Background:The relationship between microRNA(miRNA)expression patterns and tumor mutation burden(TMB)in uterine corpus endometrial carcinoma(UCEC)was investigated in this study.Methods:The UCEC dataset from The Cancer...Background:The relationship between microRNA(miRNA)expression patterns and tumor mutation burden(TMB)in uterine corpus endometrial carcinoma(UCEC)was investigated in this study.Methods:The UCEC dataset from The Cancer Genome Atlas(TCGA)database was used to identify the miRNAs that differ in expression between high TMB and low TMB sample sets.The total sample sets were divided into a training set and a test set.TMB levels were predicted using miRNA-based signature classifiers developed by Lasso Cox regression.Test sets were used to validate the classifier.This study investigated the relationship between a miRNA-based signature classifier and three immune checkpoint molecules(programmed cell death protein 1[PD-1],programmed cell death ligand 1[PD-L1],cytotoxic T lymphocyte-associated antigen 4[CTLA-4]).For the miRNA-based signature classifier,functional enrichment analysis was performed on the miRNAs.An analysis of the relationship between PD-1,PD-L1,and CTLA-4 immune checkpoint genes was carried out using the miRNA-based signature classifier.Results:We identified 27 differentially expressed miRNAs in miRNA-base signature.For predicting the TMB level,27-miRNA-based signature classifiers had accuracies of 0.8689 in the training cohort,0.8276 in the test cohort,and 0.8524 in the total cohort.The correlation between the miRNA-based signature classifier and PD-1 was negative,while the correlation between PD-L1 and CTLA4 was positive.Based on the miRNA profiling described above,we validated the expression levels of 9 miRNAs in clinical samples by quantitative reverse transcription PCR(qRT-PCR).Four of them were highly expressed and many cancer-related and immune-associated biological processes were linked to these 27 miRNAs.Thus,the developed miRNA-based signature classifier was correlated with TMB levels that could also predict TMB levels in UCEC samples.Conclusion:In this study,we investigated the relationship between a miRNAbased signature classifier and TMB levels in Uterine Corpus Endometrial Carcinoma.Further,this is the first study to confirm their relationship in clinical samples,which may provide more evidence support for immunotherapy of endometrial cancer.展开更多
Neuroendocrine neoplasm of the pancreas is a rare tumor with limited treatment options.Among such tumors,treatment for pancreatic neuroendocrine tumor(PanNET)G3 is the most difficult.Temozolomide(TMZ)is commonly used ...Neuroendocrine neoplasm of the pancreas is a rare tumor with limited treatment options.Among such tumors,treatment for pancreatic neuroendocrine tumor(PanNET)G3 is the most difficult.Temozolomide(TMZ)is commonly used to treat PanNET.However,TMZ may cause tumor gene alkylation,which induces drug resistance and rapid disease progression.Herein,we present a case of a female who was diagnosed with PanNET G3 and achieved a partial response to toripalimab,an anti-programmed cell death-ligand 1(anti-PD-L1)monoclonal antibody,after multiple cycles of TMZ treatment.Genomic profiling revealed that compared with the patient’s samples collected at baseline,the postTMZ-treatment samples had markedly higher levels of tumor mutational burden(TMB)associated with characteristic alkylating mutational signature representing a positive correlation with favorable response to anti-PD-1 treatment.In addition,we observed a germline truncating mutation of MUTYH(W156*)that was considered to be pathogenic and potentially conferred to genomic instability.This case suggests that anti-PD-1 therapy could be a treatment option for PanNET patients with increased TMB after TMZ-based treatment.展开更多
Background:Tumour mutational burden(TMB)has emerged as a predictive marker for responsiveness to immune checkpoint inhibitors(ICI)in multiple tumour types.It can be calculated from somatic mutations detected from whol...Background:Tumour mutational burden(TMB)has emerged as a predictive marker for responsiveness to immune checkpoint inhibitors(ICI)in multiple tumour types.It can be calculated from somatic mutations detected from whole exome or targeted panel sequencing data.As mutations are unevenly distributed across the cancer genome,the clinical implications from TMB calculated using different genomic regions are not clear.Methods:Pan-cancer data of 10,179 samples were collected from The Cancer Genome Atlas cohort and 6,831 cancer patients with either ICI or non-ICI treatment outcomes were derived from published papers.TMB was calculated as the count of non-synonymous mutations and normalised by the size of genomic regions.Dirichlet method,linear regression and Poisson calibration models are used to unify TMB from different gene panels.Results:We found that panels based on cancer genes usually overestimate TMB compared to whole exome,potentially leading to misclassification of patients to receive ICI.The overestimation is caused by positive selection for mutations in cancer genes and cannot be completely addressed by the removal of mutational hotspots.We compared different approaches to address this discrepancy and developed a generalised statistical model capable of interconverting TMB derived from whole exome and different panel sequencing data,enabling TMB correction for patient stratification for ICI treatment.We show that in a cohort of lung cancer patients treated with ICI,when using a TMB cutoffof 10 mut/Mb,our corrected TMB outperforms the original panel-based TMB.Conclusion:Cancer gene-based panels usually overestimate TMB,and these findings will be valuable for unifying TMB calculations across cancer gene panels in clinical practice.展开更多
BACKGROUND Tumor mutational burden(TMB)is an important independent biomarker for the response to immunotherapy in multiple cancers.However,the clinical implications of TMB in gastric cancer(GC)have not been fully eluc...BACKGROUND Tumor mutational burden(TMB)is an important independent biomarker for the response to immunotherapy in multiple cancers.However,the clinical implications of TMB in gastric cancer(GC)have not been fully elucidated.AIM To explore the landscape of mutation profiles and determine the correlation between TMB and microRNA(miRNA)expression in GC.METHODS Genomic,transcriptomic,and clinical data from The Cancer Genome Atlas were used to obtain mutational profiles and investigate the statistical correlation between mutational burden and the overall survival of GC patients.The difference in immune infiltration between high-and low-TMB subgroups was evaluated by Wilcoxon rank-sum test.Furthermore,miRNAs differentially expressed between the high-and low-TMB subgroups were identified and the least absolute shrinkage and selection operator method was employed to construct a miRNA-based signature for TMB prediction.The biological functions of the predictive miRNAs were identified with DIANA-miRPath v3.0.RESULTS C>T single nucleotide mutations exhibited the highest mutation incidence,and the top three mutated genes were TTN,TP53,and MUC16 in GC.High TMB values(top 20%)were markedly correlated with better survival outcome,and multivariable regression analysis indicated that TMB remained prognostic independent of TNM stage,histological grade,age,and gender.Different TMB levels exhibited different immune infiltration patterns.Significant differences between the high-and low-TMB subgroups were observed in the infiltration of CD8+T cells,M1 macrophages,regulatory T cells,and CD4+T cells.In addition,we developed a miRNA-based signature using 23 differentially expressed miRNAs to predict TMB values of GC patients.The predictive performance of the signature was confirmed in the testing and the whole set.Receiver operating characteristic curve analysis demonstrated the optimal performance of the signature.Finally,enrichment analysis demonstrated that the set of miRNAs was significantly enriched in many key cancer and immune-related pathways.展开更多
Background:Receptor-interacting protein kinases(RIPKs)regulate cell death,inflammation,and immune responses,yet their roles in cancer are not fully understood.This study investigates the expression,genomic alterations...Background:Receptor-interacting protein kinases(RIPKs)regulate cell death,inflammation,and immune responses,yet their roles in cancer are not fully understood.This study investigates the expression,genomic alterations,and functional implications of RIPK family members across various cancers.Methods:We collected multi-omics data from The Cancer Genome Atlas and other public databases,including gene expression,copy number variation(CNV),mutation,methylation,tumor mutation burden(TMB),and microsatellite instability(MSI).Differential expression and survival analyses were performed using DESeq2 and Cox proportional hazards models.CNV and mutation data were analyzed with GISTIC2 and Mutect2,and methylation data with the ChAMP package.Correlations with TMB and MSI were assessed using Pearson coefficients,and gene set enrichment analysis was conducted with the MSigDB Hallmark gene sets.Results:RIPK family members show significant differential expression in various cancers,with RIPK1 and RIPK4 frequently altered.Survival analysis reveals heterogeneous impacts on overall survival.CNV and mutation analyses identify high alteration frequencies for RIPK2 and RIPK7,affecting gene expression.RIPK1 and RIPK7 are hypermethylated in several cancers,inversely correlating with RIPK3 expression.RIPK1,RIPK2,RIPK5,RIPK6,and RIPK7 correlate positively with TMB,while RIPK3 shows negative correlations in some cancers.MSI analysis indicates associations with DNA mismatch repair.G ene set enrichment analysis highlights immune-related pathway enrichment for RIPK1,RIPK2,RIPK3,and RIPK6,and cell proliferation and DNA repair pathways for RIPK4 and RIPK5.RIPK family members showed heterogeneous alterations across cancers:for example,RIPK7 was mutated in up to~15%of u terine c orpus e ndometrial c arcinoma and l ung s quamous c ell c arcinoma cases,and RIPK1 and RIPK7 exhibited frequent promoter hypermethylation in multiple tumor types.Several genes displayed context-dependent associations with overall survival and with TMB/MSI.Conclusion:This pan-cancer analysis of the RIPK family reveals their diverse roles and potential as biomarkers and therapeutic targets.The findings emphasize the importance of RIPK genes in tumorigenesis and suggest context-dependent functions across cancer types.Further studies are needed to explore their mechanisms in cancer development and clinical applications.展开更多
