supported by the Young Teachers Support Program of Hubei University of Chinese Medicine(2021ZZX025)Hubei Province College Students’innovation and entrepreneurship training program(S202210507018).
文摘Background:Positive regulatory domain-containing 16(PRDM16)plays a key role in brown adipose transcription,but its function in cancer is unclear.Our research to investigate the potential roles of PRDM16 across multiple types of cancer by pan cancer analyses.Methods:UALCAN and TIMER2 database were utilized to evaluate PRDM16 expression in cancer patients.Gene Expression Profiling Interactive Analysis was employed to analyze the overall survival and disease-free survival across all The Cancer Genome Atlas Program tumors.Using the cBioPortal tool,we analyzed the mutation features of PRDM16 for the The Cancer Genome Atlas Program tumors,then utilized the Encyclopedia of RNA Interactomes database to predict the miRNA-mRNA relationships associated with the PRDM16 for all tumors.Results:The expression level of PRDM16 in the tumor tissues is lower than that in the normal tissues.Interesting,the high expression of PRDM16 has a positive effect on the prognosis of kidney clear cell carcinoma and lung adenocarcinoma,but not conducive to the prognosis of most cancers.In multiple cancer types,the expression of PRDM16 was significantly positively correlated with immune infiltration of cancer-associated fibroblasts.Kyoto Encyclopedia of Genes and Genomes and Gene Ontology analysis indicated that PRDM16 may be related to transcriptional misregulation pathway in cancer.We identified potential miRNAs that play regulatory roles of PRDM16 in kidney clear cell carcinoma and lung adenocarcinoma.Conclusion:PRDM16 is expressed in different cancers,it can be used as a biomarker for prognosis of pan-cancer and is associated with immune infiltration.
基金supported by Zhejiang Basic Public Welfare Research Project(No.LGF18H160040)。
文摘Objective:Ankyrin repeat domain-containing protein 6(ANKRD6)is an ankyrin repeat-containing protein which is structurally related to vertebrate inversin and Drosophila Diego.However,the correlations between ANKRD6 and tumor-infiltrating immune cells in cancers is not clear.Methods:ANKRD6 expression was analyzed by Oncomine,Tumor Immune Estimation Resource(TIMER)and Gene Expression Profiling Interactive Analysis(GEPIA).PrognoScan and GEPIA were used to evaluate the influence of ANKRD6 on clinical prognosis.TIMER and CIBERSORT were used to analyze correlations between ANKRD6 expression levels and tumor immune cell infiltrates.Immunohistochemical analysis of the relationship between ANKRD6 expression and overall survival,as well as the relationship between ANKRD6 expression and M2 macrophage infiltration,was performed.Results:High level of ANKRD6 expression was associated with poor prognosis of colon cancer.ANKRD6 expression level was positively correlated with infiltrating levels of CD8+T cells,CD4+T cells,macrophages,neutrophils and dendritic cells in colon cancer by using TIMER.Using CIBERSORT,we found that in plasma cells,CD8+T cells,CD4+memory resting T cells,follicular helper T cells and activated natural killer cells were significantly lower in the ANKRD6-high group than in the ANKRD6-low group.M0 and M2 macrophages were significantly higher in the ANKRD6-high group than in the ANKRD6-low group.Immunohistochemistry confirmed that M2 macrophage infiltration in the ANKRD6-high group significantly increased.Conclusions:The high ANKRD6 expression is associated with poor prognosis of colon cancer.ANKRD6 expression is positively correlated with M2 macrophage infiltration in colon cancer.
基金partially supported by NIH grants(Grant Nos.R01CA249175 and U19AI118610)。
文摘Tumor tissues contain both tumor and non-tumor cells,which include infiltrated immune cells and stromal cells,collectively called the tumor microenvironment(TME).Single-cell RNA sequencing(sc RNAseq)enables the examination of heterogeneity of tumor cells and TME.In this review,we examined sc RNAseq datasets for multiple cancer types and evaluated the heterogeneity of major cell type composition in different cancer types.We further showed that endothelial cells and fibroblasts/myofibroblasts in different cancer types can be classified into common subtypes,and the subtype composition is clearly associated with cancer characteristic and therapy response.
