Background:Tyrosine kinase inhibitors(TKIs)and anti-PD-1 antibodies in combination provide survival benefits for patients with unresectable hepatocellular carcinoma(uHCC).However,the tool used to determine which patie...Background:Tyrosine kinase inhibitors(TKIs)and anti-PD-1 antibodies in combination provide survival benefits for patients with unresectable hepatocellular carcinoma(uHCC).However,the tool used to determine which patients likely benefit most from this treatment strategy has not been reported.We sought to develop a prognostic scoring system based on tumor burden score(TBS)and alpha-fetoprotein(AFP)to predict the long-term prognosis of uHCC treated with TKIs and anti-PD-1 antibodies.Methods:Data on patients with uHCC treated with TKIs and anti-PD-1 antibodies from multiple centers were collected.The prognostic accuracy of TBS,AFP,Barcelona Clinic Liver Cancer(BCLC),and CTA(Combined TBS and AFP)for 2-year progression-free survival(PFS)and overall survival(OS)was evaluated.Results:Overall,278 patients with uHCC treated with TKIs and anti-PD-1 antibodies were enrolled,including 48 BCLC-B and 230 BCLC-C HCC patients.CTA(AUC?0.721 and 0.683)outperformed TBS(AUC?0.680 and 0.621),AFP(AUC?0.606 and 0.594),and BCLC staging(AUC?0.551 and 0.555)in predicting PFS and OS.The 2-year PFS and OS for low CTA(low TBS/low AFP)were 65.7%and 94.4%,respectively,which were significantly higher than 21.6%and 44.9%(p<0.001 and p?0.002),respectively,for intermediate CTA(low TBS/high AFP or high TBS/low AFP)and 8.7%and 12.1%(both p<0.001),respectively,for high CTA(high TBS/high AFP).Multivariable Cox regression analysis indicated that CTA grading was an independent prognostic factor for PFS and OS(referent:low CTA;intermediate CTA,HR 2.87 and 7.17;high CTA,HR 5.52 and 10.31,respectively).Conclusions:CTA grading is an accurate tool for stratifying the prognosis of uHCC treated with TKIs and anti-PD-1 antibodies and may help determine which patients may benefit more from this treatment strategy.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
Objective:Accurate prognostic predictions and personalized decision-making on induction chemotherapy(IC)for individuals with locally advanced nasopharyngeal carcinoma(LA-NPC)remain challenging.This research examined t...Objective:Accurate prognostic predictions and personalized decision-making on induction chemotherapy(IC)for individuals with locally advanced nasopharyngeal carcinoma(LA-NPC)remain challenging.This research examined the predictive function of tumor burden-incorporated machine-learning algorithms for overall survival(OS)and their value in guiding treatment in patients with LA-NPC.Methods:Individuals with LA-NPC were reviewed retrospectively.Tumor burden signature-based OS prediction models were established using a nomogram and two machine-learning methods,the interpretable eXtreme Gradi-ent Boosting(XGBoost)risk prediction model,and DeepHit time-to-event neural network.The models’prediction performances were compared using the concordance index(C-index)and the area under the curve(AUC).The patients were divided into two cohorts based on the risk predictions of the most successful model.The efficacy of IC combined with concurrent chemoradiotherapy was compared to that of chemoradiotherapy alone.Results:The 1221 eligible individuals,assigned to the training(n=813)or validation(n=408)set,showed significant respective differences in the C-indices of the XGBoost,DeepHit,and nomogram models(0.849 and 0.768,0.811 and 0.767,0.730 and 0.705).The training and validation sets had larger AUCs in the XGBoost and DeepHit models than the nomogram model in predicting OS(0.881 and 0.760,0.845 and 0.776,and 0.764 and 0.729,P<0.001).IC presented survival benefits in the XGBoost-derived high-risk but not low-risk group.Conclusion:This research used machine-learning algorithms to create and verify a comprehensive model inte-grating tumor burden with clinical variables to predict OS and determine which patients will most likely gain from IC.This model could be valuable for delivering patient counseling and conducting clinical evaluations.展开更多