BACKGROUND Intrahepatic cholangiocarcinoma(ICC)is malignancies of the biliary duct system and constitutes approximately 10%-20%of all primary liver cancers.Tumor mutation burden(TMB)is a useful biomarker across many c...BACKGROUND Intrahepatic cholangiocarcinoma(ICC)is malignancies of the biliary duct system and constitutes approximately 10%-20%of all primary liver cancers.Tumor mutation burden(TMB)is a useful biomarker across many cancer types for the identification of patients who will benefit from immunotherapy.Despite the role of TMB in calculating the effectiveness and prognosis of immune checkpoint inhibitors has been confirmed in multiple human cancer types,the prognostic value of TMB in ICC patients is rare investigated.AIM To investigate the prognostic value of TMB in patients with ICC.METHODS Data of 412 patients with ICC were included in the study.TMB was calculated as the total number of somatic non-silent protein-coding mutations divided by the coding region.The Kaplan-Meier method was used to analyze overall survival(OS),and relapse free survival(RFS).The cut-off value of TMB was determined by time-dependent receiver operating characteristic(ROC)curve.Cox regression was performed for multivariable analysis of OS.The nomogram and calibration curve were analyzed to construct and evaluate the prognostic model.RESULTS In the analysis of the time-dependent ROC curve,we defined 3.1 mut/Mb as the cut-off value of TMB.The Kaplan-Meier plot revealed that patients with high TMB had poor OS(HR=1.47,P=0.002)and RFS(HR=1.42,P=0.035).Cox regression analysis also demonstrated that TMB was an independent risk predictor for ICC(HR=1.43,P=0.0240).Furthermore,independent prognostic factors of ICC included CA19-9(HR=1.78,P=0.0005),chronic viral hepatitis(HR=1.72,P=0.0468),tumor resection(HR=2.58,P<0.0001)and disease progression(metastatic disease vs.solitary liver tumor;HR=2.55,P=0.0002).The nomogram and calibration curve also indicated the effectiveness of the constructed prognostic model.CONCLUSION TMB was an independent prognostic biomarker in patients with ICC.Moreover,patients with ICC with high TMB had poor OS and RFS as compared to those with low TMB.展开更多
BACKGROUND Ferroptosis has recently been associated with multiple degenerative diseases.Ferroptosis induction in cancer cells is a feasible method for treating neoplastic diseases.However,the association of iron proli...BACKGROUND Ferroptosis has recently been associated with multiple degenerative diseases.Ferroptosis induction in cancer cells is a feasible method for treating neoplastic diseases.However,the association of iron proliferation-related genes with prognosis in HER2+breast cancer(BC)patients is unclear.AIM To identify and evaluate fresh ferroptosis-related biomarkers for HER2+BC.METHODS First,we obtained the mRNA expression profiles and clinical information of HER2+BC patients from the TCGA and METABRIC public databases.A four gene prediction model comprising PROM2,SLC7A11,FANCD2,and FH was subsequently developed in the TCGA cohort and confirmed in the METABRIC cohort.Patients were stratified into high-risk and low-risk groups based on their median risk score,an independent predictor of overall survival(OS).Based on these findings,immune infiltration,mutations,and medication sensitivity were analyzed in various risk groupings.Additionally,we assessed patient prognosis by combining the tumor mutation burden(TMB)with risk score.Finally,we evaluated the expression of critical genes by analyzing single-cell RNA sequencing(scRNA-seq)data from malignant vs normal epithelial cells.RESULTS We found that the higher the risk score was,the worse the prognosis was(P<0.05).We also found that the immune cell infiltration,mutation,and drug sensitivity were different between the different risk groups.The highrisk subgroup was associated with lower immune scores and high TMB.Moreover,we found that the combination of the TMB and risk score could stratify patients into three groups with distinct prognoses.HRisk-HTMB patients had the worst prognosis,whereas LRisk-LTMB patients had the best prognosis(P<0.0001).Analysis of the scRNAseq data showed that PROM2,SLC7A11,and FANCD2 were significantly differentially expressed,whereas FH was not,suggesting that these genes are expressed mainly in cancer epithelial cells(P<0.01).CONCLUSION Our model helps guide the prognosis of HER2+breast cancer patients,and its combination with the TMB can aid in more accurate assessment of patient prognosis and provide new ideas for further diagnosis and treatment.展开更多
BACKGROUND Gallbladder cancer is a highly malignant and aggressive tumor,often diagnosed at an advanced stage.The prognosis for advanced gallbladder cancer remains poor,with limited options for effective treatment.CAS...BACKGROUND Gallbladder cancer is a highly malignant and aggressive tumor,often diagnosed at an advanced stage.The prognosis for advanced gallbladder cancer remains poor,with limited options for effective treatment.CASE SUMMARY A 65-year-old male patient presented with a soft tissue mass in the gallbladder.Following laparoscopic exploration,he underwent radical surgery for gallbladder cancer,with the tumor staged as pT2N1M0(stage III).Post-surgery,the patient received four cycles of adjuvant chemotherapy.However,one month later,over 60 metastatic lesions were detected in the liver,lungs,and lymph nodes.In response to the widespread metastasis,he underwent six cycles of combination therapy consisting of sintilimab,albumin-bound paclitaxel,and cisplatin.After two cycles,a partial response was achieved.Maintenance therapy was initiated with a combination of sintilimab and albumin-bound paclitaxel for four cycles.Monotherapy with sintilimab was continued thereafter until October 2023.Complete remission was confirmed in September 2021.The patient sustained this complete response for more than three years,including an eleven-month period without disease progression following the discontinuation of sintilimab.Genetic analysis revealed a tumor mutational burden of 15.4 mutations/megabase,which indicates a potentially favorable response to immunotherapy.CONCLUSION This case demonstrates the potential of combining immunotherapy(sintilimab)with chemotherapy to achieve durable remission in metastatic gallbladder cancer,even in a patient with extensive metastasis.In addition,it indicated the importance of tumor mutational burden as a predictive biomarker of immunotherapy.展开更多
Objective:The plastic role of regulatory factor X1(RFX1)in colon cancer progression and its impact on the tumor microenvironment remain poorly understood.The study aimed to clarify the molecular and clinical role of R...Objective:The plastic role of regulatory factor X1(RFX1)in colon cancer progression and its impact on the tumor microenvironment remain poorly understood.The study aimed to clarify the molecular and clinical role of RFX1 in colon cancer.Methods:We classified colon cancers into subgroups with high and low RFX1 expression and characterized their immune profiles,mutational profiles,cancer immunotherapy and drug sensitivity.By combining RFX1 expression with persistent tumor mutational burden,we proposed a novel nomogram clinical prediction model and validated its predictive performance,and the correlation between high expression and poor prognosis.Results:Compared to tumor mutational burden(TMB),persistent tumor mutational burden(pTMB)is an independent predictor of prognosis in patients with colon cancer.The predictive efficacy of the combination of RFX1 expression and pTMB was superior to and sensitive than the combination of RFX1 expression with TMB.Among them,patients in the RFX1^(high)/pTMB^(high) subgroup had the worst quality of survival and prognosis,whereas those in the RFX1low/pTMBlow subgroup had a relatively better prognosis(p<0.0001).Univariate Cox regression revealed a significant association between high RFX1 expression and increased risk in colon cancer patients(Hazard Ratio[HR]=1.58,95%Confidence Interval[CI]:1.10–2.25,p=0.012),which remained independently predictive in multivariate analysis after covariate adjustment(HR=1.52,95%CI:1.04–2.22,p=0.031).Conclusion:A nomogram model based on RFX1 combined with pTMB provides an alternative approach for the diagnosis and treatment of colon cancer.展开更多