基金supported by the Pujiang Talent Program from Shanghai Municipal Human Resource Bureau and Shanghai Science and Technology Committee to Shoukai Yu.The Grant No.is 19PJC085.
文摘Apolipoprotein E(APOE),a gene identified as one of the strongest genetic factors contributing to the risk determinant of developing late-onset Alzheimer’s disease(AD),may also contribute to the risk of cancer.However,no pan-cancer analysis has been conducted specifically for the APOE gene.In this study,we investigated the oncogenic role of the APOE gene across cancers by GEO(Gene Expression Omnibus)and TCGA(The Cancer Genome Atlas).Based on the available data,we found that most cancer types overexpress APOE,and clear associations exist between the expression level of APOE and prognosis in tumor patients.The expression of APOE also correlates with certain gender-associated tumors including,ovarian cancer,uterine carcinosarcoma,and breast cancer.However,there is a significant negative association between cancer-associatedfibroblast infiltration levels and the expression level of APOE in testicular germ cell tumors.Moreover,acute inflammatory response and protein-activation cascade-associated functions play an important role in the functional mechanisms of APOE.The present pan-cancer analysis of APOE shows that the protein phosphorylation,DNA methylation,and genetic alterations of APOE have a significant clinical relevance for survival prognosis and immune cell infiltration.This novel pan-cancer study outlines the current understanding of APOE oncogenic roles across thirty-three cancers and highlights the complex association between AD and cancers.
基金Supported by a grant from the National Natural Science Foundation of China(No.81700256).
文摘Objective Glutamine fructose-6-phosphate transaminase 2(GFPT2)is involved in a wide range of biological functions in human cancer.However,few studies have comprehensively analyzed the correlation between GFPT2 and different cancer prognoses and tumor microenvironments(TMEs).Methods We evaluated the expression level and prognostic value of GFPT2 using updated public databases and multiple comprehensive bioinformatics analysis methods and explored the relationship between GFPT2 expression and immune infiltration,immune neoantigens,tumor mutational burden(TMB),and microsatellite instability in pan-cancer.Results GFPT2 was highly expressed in five cancers.GFPT2 expression correlates with the prognosis of several cancers from The Cancer Genome Atlas(TCGA)and is significantly associated with stromal and immune scores in pan-cancer.High GFPT2 expression in BLCA,BRCA,and CHOL was positively correlated with the infiltration of immune cells,such as B-cells,CD4+T,CD8+T cells,dendritic cells,neutrophils,and macrophages.Conclusion High GFPT2 expression may modify the outcomes of patients with BLCA,BRCA,or CHOL cancers by increasing immune cell infiltration.These findings may provide insights for further investigation into GFPT2 as a potential target in pan-cancer.
基金supported by Changsha Natural Science Foundation,Hunan,China(No.kq2202382)the Natural Science Foundation of Hunan,China(No.2022JJ40802,2022JJ30928)the Project funded by China Postdoctoral Science Foundation(No.2022M713525).
文摘MYBL2(MYB proto-oncogene like 2)is an emerging prognostic marker for malignant tumors,and its potential role in osteosarcoma and its relationship with immune infiltration in pan-cancer is yet to be elucidated.We constructed a transcription factor activity profile of os-teosarcoma using the single-cell regulatory network inference algorithm based on single-cell RNA sequencing data obtained from the Gene Expression Omnibus.Subsequently,we calcu-lated the extent of MYBL2 activation in malignant proliferative osteoblasts.We also explored the association between MYBL2 and chemotherapy resistance in osteosarcoma.Furthermore,we systematically correlated MYBL2 with immunological signatures in the tumor microenviron-ment in pan-cancer,including immune cell infiltration,immune checkpoints,and tumor immu-notherapy prognosis.Finally,we developed and validated a risk score(MRGS),derived an osteosarcoma risk score nomogram based on MRGS,and tested its ability to predict prognosis.MYBL2 and gene enrichment analyses in osteosarcoma and pan-cancer revealed that MYBL2 was positively correlated with cell proliferation and tumor immune pathways.MYBL2 expres-sion positively correlated with SLC19A1 in pan-cancer and osteosarcoma cell lines.Pan-cancer immune infiltration analysis revealed that MYBL2 was correlated with myeloid-derived sup-pressor cells,Th2 cell infiltration,CD276,RELT gene expression,and tumor mutation burden.