Background:Several clinical studies have uncovered a negative correlation between baseline tumor burden and the efficacy of immune checkpoint inhibitor(ICI)treatment.This study aimed to uncover the specific mechanisms...Background:Several clinical studies have uncovered a negative correlation between baseline tumor burden and the efficacy of immune checkpoint inhibitor(ICI)treatment.This study aimed to uncover the specific mechanisms underlying the difference in sensitivity to ICI treatment between tumors with high(HTB)and low(LTB)tumor burden.Methods:For in vivo studies,several mouse models of subcutaneous tumors were established,and transcriptome sequencing,immunohistochemistry,and flow cytometry assays were used to detect the immune status in these subcutaneous tumors.For in vitro experiments,co-culture models,cytokine antibody arrays,western blotting,flow cytometry,and enzyme-linked immunosorbent assays were used to explore the underlying molecular mechanisms Results:We found that MC38 or B16 subcutaneous tumors from the HTB group did not show any response to anti-programmed cell death protein-1(PD-1)therapy.Through flow cytometry assays,we found that the infiltration with CD8^(+)T cellswas significantly decreasedwhereasM2-like macrophageswere enriched in subcutaneous tumors of HTB groups compared with those of LTB group.These changes were not affected by the initial number of injected tumor cells or tumor age,nor could they be reversed by surgical tumor reduction.Intraperitoneal colony-stimulating factor 1 receptor(CSF-1R)inhibitor PLX3397 injection at different time points of tumor growth only had an effect when administered in the early tumor stage to maintain the“heat”of the tumor microenvironment during the process of tumor growth,thereby achieving a response to ICI treatment when the tumor grew to a large size.Mechanistically,we found that insulin-like growth factor binding protein 2(IGFBP2)expression levelswere significantly elevated in HTB tumor tissues.IGFBP2 promoted the programmed death-ligand 1(PD-L1)expression in M2-like macrophages by activating signal transducer and activator of transcription 3(STAT3),and PD-L1^(+)M2-likemacrophages exerted an immunosuppressive effect by inhibiting the proliferation and activation of CD8^(+)T cells in a PD-L1-dependent fashion.Conclusions:This study suggested that the low efficacy of ICI treatment in HTB tumors is mainly attributed to the intratumoral accumulation of PD-L1^(+)M2-like macrophages via the IGFBP2-STAT3-PD-L1 signaling pathway and their substantial inhibitory effects on T cell proliferation and activation.展开更多
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
Circulating cell-free DNAs(cfDNAs)are fragmented DNA molecules released into the blood by cells.Previous studies have suggested that mitochondria-originated cfDNA fragments(mt-cfDNAs)in cancer patients are more fragme...Circulating cell-free DNAs(cfDNAs)are fragmented DNA molecules released into the blood by cells.Previous studies have suggested that mitochondria-originated cfDNA fragments(mt-cfDNAs)in cancer patients are more fragmented than those from healthy controls.However,it is still unknown where these short mtcfDNAs originate,and whether the length of mt-cfDNAs can be correlated with tumor burden and cancer progression.In this study,we first performed whole-genome sequencing analysis(WGS)of cfDNAs from a human tumor cell line-xenotransplantation mouse model and found that mt-cfDNAs released from transplanted tumor cells were shorter than the mouse counterpart.We next analyzed blood cfDNA samples from hepatocellular carcinoma and prostate cancer patients and found that mt-cfDNA lengths were inversely related to tumor size as well as the concentration of circulating tumor DNA.Our study suggested that monitoring the size of mt-cfDNAs in cancer patients would be a useful way to estimate tumor burden and cancer progression.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 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 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