Pancreatic ductal adenocarcinoma(PDAC)remains one of the most lethal ma-lignancies with limited treatment efficacy.Advances in precision oncology,enabled by next-generation sequencing,have highlighted key molecular ta...Pancreatic ductal adenocarcinoma(PDAC)remains one of the most lethal ma-lignancies with limited treatment efficacy.Advances in precision oncology,enabled by next-generation sequencing,have highlighted key molecular targets.Kirsten rat sarcoma viral oncogene homolog mutations,present in up to 90%of cases,drive aggressive biology,though most variants remain undruggable;allele-specific inhibitors and exosome-based RNA interference are under exploration.Breast cancer susceptibility gene 1/2 mutations occur in 4%-7%of patients,con-ferring sensitivity to platinum agents and poly(ADP-ribose)polymerase inhi-bitors.Other rare but actionable alterations-such as v-raf murine sarcoma viral oncogene homolog B1(V600),neurotrophic tyrosine receptor kinase,fibroblast growth factor receptor 2,and RET fusions-show benefit in tumor-agnostic trials,broadening options for selected subgroups.Immunotherapy is limited,as high tumor mutational burden and mismatch repair deficiency are uncommon in PDAC,though predictive when present.Co-mutations in tumor protein p53,cyclin-dependent kinase inhibitor 2A,and SMAD4 further stratify prognosis and influence therapy response.Cross-cancer analyses underscore the necessity of PDAC-specific strategies despite shared genomic drivers.Collectively,these insights support routine germline and somatic testing,enrollment in biomarker-matched trials,and rational combination strategies,establishing molecular profiling as central to advancing precision treatment in pancreatic cancer.展开更多
BACKGROUND There has been no report to use camrelizumab with chemotherapy for advanced bladder cancer patients with positive programmed death-ligand 1(PD-L1)expression and high tumor mutational burden(TMB).More effect...BACKGROUND There has been no report to use camrelizumab with chemotherapy for advanced bladder cancer patients with positive programmed death-ligand 1(PD-L1)expression and high tumor mutational burden(TMB).More effective predictors of bladder cancer immunotherapy have yet to be explored,and the combination of multiple factors may be more predictive than a single factor.CASE SUMMARY We report the case of a 74-year-old male patient with recurrent metastatic bladder cancer,which demonstrated positive PD-L1 expression and high TMB.The immune checkpoint inhibitor camrelizumab was administered to the patient in combination with gemcitabine and cisplatin.The patient achieved a partial response with a progression-free survival of 11 mo.CONCLUSION This is the first report to use camrelizumab with chemotherapy for advanced bladder cancer patients with positive PD-L1 expression and high TMB.展开更多
Bile duct tumors are comprised of tumors that originate from both intrahepatic and extrahepatic bile ducts and gallbladder tumors.These are aggressive tumors and chemotherapy is still the main treatment for advanced-s...Bile duct tumors are comprised of tumors that originate from both intrahepatic and extrahepatic bile ducts and gallbladder tumors.These are aggressive tumors and chemotherapy is still the main treatment for advanced-stage disease and most of these cases have a poor overall survival.Strategies are aimed at treatments with better outcomes and less toxicity which makes immunotherapy an area of significant importance.Recent Food and Drug Administration approvals of immune checkpoint inhibitors(ICI)for agnostic tumors based on biomarkers such as microsatellite instability-high and tumor mutation burden-high are important steps in the treatment of patients with advanced bile duct tumors.Despite limited responses with isolated checkpoint inhibitors in later lines of systemic treatment in advanced disease,drug combination strategies have been demonstrating encouraging results to enhance ICI efficacy.展开更多
The COP9 signalosome subunit 6(COPS6)is abnormally overexpressed in many malignancies,yet its precise role in carcinogenesis is unknown.To gain a better understanding of COPS6's role,the authors conducted a pan-ca...The COP9 signalosome subunit 6(COPS6)is abnormally overexpressed in many malignancies,yet its precise role in carcinogenesis is unknown.To gain a better understanding of COPS6's role,the authors conducted a pan-cancer analysis using various bioinformatics techniques such as differential expression patterns,prognostic value,gene mutations,immune infiltration,correlation analysis,and functional enrichment assessment.Results showed that COPS6 was highly correlated with prognosis,immune cell infiltration level,tumor mutation burden,and microsatellite instability in patients with a range of tumor types.This suggests that COPS6 may be a potential target for cancer treatment.Overall,this research provides insight into COPS6's role in cancer development and its potential therapeutic applications.展开更多
BACKGROUND The COP9 signalosome subunit 6(COPS6)has been implicated in cancer progression,while its precise role in most types of cancer remains elusive.AIM To investigate the functional and clinical relevance of COPS...BACKGROUND The COP9 signalosome subunit 6(COPS6)has been implicated in cancer progression,while its precise role in most types of cancer remains elusive.AIM To investigate the functional and clinical relevance of COPS6 across various tumor types using publicly available databases.METHODS We used R software and online analysis databases to analyze the differential expression,prognosis,mutation and related functions of COPS6 in pan-cancer.RESULTS Differential expression analysis and survival analysis demonstrated that COPS6 was highly expressed and associated with high-risk profiles in the majority of cancer types.Possible associations between COPS6 expression level and prognostic outcomes were found using data from public databases.Mutational analysis revealed that missense mutations were the predominant type of COPS6 mutation.Additionally,positive correlations were identified between COPS6 expression level and tumor mutational burden and microsatellite instability in most types of cancer.Immune infiltration analysis demonstrated a negative correlation between COPS6 expression level and CD8+T cell infiltration in certain types of cancer.The correlation between COPS6 expression level and cancerassociated fibroblast infiltration exhibited heterogeneity,in which a positive correlation was found in head and neck squamous cell carcinoma and tenosynovial giant cell tumor,and a negative correlation was identified in diffuse large B-cell lymphoma and thymoma.The correlation between COPS6 expression level and macrophage infiltration was closely related to macrophage type.Gene co-expression and enrichment analysis highlighted transcription elongation factor B polypeptide 2 and G protein pathway suppressor 1 were significantly and positively associated with COPS6 expression level.These genes were predominantly involved in processes,such as ubiquitin-mediated proteolysis and human immunodeficiency virus 1 infection.CONCLUSION In conclusion,this study systematically explored the significance of COPS6 across different tumor types,providing a solid foundation for considering COPS6 as a novel biomarker in cancer research.展开更多
Background:The Fascin(FSCN)family,comprising actin-bundling proteins,plays vital roles in cytoskeletal reorganization and cell migration.FSCN1,FSCN2,and FSCN3 are implicated in cancer progression through cell motility...Background:The Fascin(FSCN)family,comprising actin-bundling proteins,plays vital roles in cytoskeletal reorganization and cell migration.FSCN1,FSCN2,and FSCN3 are implicated in cancer progression through cell motility,invasion,and metastasis.However,their specific contributions across different cancer types remain unclear.Methods:We conducted a pan-cancer bioinformatics analysis of FSCN genes using data from The Cancer Genome Atlas.This included differential expression patterns,copy number variations(CNVs),mutations,methylation status,and correlations with tumor mutational burden,microsatellite instability,and immune checkpoint molecule expression.Differential expression was analyzed using DESeq2,while CNV and mutation analyses utilized GISTIC2.0 and MuTect2.Methylation data were assessed using the Illumina Human Methylation 450K BeadChip.Results:FSCN1 and FSCN2 showed significant differential expression in multiple cancers,often correlating with poor prognosis.FSCN3 exhibited less variability but a protective role in certain contexts.CNV analysis indicated frequent gene gains in FSCN genes,correlating with increased expression.FSCN3 had a higher mutation rate,suggesting genetic instability.Methylation analysis showed hypomethylation of FSCN1 and FSCN2 in tumors compared to normal tissues,whereas FSCN3 had minor changes.Significant associations were found between FSCN gene expression and tumor mutational burden,microsatellite instability,and immune checkpoint molecules,suggesting their involvement in tumor immunogenicity and the immune microenvironment.Conclusions:This pan-cancer analysis highlights the multifaceted roles of FSCN genes in cancer biology,emphasizing their potential as biomarkers and therapeutic targets.FSCN1 and FSCN2 are associated with poor prognosis and aggressive phenotypes,while FSCN3 shows protective roles in specific contexts.These findings offer new avenues for cancer diagnosis and treatment,particularly in personalized medicine.Future studies should validate these findings and explore the underlying mechanisms to fully harness the clinical potential of FSCN family proteins in oncology.展开更多