文摘Background:The molecular mechanisms driving tumorigenesis have continually been the focus of researchers.Cuproplasia is defined as copper-dependent cell growth and proliferation,including its primary and secondary roles in tumor formation and proliferation through signaling pathways.In this study,we analyzed the differences in the expression of cuproplasia-associated genes(CAGs)in pan-cancerous tissues and investigated their role in immune-regulation and tumor prognostication.Methods:Raw data from 11,057 cancer samples were acquired from multiple databases.Pan-cancer analysis was conducted to analyze the CAG expression,single-nucleotide variants,copy number variants,methylation signatures,and genomic signatures of micro RNA(miRNA)-messenger RNA(mRNA)interactions.The Genomics of Drug Sensitivity in Cancer and the Cancer Therapeutics Response Portal databases were used to evaluate drug sensitivity and resistance against CAGs.Using single-sample Gene Set Enrichment Analysis(ssGSEA)and Immune Cell Abundance Identifier database,immune cell infiltration was analyzed with the ssGSEA score as the standard.Results:Aberrantly expressed CAGs were found in multiple cancers.The frequency of single-nucleotide variations in CAGs ranged from 1%to 54%among different cancers.Furthermore,the correlation between CAG expression in the tumor microenvironment and immune cell infiltration varied among different cancers.ATP7A and ATP7B were negatively correlated with macrophages in 16 tumors including breast invasive carcinoma and esophageal carcinoma,while the converse was true for MT1A and MT2A.In addition,we established cuproplasia scores and demonstrated their strong correlation with patient prognosis,immunotherapy responsiveness,and disease progression(P<0.05).Finally,we identified potential candidate drugs by matching gene targets with existing drugs.Conclusions:This study reports the genomic characterization and clinical features of CAGs in pan-cancers.It helps clarify the relationship between CAGs and tumorigenesis,and may be helpful in the development of biomarkers and new therapeutic agents.
基金supported by Joint Funds for the innovation of science and Technology,Fujian province(Grant number:2020Y9039)Fujian Provincial Health Technology Project(Grant number:2022GGA032).
文摘Recent studies suggested that cancer was a risk factor for coronavirus disease 2019 (COVID-19). Toll-like receptor 7 (TLR7), a severe acute respiratory syndrome 2 (SARS-CoV-2) virus’’s nucleic acid sensor, was discovered to be aberrantly expressed in many types of cancers. However, its expression pattern across cancers and association with COVID-19 has not been systematically studied. In this study, we proposed a computational framework to comprehensively study the roles of TLR7 in COVID-19 and pan-cancers at genetic, gene expression, protein, epigenetic, and single-cell levels. We found TLR7 mRNA expression was significantly up-regulated in 6 cancer types and down-regulated in 6 cancer types, further validated in the HPA database at the protein level. The genes significantly co-expressed with TLR7 were mainly enriched in the toll-like receptor signaling pathway, endolysosome, and signaling pattern recognition receptor activity. In addition, the abnormal TLR7 expression was associated with Mismatch repair (MMR), microsatellite instability (MSI), tumor mutational burden (TMB) in various cancers. Mined by the ESTIMATE algorithm, the expression of TLR7 was also closely linked to various immune infiltration patterns in pan-cancer, and TLR7 was mainly enriched in macrophages, as revealed by single-cell RNA sequencing. Finally, TLR7 expressions were very sensitive to a few targeted drugs, such as Alectinib and Imiquimod. In conclusion, TLR7 might be essential in the pathogenesis of COVID-19 and cancers.