目的分析2019年广西恶性肿瘤流行情况与疾病负担特征,为广西恶性肿瘤防治提供参考。方法根据广西56个肿瘤登记地区上报的2019年肿瘤登记数据,计算2019年广西恶性肿瘤发病率、中国人口年龄标准化发病率(简称中标发病率)、死亡率、中国人...目的分析2019年广西恶性肿瘤流行情况与疾病负担特征,为广西恶性肿瘤防治提供参考。方法根据广西56个肿瘤登记地区上报的2019年肿瘤登记数据,计算2019年广西恶性肿瘤发病率、中国人口年龄标准化发病率(简称中标发病率)、死亡率、中国人口年龄标准化死亡率(简称中标死亡率),分析2019年广西恶性肿瘤发病和死亡情况;计算伤残调整生命年(disability adjusted life years,DALYs)、早死所致的寿命损失年(years of life lost,YLLs)等指标,评价2019年广西恶性肿瘤的疾病负担。结果2019年广西56个肿瘤登记地区报告恶性肿瘤新发病例数为71430例,粗发病率为219.87/10万,中标发病率为172.17/10万;报告恶性肿瘤死亡数为45485例,粗死亡率为140.01/10万,中标死亡率为105.25/10万。2019年广西全部恶性肿瘤合计损失的DALYs为660930.15人年,YLLs占DALYs的97.4%,DALYs率为2034.40/10万。2019年广西恶性肿瘤的发病率、死亡率及DALYs率呈现男性高于女性、城市地区高于农村地区的特点。此外,在广西5个地理区域中,恶性肿瘤发病率、死亡率及DALYs率最高的地区分别是桂北地区、桂南地区和桂西地区。2019年广西恶性肿瘤发病前10位癌种分别是肝癌、肺癌、女性乳腺癌、结直肠癌、子宫颈癌、胃癌、鼻咽癌、子宫体癌、前列腺癌和甲状腺癌,发病数占全部恶性肿瘤的75.3%;恶性肿瘤死亡前10位癌种分别是肝癌、肺癌、结直肠癌、胃癌、女性乳腺癌、子宫颈癌、鼻咽癌、食管癌、白血病和脑癌,死亡数占全部恶性肿瘤死亡的82.1%。结论2019年广西恶性肿瘤的疾病负担仍处于较高水平,具有明显的性别差异及地区差异。肝癌、肺癌、女性乳腺癌、结直肠癌、子宫颈癌以及鼻咽癌等仍是广西重点防控的恶性肿瘤。此外,甲状腺癌发病顺位上升到恶性肿瘤发病顺位第10位,应重点关注并及早采取措施加以防范。展开更多
目的:研究可预测PD-1/PD-L1抑制剂治疗恶性肿瘤临床疗效的潜在生物标志物。方法:检索PubMed、Web of Science、CNKI、万方和维普数据库,检索时限为各数据库建库至2022年9月20日。由2名评价员独立筛选文献、提取资料并评价纳入研究的偏...目的:研究可预测PD-1/PD-L1抑制剂治疗恶性肿瘤临床疗效的潜在生物标志物。方法:检索PubMed、Web of Science、CNKI、万方和维普数据库,检索时限为各数据库建库至2022年9月20日。由2名评价员独立筛选文献、提取资料并评价纳入研究的偏倚风险后,采用RevMan5.4和STATA16.0软件进行Meta分析。结果:共纳入18项研究,共计4018例患者。在随访的1年和2年内,发现高水平肿瘤突变负担(TMB)的肿瘤患者使用PD-1/PD-L1抑制剂的总生存率(OS)(P=0.003,P=0.01)和无进展生存率(PFS)(P=0.0002,P=0.04)更高。在不同的随访时间内,以1%为临界值,PD-L1表达高低作为预测PD-1/PD-L1抑制剂OS和PFS的生物标志物差异无统计学意义(P>0.05)。结论:TMB可以作为预测PD-1/PD-L1抑制剂治疗恶性肿瘤患者后2年内临床疗效的生物学指标,但其效用能否持续更长时间有待进一步研究;PD-L1单项检测目前不能成为预测应用PD-1/PD-L1抑制剂受益与否的生物学标志物。展开更多
基金supported by the National Natural Science Foundation of China(No.62275050)the Major Research Projects for Young and Middle-aged Talent of Fujian Provincial Health Commission(No.2021ZQNZD013)+1 种基金Fujian Provincial Clinical Research Center for Hepatobiliary and Pancreatic Tumors(Grant number:2020Y2013)the Scientific Foundation of Fuzhou Municipal Health Commission(Grant number:2021-S-wp1).
文摘Background:Tyrosine kinase inhibitors(TKIs)and anti-PD-1 antibodies in combination provide survival benefits for patients with unresectable hepatocellular carcinoma(uHCC).However,the tool used to determine which patients likely benefit most from this treatment strategy has not been reported.We sought to develop a prognostic scoring system based on tumor burden score(TBS)and alpha-fetoprotein(AFP)to predict the long-term prognosis of uHCC treated with TKIs and anti-PD-1 antibodies.Methods:Data on patients with uHCC treated with TKIs and anti-PD-1 antibodies from multiple centers were collected.The prognostic accuracy of TBS,AFP,Barcelona Clinic Liver Cancer(BCLC),and CTA(Combined TBS and AFP)for 2-year progression-free survival(PFS)and overall survival(OS)was evaluated.Results:Overall,278 patients with uHCC treated with TKIs and anti-PD-1 antibodies were enrolled,including 48 BCLC-B and 230 BCLC-C HCC patients.CTA(AUC?0.721 and 0.683)outperformed TBS(AUC?0.680 and 0.621),AFP(AUC?0.606 and 0.594),and BCLC staging(AUC?0.551 and 0.555)in predicting PFS and OS.The 2-year PFS and OS for low CTA(low TBS/low AFP)were 65.7%and 94.4%,respectively,which were significantly higher than 21.6%and 44.9%(p<0.001 and p?0.002),respectively,for intermediate CTA(low TBS/high AFP or high TBS/low AFP)and 8.7%and 12.1%(both p<0.001),respectively,for high CTA(high TBS/high AFP).Multivariable Cox regression analysis indicated that CTA grading was an independent prognostic factor for PFS and OS(referent:low CTA;intermediate CTA,HR 2.87 and 7.17;high CTA,HR 5.52 and 10.31,respectively).Conclusions:CTA grading is an accurate tool for stratifying the prognosis of uHCC treated with TKIs and anti-PD-1 antibodies and may help determine which patients may benefit more from this treatment strategy.