Objective:DNA damage response(DDR)genes have low mutation rates,which may restrict their clinical applications in predicting the outcomes of immune checkpoint inhibitor(ICI)treatment.Thus,a systemic analysis of multip...Objective:DNA damage response(DDR)genes have low mutation rates,which may restrict their clinical applications in predicting the outcomes of immune checkpoint inhibitor(ICI)treatment.Thus,a systemic analysis of multiple DDR genes is needed to identify potential biomarkers of ICI efficacy.Methods:A total of 39,631 patients with mutation data were selected from the cBioPortal database.A total of 155 patients with mutation data were obtained from the Fudan University Shanghai Cancer Center(FUSCC).A total of 1,660 patients from the MSK-IMPACT cohort who underwent ICI treatment were selected for survival analysis.A total of 249 patients who underwent ICI treatment from the Dana-Farber Cancer Institute(DFCI)cohort were obtained from a published dataset.The Cancer Genome Atlas(TCGA)level 3 RNA-Seq version 2 RSEM data for gastric cancer were downloaded from cBioPortal.Results:Six MMR and 30 DDR genes were included in this study.Six MMR and 20 DDR gene mutations were found to predict the therapeutic efficacy of ICI,and most of them predicted the therapeutic efficacy of ICI,in a manner dependent on TMB,except for 4 combined DDR gene mutations,which were associated with the therapeutic efficacy of ICI independently of the TMB.Single MMR/DDR genes showed low mutation rates;however,the mutation rate of all the MMR/DDR genes associated with the therapeutic efficacy of ICI was relatively high,reaching 10%–30%in several cancer types.Conclusions:Coanalysis of multiple MMR/DDR mutations aids in selecting patients who are potential candidates for immunotherapy.展开更多
BACKGROUND Undifferentiated embryonal sarcoma of the liver(UESL)is a neoplasm that rarely develops in adults.The main treatments for UESL are upfront gross total surgical resection and adjuvant multiagent chemotherapy...BACKGROUND Undifferentiated embryonal sarcoma of the liver(UESL)is a neoplasm that rarely develops in adults.The main treatments for UESL are upfront gross total surgical resection and adjuvant multiagent chemotherapy.Here,we report a case of recurrent UESL in an adult treated with pembrolizumab and discuss a method to identify proper candidates for antibody of programmed cell death protein 1(anti-PD-1)treatment.CASE SUMMARY A 69-year-old woman was admitted for abdominal pain that developed for 1 wk.Computed tomography showed a 16 cm mass in the right lobe of the liver.Right hemihepatectomy and lymphadenectomy were performed,and histological diagnosis was UESL.Six months later,the patient suffered from painless obstructive jaundice,and positron emission tomography-computed tomography revealed multiple metastases.Then,percutaneous transhepatic cholangial drainage was applied to reduce jaundice,and radiofrequency ablation was used to control the lesion near the hepatic hilum.However,the patient suffered from a serious fever caused by the tumor.The patient received treatment with pembrolizumab,and the prescribed dosage was 2 mg/kg every 3 wk.After the seventh dose,positron emission tomography-computed tomography revealed that the multiple metastases had nearly disappeared.Radiologic exam was used to evaluate the disease state,and no new lesions were found.Next-generation sequencing and immunohistology were applied to determine the reason why the patient had such a favorable response to pembrolizumab.Tumor mutation burden,microsatellite instability,and programmed death ligand 1 expression can be combined to predict the effect of PD-1 antibodies. When every one of thesebiomarkers are detected in a tumor patient, the patient may be a proper candidatefor PD-1 antibodies.CONCLUSION Anti-PD-1 treatment for tumors needs further research to identify indications andproper biomarkers.展开更多
Gastrointestinal(GI) cancers prevail and account for an extremely high number of cancer deaths worldwide. The traditional treatment strategies, including surgery, chemotherapy, radiotherapy, and targeted therapy, have...Gastrointestinal(GI) cancers prevail and account for an extremely high number of cancer deaths worldwide. The traditional treatment strategies, including surgery, chemotherapy, radiotherapy, and targeted therapy, have a limited therapeutic effect for advanced GI cancers. Recently, immunotherapy has shown promise in treating various refractory malignancies, including the GI cancers with mismatch repair deficiency(dMMR) or microsatellite instability(MSI). Thus,immunotherapy could be a promising treatment approach for GI cancers.Unfortunately, only a small proportion of GI cancer patients currently respond to immunotherapy. Therefore, it is important to discover predictive biomarkers for stratifying GI cancer patients response to immunotherapy. Certain genomic features, such as dMMR/MSI, tumor mutation burden(TMB), and tumor aneuploidy have been associated with tumor immunity and im-munotherapy response and may serve as predictive biomarkers for cancer immunotherapy. In this review, we examined the correlations between tumor immunity and three genomic features: dMMR/MSI, TMB, and tumor aneuploidy. We also explored their correlations using The Cancer Genome Atlas data and confirmed that the dMMR/MSI status, high TMB, and low tumor aneuploidy are associated with elevated tumor immunity in GI cancers. To improve the immunotherapeutic potential in GI cancers, more genetic or genomic features associated with tumor immune response need to be identified. Furthermore, it is worth exploring the combination of different immunotherapeutic methods and the combination of immunotherapy with other therapeutic approaches for cancer therapy.展开更多
BACKGROUND Colon cancer is a common malignant disease of the gastrointestinal tract and usually occurs at the junction of the rectum and sigmoid colon.Lymphatic and hematogenous metastases occur frequently in colon ca...BACKGROUND Colon cancer is a common malignant disease of the gastrointestinal tract and usually occurs at the junction of the rectum and sigmoid colon.Lymphatic and hematogenous metastases occur frequently in colon cancer and the most common metastatic sites include the liver,lung,peritoneum,bone,and lymph nodes.As a manifestation of advanced tumor spread and metastasis,soft tissue metastasis,especially skeletal muscle metastasis with bone metaplasia caused by colon cancer,is rare,accounting for less than 1%of metastases.CASE SUMMARY A 43-year-old male patient developed skeletal muscle metastasis with bone metaplasia of the right proximal thigh 5 mo after colon cancer was diagnosed.The patient was admitted to the hospital because of pain caused by a local mass on his right thigh.Positron emission tomography-computed tomography showed many enlarged lymph nodes around the abdominal aorta but no signs of lung or liver metastases.Color ultrasound revealed a mass located in the skeletal muscle and the results of histological biopsy revealed a poorly differentiated adenocarcinoma suspected to be distant metastases from colon cancer.Immunohistochemistry showed small woven bone components that were considered to be ossified.CONCLUSION This case reminds us that for patients with advanced colorectal tumors,we should be alert to the possibility of unconventional metastasis.展开更多
ATP binding cassette subfamily C member 8(ABCC8)encodes a protein regulating the ATP-sensitive potassium channel.Whether the level of ABCC8 mRNA in lower grade glioma(LGG)correlates with immune cell infiltration and p...ATP binding cassette subfamily C member 8(ABCC8)encodes a protein regulating the ATP-sensitive potassium channel.Whether the level of ABCC8 mRNA in lower grade glioma(LGG)correlates with immune cell infiltration and patient outcomes has not been evaluated until now.Comparisons of ABCC8 expression between different tumors and normal tissues were evaluated by exploring publicly available datasets.The association between ABCC8 and tumor immune cell infiltration,diverse gene mutation characteristics,tumor mutation burden(TMB),and survival in LGG was also investigated in several independent datasets.Pathway enrichment analysis was conducted to search for ABCC8-associated signaling pathways.Through an online database,we found that ABCC8 expression in LGG was lower than in normal tissues.Then,the association of ABCC8 expression and immune cell infiltration in LGG was discussed.As we expected,the ABCC8 mRNA levels were negatively associated with non-T immune cell infiltration levels in all datasets.Consistently,TCGA_LGG RNA-seq data revealed that ABCC8 downregulated several non-T immune cell-associated signaling pathways in gene set enrichment analysis.Different ABCC8 expression groups showed diverse gene mutation characteristics and TMB.The high expression of ABCC8 was linked to improved survival of LGG patients.A pathway enrichment analysis of ABCC8-associated genes indicated that the GABAergic synapse signaling pathway might be involved in regulating immunity in LGG.Our findings show that ABCC8 reflects LGG tumor immunity and is an ideal prognostic biomarker for LGG.展开更多
基金the National Natural Science Foundation(81803877,82104705)the Natural Science Foundation of Guangdong Province of China(2017A030310178)+5 种基金the Guangdong Sci-Tech Commissioner(20211800500322)the China Postdoctoral Science Foundation(2020M682817)Guangdong Basic and Applied Basic Research Foundation(2020A1515110651,2020B1515120063)Guangdong Medical Science and Technology Research Foundation(A2021476)Traditional Chinese Medicine Research Project of Guangdong Province Traditional Chinese Medicine Bureau(20221256)the Dongguan Social Technology Development Fund(202050715001207).