基金financially supported by National Natural Science Foundation of China (No. 22176167)the Key R&D Program of Zhejiang Province (No. 2021C03125)Natural Science Foundation of Zhejiang Province (No. LY19B050007)。
文摘Accumulating evidence in recent years indicates that DNA methylation(5-methyl-2-deoxycytidine,5-mdC) and hydroxymethylation(5-hydroxymethyl-2-deoxycytidine, 5-hmd C) have been implicated in various biological processes, and the aberrations of these DNA cytosine modifications is tightly associated with cancer. N6-methyl-2-deoxyadenosine(m~6dA), as a newly discovered epigenetic modification in genome of mammals, has been demonstrated to play vital regulatory roles in tumorigenesis. However, the content information of m~6dA in human tumor tissues is still limited and pan-cancer analysis of these DNA epigenetic modifications is lacked. Herein, we developed a sensitive and robust stable isotopediluted hydrophilic interaction liquid chromatography-tandem mass spectrometry(HILIC-MS/MS) method for accurate quantification of m~6dA, 5-mdC and 5-hmdC in genomic DNA from 82 pairs of human tumor tissues and matched tumor-adjacent normal tissues. The types of tumors included esophagus cancer, lung cancer, breast cancer, liver cancer, pancreatic cancer, gastric cancer, stromal tumor and colorectal cancer.Compared to the normal tissues, we revealed the level of m6dA was increased in tumor tissues of esophagus cancer, lung cancer and liver cancer, whereas the level of m~6dA was diminished in tumor tissues of pancreatic cancer and gastric cancer;while the contents of 5-mdC and 5-hmdC exhibited significant decrease in tumor tissues of most types of cancer. It is worth noting that we revealed, for the first time,the content of genomic m~6dA in pancreatic cancer, stromal tumor and colorectal cancer. The significant changes of these DNA epigenetic modifications indicate they may serve as indicators of cancers. In addition, this study will benefit for better understanding of the regulatory roles of these DNA epigenetic modifications in cancers.
基金This study was funded by The National Key R&D Program of China(2017YFC1308702,2017YFC1311000,2018YFC1312100)the Beijing Municipal Science&Technology Commission(Z181100006218032,Z181100001918002)+1 种基金the CAMS Initiative for Innovative Medicine(2017-I2M-1-005,2017-I2M-2-003,2019-I2M-2-002)Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences(2017PT32001,2017PT32017).
文摘Background:Cancer cells reprogram metabolism for proliferation.Phosphoglycerate kinase 1(PGK1),as a glycolytic enzyme and newly identified protein kinase,coordinates glycolysis and mitochondrial metabolism.However,the clini-cal significance of PGK1 expression and function in cancer progression is unclear.Here,we investigated the relation-ship between the progression and prognosis of multiple cancer types and PGK1 expression and its function in the mitochondrial metabolism regulation.Methods:We performed pan-cancer analyses of PGK1 mRNA level and DNA methylation in 11,908 tumor tissues and 1582 paired normal tissues across 34 cancer types in The Cancer Genome Atlas datasets.Using specific antibodies against PGK1 S203 and PDHK1 T338 phosphorylation,we performed immunohistochemistry with tissue microarray assay in additional 818 cancer cases with 619 paired normal tissues from five cancer types.Results:The PGK1 mRNA level was significantly elevated with hypomethylation in promotor regions and associated with advanced TNM stage in 15 and four cancer types,respectively.In breast carcinoma,elevated PGK1 mRNA level and promoter hypomethylation were associated with poor prognosis.Positively correlated PGK1 S203 and PDHK1 T338 phosphorylation levels were significantly associated with short overall survival(OS)in cancers of the breast,liver,lung,stomach,and esophagus and with advanced TNM stage in breast and esophageal cancers.PGK1 pS203 and PDHK1 pT338 were also independent predictors of short OS in liver,lung,and stomach cancer.Conclusions:The elevated expression,promoter hypomethylation,and phosphorylation of PGK1 and PDHK1 were related with disease progression and short OS in diverse types of cancer.PGK1 and PDHK1 phosphorylation may be potential prognostic biomarkers.
基金This work was supported in part by National Natural Science Foundation Grants of China(81530003)China Postdoctoral Science Foundation(2017M611580).
文摘Changes in the abundance and activity of long non-coding RNAs(lncRNAs)have an important impact on the development of cancer.The nuclear paraspeckle assembly transcript 1(NEAT1)has been reported to be overexpressed in many types of cancer since its discovery.However,inconsistencies exist as NEAT1 can also function as a tumor suppressor in certain types of cancer,such as acute promyelocytic leukemia.Here we systematically describe our current understanding of NEAT1 in tumor initiation and progression.First,we analyzed the expression patterns of NEAT1 in various normal tissues and malignant cancers using data from public data portals,the Genotype-Tissue Expression Project(GTEx)and the Cancer Genome Atlas(TCGA),together with recent progress in the study of NEAT1 in various types of cancer.Second,we discussed the functions and mechanisms of NEAT1 in modulating tumor activity.Then,the upstream transcription factors and downstream microRNA targets of NEAT1 in the transcription cascade of cancers were also summarized.These data highlight the emerging role of NEAT1 in tumorigenesis,and present promising targetable pathways and clinical opportunities for tumor prevention and classifications.