文摘Background:The relationship between microRNA(miRNA)expression patterns and tumor mutation burden(TMB)in uterine corpus endometrial carcinoma(UCEC)was investigated in this study.Methods:The UCEC dataset from The Cancer Genome Atlas(TCGA)database was used to identify the miRNAs that differ in expression between high TMB and low TMB sample sets.The total sample sets were divided into a training set and a test set.TMB levels were predicted using miRNA-based signature classifiers developed by Lasso Cox regression.Test sets were used to validate the classifier.This study investigated the relationship between a miRNA-based signature classifier and three immune checkpoint molecules(programmed cell death protein 1[PD-1],programmed cell death ligand 1[PD-L1],cytotoxic T lymphocyte-associated antigen 4[CTLA-4]).For the miRNA-based signature classifier,functional enrichment analysis was performed on the miRNAs.An analysis of the relationship between PD-1,PD-L1,and CTLA-4 immune checkpoint genes was carried out using the miRNA-based signature classifier.Results:We identified 27 differentially expressed miRNAs in miRNA-base signature.For predicting the TMB level,27-miRNA-based signature classifiers had accuracies of 0.8689 in the training cohort,0.8276 in the test cohort,and 0.8524 in the total cohort.The correlation between the miRNA-based signature classifier and PD-1 was negative,while the correlation between PD-L1 and CTLA4 was positive.Based on the miRNA profiling described above,we validated the expression levels of 9 miRNAs in clinical samples by quantitative reverse transcription PCR(qRT-PCR).Four of them were highly expressed and many cancer-related and immune-associated biological processes were linked to these 27 miRNAs.Thus,the developed miRNA-based signature classifier was correlated with TMB levels that could also predict TMB levels in UCEC samples.Conclusion:In this study,we investigated the relationship between a miRNAbased signature classifier and TMB levels in Uterine Corpus Endometrial Carcinoma.Further,this is the first study to confirm their relationship in clinical samples,which may provide more evidence support for immunotherapy of endometrial cancer.
文摘Neuroendocrine neoplasm of the pancreas is a rare tumor with limited treatment options.Among such tumors,treatment for pancreatic neuroendocrine tumor(PanNET)G3 is the most difficult.Temozolomide(TMZ)is commonly used to treat PanNET.However,TMZ may cause tumor gene alkylation,which induces drug resistance and rapid disease progression.Herein,we present a case of a female who was diagnosed with PanNET G3 and achieved a partial response to toripalimab,an anti-programmed cell death-ligand 1(anti-PD-L1)monoclonal antibody,after multiple cycles of TMZ treatment.Genomic profiling revealed that compared with the patient’s samples collected at baseline,the postTMZ-treatment samples had markedly higher levels of tumor mutational burden(TMB)associated with characteristic alkylating mutational signature representing a positive correlation with favorable response to anti-PD-1 treatment.In addition,we observed a germline truncating mutation of MUTYH(W156*)that was considered to be pathogenic and potentially conferred to genomic instability.This case suggests that anti-PD-1 therapy could be a treatment option for PanNET patients with increased TMB after TMZ-based treatment.
基金supported by the Research Grants Council,HK(grant number:17100920)seed funding from The University of Hong Kong.
文摘Background:Tumour mutational burden(TMB)has emerged as a predictive marker for responsiveness to immune checkpoint inhibitors(ICI)in multiple tumour types.It can be calculated from somatic mutations detected from whole exome or targeted panel sequencing data.As mutations are unevenly distributed across the cancer genome,the clinical implications from TMB calculated using different genomic regions are not clear.Methods:Pan-cancer data of 10,179 samples were collected from The Cancer Genome Atlas cohort and 6,831 cancer patients with either ICI or non-ICI treatment outcomes were derived from published papers.TMB was calculated as the count of non-synonymous mutations and normalised by the size of genomic regions.Dirichlet method,linear regression and Poisson calibration models are used to unify TMB from different gene panels.Results:We found that panels based on cancer genes usually overestimate TMB compared to whole exome,potentially leading to misclassification of patients to receive ICI.The overestimation is caused by positive selection for mutations in cancer genes and cannot be completely addressed by the removal of mutational hotspots.We compared different approaches to address this discrepancy and developed a generalised statistical model capable of interconverting TMB derived from whole exome and different panel sequencing data,enabling TMB correction for patient stratification for ICI treatment.We show that in a cohort of lung cancer patients treated with ICI,when using a TMB cutoffof 10 mut/Mb,our corrected TMB outperforms the original panel-based TMB.Conclusion:Cancer gene-based panels usually overestimate TMB,and these findings will be valuable for unifying TMB calculations across cancer gene panels in clinical practice.
基金Supported by National Key Development Plan for Precision Medicine Research,No.2017YFC0910002.
文摘BACKGROUND Tumor mutational burden(TMB)is an important independent biomarker for the response to immunotherapy in multiple cancers.However,the clinical implications of TMB in gastric cancer(GC)have not been fully elucidated.AIM To explore the landscape of mutation profiles and determine the correlation between TMB and microRNA(miRNA)expression in GC.METHODS Genomic,transcriptomic,and clinical data from The Cancer Genome Atlas were used to obtain mutational profiles and investigate the statistical correlation between mutational burden and the overall survival of GC patients.The difference in immune infiltration between high-and low-TMB subgroups was evaluated by Wilcoxon rank-sum test.Furthermore,miRNAs differentially expressed between the high-and low-TMB subgroups were identified and the least absolute shrinkage and selection operator method was employed to construct a miRNA-based signature for TMB prediction.The biological functions of the predictive miRNAs were identified with DIANA-miRPath v3.0.RESULTS C>T single nucleotide mutations exhibited the highest mutation incidence,and the top three mutated genes were TTN,TP53,and MUC16 in GC.High TMB values(top 20%)were markedly correlated with better survival outcome,and multivariable regression analysis indicated that TMB remained prognostic independent of TNM stage,histological grade,age,and gender.Different TMB levels exhibited different immune infiltration patterns.Significant differences between the high-and low-TMB subgroups were observed in the infiltration of CD8+T cells,M1 macrophages,regulatory T cells,and CD4+T cells.In addition,we developed a miRNA-based signature using 23 differentially expressed miRNAs to predict TMB values of GC patients.The predictive performance of the signature was confirmed in the testing and the whole set.Receiver operating characteristic curve analysis demonstrated the optimal performance of the signature.Finally,enrichment analysis demonstrated that the set of miRNAs was significantly enriched in many key cancer and immune-related pathways.
基金supported by grants from the Tianjin Health Technology Project(Grant no.2022QN106).
文摘Background:Receptor-interacting protein kinases(RIPKs)regulate cell death,inflammation,and immune responses,yet their roles in cancer are not fully understood.This study investigates the expression,genomic alterations,and functional implications of RIPK family members across various cancers.Methods:We collected multi-omics data from The Cancer Genome Atlas and other public databases,including gene expression,copy number variation(CNV),mutation,methylation,tumor mutation burden(TMB),and microsatellite instability(MSI).Differential expression and survival analyses were performed using DESeq2 and Cox proportional hazards models.CNV and mutation data were analyzed with GISTIC2 and Mutect2,and methylation data with the ChAMP package.Correlations with TMB and MSI were assessed using Pearson coefficients,and gene set enrichment analysis was conducted with the MSigDB Hallmark gene sets.Results:RIPK family members show significant differential expression in various cancers,with RIPK1 and RIPK4 frequently altered.Survival analysis reveals heterogeneous impacts on overall survival.CNV and mutation analyses identify high alteration frequencies for RIPK2 and RIPK7,affecting gene expression.RIPK1 and RIPK7 are hypermethylated in several cancers,inversely correlating with RIPK3 expression.RIPK1,RIPK2,RIPK5,RIPK6,and RIPK7 correlate positively with TMB,while RIPK3 shows negative correlations in some cancers.MSI analysis indicates associations with DNA mismatch repair.G ene set enrichment analysis highlights immune-related pathway enrichment for RIPK1,RIPK2,RIPK3,and RIPK6,and cell proliferation and DNA repair pathways for RIPK4 and RIPK5.RIPK family members showed heterogeneous alterations across cancers:for example,RIPK7 was mutated in up to~15%of u terine c orpus e ndometrial c arcinoma and l ung s quamous c ell c arcinoma cases,and RIPK1 and RIPK7 exhibited frequent promoter hypermethylation in multiple tumor types.Several genes displayed context-dependent associations with overall survival and with TMB/MSI.Conclusion:This pan-cancer analysis of the RIPK family reveals their diverse roles and potential as biomarkers and therapeutic targets.The findings emphasize the importance of RIPK genes in tumorigenesis and suggest context-dependent functions across cancer types.Further studies are needed to explore their mechanisms in cancer development and clinical applications.
基金Supported by Shandong Scientific and Technological Research Program,No.2019GSF108254and Shandong Natural Science Foundation,No.ZR2021MH339.
文摘BACKGROUND Intrahepatic cholangiocarcinoma(ICC)is malignancies of the biliary duct system and constitutes approximately 10%-20%of all primary liver cancers.Tumor mutation burden(TMB)is a useful biomarker across many cancer types for the identification of patients who will benefit from immunotherapy.Despite the role of TMB in calculating the effectiveness and prognosis of immune checkpoint inhibitors has been confirmed in multiple human cancer types,the prognostic value of TMB in ICC patients is rare investigated.AIM To investigate the prognostic value of TMB in patients with ICC.METHODS Data of 412 patients with ICC were included in the study.TMB was calculated as the total number of somatic non-silent protein-coding mutations divided by the coding region.The Kaplan-Meier method was used to analyze overall survival(OS),and relapse free survival(RFS).The cut-off value of TMB was determined by time-dependent receiver operating characteristic(ROC)curve.Cox regression was performed for multivariable analysis of OS.The nomogram and calibration curve were analyzed to construct and evaluate the prognostic model.RESULTS In the analysis of the time-dependent ROC curve,we defined 3.1 mut/Mb as the cut-off value of TMB.The Kaplan-Meier plot revealed that patients with high TMB had poor OS(HR=1.47,P=0.002)and RFS(HR=1.42,P=0.035).Cox regression analysis also demonstrated that TMB was an independent risk predictor for ICC(HR=1.43,P=0.0240).Furthermore,independent prognostic factors of ICC included CA19-9(HR=1.78,P=0.0005),chronic viral hepatitis(HR=1.72,P=0.0468),tumor resection(HR=2.58,P<0.0001)and disease progression(metastatic disease vs.solitary liver tumor;HR=2.55,P=0.0002).The nomogram and calibration curve also indicated the effectiveness of the constructed prognostic model.CONCLUSION TMB was an independent prognostic biomarker in patients with ICC.Moreover,patients with ICC with high TMB had poor OS and RFS as compared to those with low TMB.
基金The Science and Technology Commission of Shanxi province,No.201901D111428.
文摘BACKGROUND Ferroptosis has recently been associated with multiple degenerative diseases.Ferroptosis induction in cancer cells is a feasible method for treating neoplastic diseases.However,the association of iron proliferation-related genes with prognosis in HER2+breast cancer(BC)patients is unclear.AIM To identify and evaluate fresh ferroptosis-related biomarkers for HER2+BC.METHODS First,we obtained the mRNA expression profiles and clinical information of HER2+BC patients from the TCGA and METABRIC public databases.A four gene prediction model comprising PROM2,SLC7A11,FANCD2,and FH was subsequently developed in the TCGA cohort and confirmed in the METABRIC cohort.Patients were stratified into high-risk and low-risk groups based on their median risk score,an independent predictor of overall survival(OS).Based on these findings,immune infiltration,mutations,and medication sensitivity were analyzed in various risk groupings.Additionally,we assessed patient prognosis by combining the tumor mutation burden(TMB)with risk score.Finally,we evaluated the expression of critical genes by analyzing single-cell RNA sequencing(scRNA-seq)data from malignant vs normal epithelial cells.RESULTS We found that the higher the risk score was,the worse the prognosis was(P<0.05).We also found that the immune cell infiltration,mutation,and drug sensitivity were different between the different risk groups.The highrisk subgroup was associated with lower immune scores and high TMB.Moreover,we found that the combination of the TMB and risk score could stratify patients into three groups with distinct prognoses.HRisk-HTMB patients had the worst prognosis,whereas LRisk-LTMB patients had the best prognosis(P<0.0001).Analysis of the scRNAseq data showed that PROM2,SLC7A11,and FANCD2 were significantly differentially expressed,whereas FH was not,suggesting that these genes are expressed mainly in cancer epithelial cells(P<0.01).CONCLUSION Our model helps guide the prognosis of HER2+breast cancer patients,and its combination with the TMB can aid in more accurate assessment of patient prognosis and provide new ideas for further diagnosis and treatment.
文摘BACKGROUND Gallbladder cancer is a highly malignant and aggressive tumor,often diagnosed at an advanced stage.The prognosis for advanced gallbladder cancer remains poor,with limited options for effective treatment.CASE SUMMARY A 65-year-old male patient presented with a soft tissue mass in the gallbladder.Following laparoscopic exploration,he underwent radical surgery for gallbladder cancer,with the tumor staged as pT2N1M0(stage III).Post-surgery,the patient received four cycles of adjuvant chemotherapy.However,one month later,over 60 metastatic lesions were detected in the liver,lungs,and lymph nodes.In response to the widespread metastasis,he underwent six cycles of combination therapy consisting of sintilimab,albumin-bound paclitaxel,and cisplatin.After two cycles,a partial response was achieved.Maintenance therapy was initiated with a combination of sintilimab and albumin-bound paclitaxel for four cycles.Monotherapy with sintilimab was continued thereafter until October 2023.Complete remission was confirmed in September 2021.The patient sustained this complete response for more than three years,including an eleven-month period without disease progression following the discontinuation of sintilimab.Genetic analysis revealed a tumor mutational burden of 15.4 mutations/megabase,which indicates a potentially favorable response to immunotherapy.CONCLUSION This case demonstrates the potential of combining immunotherapy(sintilimab)with chemotherapy to achieve durable remission in metastatic gallbladder cancer,even in a patient with extensive metastasis.In addition,it indicated the importance of tumor mutational burden as a predictive biomarker of immunotherapy.
基金sponsored by the National Natural Science Foundation of China(82002507)Shanghai Sailing Program(20YF1430100)Shanghai Hospital Development Center(SHDC2023CRT004).