基金China Scholarship Council,Grant/Award Number:201806015028Chinese National Natural Science Foundation,Grant/Award Numbers:81101998,81872018,81372292+1 种基金Chinese Ministry of Science and Technology,Grant/Award Number:2017YFC0110200Mayo Clinic Center for Individualized Medicine。
文摘Background:Human epidermal growth factor receptor(EGFR)is an oncogenic gene and one of top targets of precision therapy in lung cancer with EGFR mutations.Although there are many reports for some individual cancers,comprehensive profiling of EGFR mutations,overexpression,amplification,DNA methylation,and their clinical associations across many different cancers simultaneously was not available.This study aimed to fill the gap and provide insights to the alteration spectrum of EGFR and its therapeutic and prognostic implications.Methods:The Cancer Genome Atlas(TCGA)datasets for 32 cancer types involving 11,314 patients were analyzed for alterations(mutations and amplification/deletion),abnormal expression and DNA methylation in EGFR gene.Mutation frequency,genomic location distribution,functional impact,and clinical targeted therapy implication were compared among different cancer types,and their associations with patient survival were analyzed.Results:EGFR alteration frequency,mutation sites across functional domains,amplification,overexpression,and DNA methylation patterns differed greatly among different cancer types.The overall mutation frequency in all cancers combined was relatively low.Targetable mutations,mainly in lung cancer,were primarily found in the Pkinase_Tyr domain.Glioblastoma multiforme had the highest rate of alterations,but it was dominated by gene amplification and most mutations were in the Furin-like domain where targeted therapy was less effective.Low-grade glioma often had gene amplification and increased EGFR expression which was associated with poor outcome.Colon and pancreatic adenocarcinoma had very few EGFR mutations;however,high EGFR expression was significantly associated with short patient survival.Squamous cell carcinoma regardless of their sites(the head and neck,lung,or esophagus)exhibited similar characteristics with an alteration frequency of about 5.0%,was dominated by gene amplification,and had increased EGFR expression generally associated with short patient survival.DNA methylation was highly associated with EGFR expression and patient outcomes in some cancers.Conclusions:EGFR aberration type,frequency,distribution in functional domains,and expression vary from cancer to cancer.While mutations in the Pkinase_Tyr domain are more important for treatment selection,increased expression from amplification or deregulation affects more tumor types and leads to worse outcome,which calls for new treatment strategies for these EGFR-driven tumors.
文摘Tumor development is a process involving loss of the differentiation phenotype and acquisition of stem-like characteristics,which is driven by intracellular rewiring of signaling network.The measurement of network reprogramming and disorder would be challenging due to the complexity and heterogeneity of tumors.Here,we proposed signaling entropy(SR)to assess the degree of tumor network disorder.We calculated SR for 33 tumor types in The Cancer Genome Atlas database based on transcrip-tomic and proteomic data.The SR of tumors was significantly higher than that of normal samples and was highly correlated with cell sternness,cancer type,tumor grade,and metastasis.We further demonstrated the sensitivity and accuracy of using local SR in prognosis prediction and drug response evaluation.Overall,SR could reveal cancer network disorders related to tumor malignant potency,clinical prognosis,and drug response.
基金supported by grants from the National Natural Science Foundation of China(82071782)the Shanghai Committee of Science and Technology(20XD1400800)to JL.