文摘Objective:The plastic role of regulatory factor X1(RFX1)in colon cancer progression and its impact on the tumor microenvironment remain poorly understood.The study aimed to clarify the molecular and clinical role of RFX1 in colon cancer.Methods:We classified colon cancers into subgroups with high and low RFX1 expression and characterized their immune profiles,mutational profiles,cancer immunotherapy and drug sensitivity.By combining RFX1 expression with persistent tumor mutational burden,we proposed a novel nomogram clinical prediction model and validated its predictive performance,and the correlation between high expression and poor prognosis.Results:Compared to tumor mutational burden(TMB),persistent tumor mutational burden(pTMB)is an independent predictor of prognosis in patients with colon cancer.The predictive efficacy of the combination of RFX1 expression and pTMB was superior to and sensitive than the combination of RFX1 expression with TMB.Among them,patients in the RFX1^(high)/pTMB^(high) subgroup had the worst quality of survival and prognosis,whereas those in the RFX1low/pTMBlow subgroup had a relatively better prognosis(p<0.0001).Univariate Cox regression revealed a significant association between high RFX1 expression and increased risk in colon cancer patients(Hazard Ratio[HR]=1.58,95%Confidence Interval[CI]:1.10–2.25,p=0.012),which remained independently predictive in multivariate analysis after covariate adjustment(HR=1.52,95%CI:1.04–2.22,p=0.031).Conclusion:A nomogram model based on RFX1 combined with pTMB provides an alternative approach for the diagnosis and treatment of colon cancer.
文摘Pancreatic ductal adenocarcinoma(PDAC)remains one of the most lethal ma-lignancies with limited treatment efficacy.Advances in precision oncology,enabled by next-generation sequencing,have highlighted key molecular targets.Kirsten rat sarcoma viral oncogene homolog mutations,present in up to 90%of cases,drive aggressive biology,though most variants remain undruggable;allele-specific inhibitors and exosome-based RNA interference are under exploration.Breast cancer susceptibility gene 1/2 mutations occur in 4%-7%of patients,con-ferring sensitivity to platinum agents and poly(ADP-ribose)polymerase inhi-bitors.Other rare but actionable alterations-such as v-raf murine sarcoma viral oncogene homolog B1(V600),neurotrophic tyrosine receptor kinase,fibroblast growth factor receptor 2,and RET fusions-show benefit in tumor-agnostic trials,broadening options for selected subgroups.Immunotherapy is limited,as high tumor mutational burden and mismatch repair deficiency are uncommon in PDAC,though predictive when present.Co-mutations in tumor protein p53,cyclin-dependent kinase inhibitor 2A,and SMAD4 further stratify prognosis and influence therapy response.Cross-cancer analyses underscore the necessity of PDAC-specific strategies despite shared genomic drivers.Collectively,these insights support routine germline and somatic testing,enrollment in biomarker-matched trials,and rational combination strategies,establishing molecular profiling as central to advancing precision treatment in pancreatic cancer.
文摘BACKGROUND There has been no report to use camrelizumab with chemotherapy for advanced bladder cancer patients with positive programmed death-ligand 1(PD-L1)expression and high tumor mutational burden(TMB).More effective predictors of bladder cancer immunotherapy have yet to be explored,and the combination of multiple factors may be more predictive than a single factor.CASE SUMMARY We report the case of a 74-year-old male patient with recurrent metastatic bladder cancer,which demonstrated positive PD-L1 expression and high TMB.The immune checkpoint inhibitor camrelizumab was administered to the patient in combination with gemcitabine and cisplatin.The patient achieved a partial response with a progression-free survival of 11 mo.CONCLUSION This is the first report to use camrelizumab with chemotherapy for advanced bladder cancer patients with positive PD-L1 expression and high TMB.
文摘Bile duct tumors are comprised of tumors that originate from both intrahepatic and extrahepatic bile ducts and gallbladder tumors.These are aggressive tumors and chemotherapy is still the main treatment for advanced-stage disease and most of these cases have a poor overall survival.Strategies are aimed at treatments with better outcomes and less toxicity which makes immunotherapy an area of significant importance.Recent Food and Drug Administration approvals of immune checkpoint inhibitors(ICI)for agnostic tumors based on biomarkers such as microsatellite instability-high and tumor mutation burden-high are important steps in the treatment of patients with advanced bile duct tumors.Despite limited responses with isolated checkpoint inhibitors in later lines of systemic treatment in advanced disease,drug combination strategies have been demonstrating encouraging results to enhance ICI efficacy.
文摘The COP9 signalosome subunit 6(COPS6)is abnormally overexpressed in many malignancies,yet its precise role in carcinogenesis is unknown.To gain a better understanding of COPS6's role,the authors conducted a pan-cancer analysis using various bioinformatics techniques such as differential expression patterns,prognostic value,gene mutations,immune infiltration,correlation analysis,and functional enrichment assessment.Results showed that COPS6 was highly correlated with prognosis,immune cell infiltration level,tumor mutation burden,and microsatellite instability in patients with a range of tumor types.This suggests that COPS6 may be a potential target for cancer treatment.Overall,this research provides insight into COPS6's role in cancer development and its potential therapeutic applications.
基金Supported by National Natural Science Foundation of China,No.31900558the Hubei Provincial Youth Talents Program for Public Health,No.WSJKRC2022013Wuhan Young and Middle-Aged Medical Backbone Talents Training Project,No.WHQG201904.
文摘BACKGROUND The COP9 signalosome subunit 6(COPS6)has been implicated in cancer progression,while its precise role in most types of cancer remains elusive.AIM To investigate the functional and clinical relevance of COPS6 across various tumor types using publicly available databases.METHODS We used R software and online analysis databases to analyze the differential expression,prognosis,mutation and related functions of COPS6 in pan-cancer.RESULTS Differential expression analysis and survival analysis demonstrated that COPS6 was highly expressed and associated with high-risk profiles in the majority of cancer types.Possible associations between COPS6 expression level and prognostic outcomes were found using data from public databases.Mutational analysis revealed that missense mutations were the predominant type of COPS6 mutation.Additionally,positive correlations were identified between COPS6 expression level and tumor mutational burden and microsatellite instability in most types of cancer.Immune infiltration analysis demonstrated a negative correlation between COPS6 expression level and CD8+T cell infiltration in certain types of cancer.The correlation between COPS6 expression level and cancerassociated fibroblast infiltration exhibited heterogeneity,in which a positive correlation was found in head and neck squamous cell carcinoma and tenosynovial giant cell tumor,and a negative correlation was identified in diffuse large B-cell lymphoma and thymoma.The correlation between COPS6 expression level and macrophage infiltration was closely related to macrophage type.Gene co-expression and enrichment analysis highlighted transcription elongation factor B polypeptide 2 and G protein pathway suppressor 1 were significantly and positively associated with COPS6 expression level.These genes were predominantly involved in processes,such as ubiquitin-mediated proteolysis and human immunodeficiency virus 1 infection.CONCLUSION In conclusion,this study systematically explored the significance of COPS6 across different tumor types,providing a solid foundation for considering COPS6 as a novel biomarker in cancer research.
基金supported by grants from the Tianjin Health Technology Project(Grant no.2022QN106).
文摘Background:The Fascin(FSCN)family,comprising actin-bundling proteins,plays vital roles in cytoskeletal reorganization and cell migration.FSCN1,FSCN2,and FSCN3 are implicated in cancer progression through cell motility,invasion,and metastasis.However,their specific contributions across different cancer types remain unclear.Methods:We conducted a pan-cancer bioinformatics analysis of FSCN genes using data from The Cancer Genome Atlas.This included differential expression patterns,copy number variations(CNVs),mutations,methylation status,and correlations with tumor mutational burden,microsatellite instability,and immune checkpoint molecule expression.Differential expression was analyzed using DESeq2,while CNV and mutation analyses utilized GISTIC2.0 and MuTect2.Methylation data were assessed using the Illumina Human Methylation 450K BeadChip.Results:FSCN1 and FSCN2 showed significant differential expression in multiple cancers,often correlating with poor prognosis.FSCN3 exhibited less variability but a protective role in certain contexts.CNV analysis indicated frequent gene gains in FSCN genes,correlating with increased expression.FSCN3 had a higher mutation rate,suggesting genetic instability.Methylation analysis showed hypomethylation of FSCN1 and FSCN2 in tumors compared to normal tissues,whereas FSCN3 had minor changes.Significant associations were found between FSCN gene expression and tumor mutational burden,microsatellite instability,and immune checkpoint molecules,suggesting their involvement in tumor immunogenicity and the immune microenvironment.Conclusions:This pan-cancer analysis highlights the multifaceted roles of FSCN genes in cancer biology,emphasizing their potential as biomarkers and therapeutic targets.FSCN1 and FSCN2 are associated with poor prognosis and aggressive phenotypes,while FSCN3 shows protective roles in specific contexts.These findings offer new avenues for cancer diagnosis and treatment,particularly in personalized medicine.Future studies should validate these findings and explore the underlying mechanisms to fully harness the clinical potential of FSCN family proteins in oncology.
基金This work was supported by the National Key R&D Program of China(Grant No.2018YFC1313300)the National Natural Science Foundation of China(Grant No.81572331).
文摘Objective:DNA damage response(DDR)genes have low mutation rates,which may restrict their clinical applications in predicting the outcomes of immune checkpoint inhibitor(ICI)treatment.Thus,a systemic analysis of multiple DDR genes is needed to identify potential biomarkers of ICI efficacy.Methods:A total of 39,631 patients with mutation data were selected from the cBioPortal database.A total of 155 patients with mutation data were obtained from the Fudan University Shanghai Cancer Center(FUSCC).A total of 1,660 patients from the MSK-IMPACT cohort who underwent ICI treatment were selected for survival analysis.A total of 249 patients who underwent ICI treatment from the Dana-Farber Cancer Institute(DFCI)cohort were obtained from a published dataset.The Cancer Genome Atlas(TCGA)level 3 RNA-Seq version 2 RSEM data for gastric cancer were downloaded from cBioPortal.Results:Six MMR and 30 DDR genes were included in this study.Six MMR and 20 DDR gene mutations were found to predict the therapeutic efficacy of ICI,and most of them predicted the therapeutic efficacy of ICI,in a manner dependent on TMB,except for 4 combined DDR gene mutations,which were associated with the therapeutic efficacy of ICI independently of the TMB.Single MMR/DDR genes showed low mutation rates;however,the mutation rate of all the MMR/DDR genes associated with the therapeutic efficacy of ICI was relatively high,reaching 10%–30%in several cancer types.Conclusions:Coanalysis of multiple MMR/DDR mutations aids in selecting patients who are potential candidates for immunotherapy.
基金National Natural Science Foundation of China,No.31971249.
文摘BACKGROUND Undifferentiated embryonal sarcoma of the liver(UESL)is a neoplasm that rarely develops in adults.The main treatments for UESL are upfront gross total surgical resection and adjuvant multiagent chemotherapy.Here,we report a case of recurrent UESL in an adult treated with pembrolizumab and discuss a method to identify proper candidates for antibody of programmed cell death protein 1(anti-PD-1)treatment.CASE SUMMARY A 69-year-old woman was admitted for abdominal pain that developed for 1 wk.Computed tomography showed a 16 cm mass in the right lobe of the liver.Right hemihepatectomy and lymphadenectomy were performed,and histological diagnosis was UESL.Six months later,the patient suffered from painless obstructive jaundice,and positron emission tomography-computed tomography revealed multiple metastases.Then,percutaneous transhepatic cholangial drainage was applied to reduce jaundice,and radiofrequency ablation was used to control the lesion near the hepatic hilum.However,the patient suffered from a serious fever caused by the tumor.The patient received treatment with pembrolizumab,and the prescribed dosage was 2 mg/kg every 3 wk.After the seventh dose,positron emission tomography-computed tomography revealed that the multiple metastases had nearly disappeared.Radiologic exam was used to evaluate the disease state,and no new lesions were found.Next-generation sequencing and immunohistology were applied to determine the reason why the patient had such a favorable response to pembrolizumab.Tumor mutation burden,microsatellite instability,and programmed death ligand 1 expression can be combined to predict the effect of PD-1 antibodies. When every one of thesebiomarkers are detected in a tumor patient, the patient may be a proper candidatefor PD-1 antibodies.CONCLUSION Anti-PD-1 treatment for tumors needs further research to identify indications andproper biomarkers.
基金the China Pharmaceutical University,No:3150120001
文摘Gastrointestinal(GI) cancers prevail and account for an extremely high number of cancer deaths worldwide. The traditional treatment strategies, including surgery, chemotherapy, radiotherapy, and targeted therapy, have a limited therapeutic effect for advanced GI cancers. Recently, immunotherapy has shown promise in treating various refractory malignancies, including the GI cancers with mismatch repair deficiency(dMMR) or microsatellite instability(MSI). Thus,immunotherapy could be a promising treatment approach for GI cancers.Unfortunately, only a small proportion of GI cancer patients currently respond to immunotherapy. Therefore, it is important to discover predictive biomarkers for stratifying GI cancer patients response to immunotherapy. Certain genomic features, such as dMMR/MSI, tumor mutation burden(TMB), and tumor aneuploidy have been associated with tumor immunity and im-munotherapy response and may serve as predictive biomarkers for cancer immunotherapy. In this review, we examined the correlations between tumor immunity and three genomic features: dMMR/MSI, TMB, and tumor aneuploidy. We also explored their correlations using The Cancer Genome Atlas data and confirmed that the dMMR/MSI status, high TMB, and low tumor aneuploidy are associated with elevated tumor immunity in GI cancers. To improve the immunotherapeutic potential in GI cancers, more genetic or genomic features associated with tumor immune response need to be identified. Furthermore, it is worth exploring the combination of different immunotherapeutic methods and the combination of immunotherapy with other therapeutic approaches for cancer therapy.
基金Supported by the Science and Technology Development Project of Jilin Province,No.3D5197434429the Youth Program of the National Natural Science Foundation of China,No.3A4205367429+1 种基金the Education Project of Jilin UniversityNo.419070600046。
文摘BACKGROUND Colon cancer is a common malignant disease of the gastrointestinal tract and usually occurs at the junction of the rectum and sigmoid colon.Lymphatic and hematogenous metastases occur frequently in colon cancer and the most common metastatic sites include the liver,lung,peritoneum,bone,and lymph nodes.As a manifestation of advanced tumor spread and metastasis,soft tissue metastasis,especially skeletal muscle metastasis with bone metaplasia caused by colon cancer,is rare,accounting for less than 1%of metastases.CASE SUMMARY A 43-year-old male patient developed skeletal muscle metastasis with bone metaplasia of the right proximal thigh 5 mo after colon cancer was diagnosed.The patient was admitted to the hospital because of pain caused by a local mass on his right thigh.Positron emission tomography-computed tomography showed many enlarged lymph nodes around the abdominal aorta but no signs of lung or liver metastases.Color ultrasound revealed a mass located in the skeletal muscle and the results of histological biopsy revealed a poorly differentiated adenocarcinoma suspected to be distant metastases from colon cancer.Immunohistochemistry showed small woven bone components that were considered to be ossified.CONCLUSION This case reminds us that for patients with advanced colorectal tumors,we should be alert to the possibility of unconventional metastasis.
基金supported by the Scientific and Technological Innovation Program for Clinical Medicine of Jinan(202019132)to LIPING GONG.
文摘ATP binding cassette subfamily C member 8(ABCC8)encodes a protein regulating the ATP-sensitive potassium channel.Whether the level of ABCC8 mRNA in lower grade glioma(LGG)correlates with immune cell infiltration and patient outcomes has not been evaluated until now.Comparisons of ABCC8 expression between different tumors and normal tissues were evaluated by exploring publicly available datasets.The association between ABCC8 and tumor immune cell infiltration,diverse gene mutation characteristics,tumor mutation burden(TMB),and survival in LGG was also investigated in several independent datasets.Pathway enrichment analysis was conducted to search for ABCC8-associated signaling pathways.Through an online database,we found that ABCC8 expression in LGG was lower than in normal tissues.Then,the association of ABCC8 expression and immune cell infiltration in LGG was discussed.As we expected,the ABCC8 mRNA levels were negatively associated with non-T immune cell infiltration levels in all datasets.Consistently,TCGA_LGG RNA-seq data revealed that ABCC8 downregulated several non-T immune cell-associated signaling pathways in gene set enrichment analysis.Different ABCC8 expression groups showed diverse gene mutation characteristics and TMB.The high expression of ABCC8 was linked to improved survival of LGG patients.A pathway enrichment analysis of ABCC8-associated genes indicated that the GABAergic synapse signaling pathway might be involved in regulating immunity in LGG.Our findings show that ABCC8 reflects LGG tumor immunity and is an ideal prognostic biomarker for LGG.