文摘The DEAD-box RNA helicase(DDX)family plays a critical role in the growth and development of multiple organisms.DDX1 is involved in mRNA/rRNA processing and mature,virus replication and transcription,hormone metabolism,tumo-rigenesis,and tumor development.However,how DDX1 functions in various cancers remains unclear.Here,we explored the potential oncogenic roles of DDX1 across 33 tumors with The Cancer Genome Atlas(TCGA)and the Genotype-Tissue Expression(GTEx)databases.DDX1 is highly expressed in breast cancer(BRCA),cholangiocarcinoma(CHOL),and colon adenocarcinoma(COAD),but it is lowly expressed in renal cancers,including kidney renal clear cell carcinoma(KIRC),kidney chromophobe(KICH),and kidney renal papillary cell carcinoma(KIRP).Low expression of DDX1 in KIRC is cor-related with a good prognosis of overall survival(OS)and disease-free survival(DFS).Highly expressed DDX1 is linked to a poor prognosis of OS for adrenocortical carcinoma(ACC),bladder urothelial carcinoma(BLCA),KICH,and liver hepatocellular carcinoma(LIHC).Also,the residue Ser481 of DDX1 had an enhanced phosphorylation level in BRCA and ovarian cancer(OV)but decreased in KIRC.Immune infiltration analysis exhibited that DDX1 expression affected CD8+T cells,and it was significantly associated with MSI(microsatellite instability),TMB(tumor mutational burden),and ICT(immune checkpoint blockade therapy)in tumors.In addition,the depletion of DDX1 dramatically affected the cell viability of human tumor-derived cell lines.DDX1 could affect the DNA repair pathway and the RNA transport/DNA replication processes during tumorigenesis by analyzing the CancerSEA database.Thus,our pan-cancer analysis revealed that DDX1 had complicated impacts on different cancers and might act as a prognostic marker for cancers such as renal cancer.
基金Supported by The 2021 Central-Guided Local Science and Technology Development FundLanzhou COVID-19 Prevention and Control Technology Research Project,No.2020-XG-1Gansu Province Outstanding Graduate Student"Innovation Star"Project,No.2022CXZX-748,No.2022CXZX-746.
文摘BACKGROUND The pyruvate dehydrogenase E1 subunitβ(PDHB)gene which regulates energy metabolism is located in mitochondria.However,few studies have elucidated the role and mechanism of PDHB in different cancers.AIM To comprehensive pan-cancer analysis of PDHB was performed based on bioinformatics approaches to explore its tumor diagnostic and prognostic value and tumor immune relevance in cancer.In vitro experiments were performed to examine the biological regulation of PDHB in liver cancer.METHODS Pan-cancer data related to PDHB were obtained from the Cancer Genome Atlas(TCGA)database.Analysis of the gene expression profiles of PDHB was based on TCGA and Genotype Tissue Expression Dataset databases.Cox regression analysis and Kaplan-Meier methods were used to assess the correlation between PDHB expression and survival prognosis in cancer patients.The correlation between PDHB and receiver operating characteristic diagnostic curve,clinicopathological staging,somatic mutation,tumor mutation burden(TMB),microsatellite instability(MSI),DNA methylation,and drug susceptibility in pan-cancer was also analyzed.Various algorithms were used to analyze the correlation between PDHB and immune cell infiltration and tumor chemotaxis environment,as well as the co-expression analysis of PDHB and immune checkpoint(ICP)genes.The expression and functional phenotype of PDHB in single tumor cells were studied by single-cell sequencing,and the functional enrichment analysis of PDHB-related genes was performed.The study also validated the level of mRNA or protein expression of PDHB in several cancers.Finally,in vitro experiments verified the regulatory effect of PDHB on the proliferation,migration,and invasion of liver cancer.RESULTS PDHB was significantly and differently expressed in most cancers.PDHB was significantly associated with prognosis in patients with a wide range of cancers,including kidney renal clear cell carcinoma,kidney renal papillary cell carcinoma,breast invasive carcinoma,and brain lower grade glioma.In some cancers,PDHB expression was clearly associated with gene mutations,clinicopathological stages,and expression of TMB,MSI,and ICP genes.The expression of PDHB was closely related to the infiltration of multiple immune cells in the immune microenvironment and the regulation of tumor chemotaxis environment.In addition,single-cell sequencing results showed that PDHB correlated with different biological phenotypes of multiple cancer single cells.This study further demonstrated that down-regulation of PDHB expression inhibited the proliferation,migration,and invasion functions of hepatoma cells.CONCLUSION As a member of pan-cancer,PDHB may be a novel cancer marker with potential value in diagnosing cancer,predicting prognosis,and in targeted therapy.