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Objective:Accurate prognostic predictions and personalized decision-making on induction chemotherapy(IC)for individuals with locally advanced nasopharyngeal carcinoma(LA-NPC)remain challenging.This research examined the predictive function of tumor burden-incorporated machine-learning algorithms for overall survival(OS)and their value in guiding treatment in patients with LA-NPC.Methods:Individuals with LA-NPC were reviewed retrospectively.Tumor burden signature-based OS prediction models were established using a nomogram and two machine-learning methods,the interpretable eXtreme Gradi-ent Boosting(XGBoost)risk prediction model,and DeepHit time-to-event neural network.The models’prediction performances were compared using the concordance index(C-index)and the area under the curve(AUC).The patients were divided into two cohorts based on the risk predictions of the most successful model.The efficacy of IC combined with concurrent chemoradiotherapy was compared to that of chemoradiotherapy alone.Results:The 1221 eligible individuals,assigned to the training(n=813)or validation(n=408)set,showed significant respective differences in the C-indices of the XGBoost,DeepHit,and nomogram models(0.849 and 0.768,0.811 and 0.767,0.730 and 0.705).The training and validation sets had larger AUCs in the XGBoost and DeepHit models than the nomogram model in predicting OS(0.881 and 0.760,0.845 and 0.776,and 0.764 and 0.729,P<0.001).IC presented survival benefits in the XGBoost-derived high-risk but not low-risk group.Conclusion:This research used machine-learning algorithms to create and verify a comprehensive model inte-grating tumor burden with clinical variables to predict OS and determine which patients will most likely gain from IC.This model could be valuable for delivering patient counseling and conducting clinical evaluations.
基金National Natural Science Foundation of China,Grant/Award Numbers:82073303,82103335,82102731Science and Technology Planning Project of Guangzhou,Grant/Award Number:202201011560Natural Science Foundation of Guangdong Province of China,Grant/Award Number:2022A1515012418。
文摘Background:Several clinical studies have uncovered a negative correlation between baseline tumor burden and the efficacy of immune checkpoint inhibitor(ICI)treatment.This study aimed to uncover the specific mechanisms underlying the difference in sensitivity to ICI treatment between tumors with high(HTB)and low(LTB)tumor burden.Methods:For in vivo studies,several mouse models of subcutaneous tumors were established,and transcriptome sequencing,immunohistochemistry,and flow cytometry assays were used to detect the immune status in these subcutaneous tumors.For in vitro experiments,co-culture models,cytokine antibody arrays,western blotting,flow cytometry,and enzyme-linked immunosorbent assays were used to explore the underlying molecular mechanisms Results:We found that MC38 or B16 subcutaneous tumors from the HTB group did not show any response to anti-programmed cell death protein-1(PD-1)therapy.Through flow cytometry assays,we found that the infiltration with CD8^(+)T cellswas significantly decreasedwhereasM2-like macrophageswere enriched in subcutaneous tumors of HTB groups compared with those of LTB group.These changes were not affected by the initial number of injected tumor cells or tumor age,nor could they be reversed by surgical tumor reduction.Intraperitoneal colony-stimulating factor 1 receptor(CSF-1R)inhibitor PLX3397 injection at different time points of tumor growth only had an effect when administered in the early tumor stage to maintain the“heat”of the tumor microenvironment during the process of tumor growth,thereby achieving a response to ICI treatment when the tumor grew to a large size.Mechanistically,we found that insulin-like growth factor binding protein 2(IGFBP2)expression levelswere significantly elevated in HTB tumor tissues.IGFBP2 promoted the programmed death-ligand 1(PD-L1)expression in M2-like macrophages by activating signal transducer and activator of transcription 3(STAT3),and PD-L1^(+)M2-likemacrophages exerted an immunosuppressive effect by inhibiting the proliferation and activation of CD8^(+)T cells in a PD-L1-dependent fashion.Conclusions:This study suggested that the low efficacy of ICI treatment in HTB tumors is mainly attributed to the intratumoral accumulation of PD-L1^(+)M2-like macrophages via the IGFBP2-STAT3-PD-L1 signaling pathway and their substantial inhibitory effects on T cell proliferation and activation.
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.
基金We would like to thank Dr.Anthony E.Sisk Jr.at UCLA Genitourinary Pathology Unit for histological analysis.This study is funded by National Institutes of Health(Grant No:RO1 DE DE025474,P50CA092131,and P50CA211015),and CIRM Stem Cell Genomics Centers of Excellence Award.
文摘Circulating cell-free DNAs(cfDNAs)are fragmented DNA molecules released into the blood by cells.Previous studies have suggested that mitochondria-originated cfDNA fragments(mt-cfDNAs)in cancer patients are more fragmented than those from healthy controls.However,it is still unknown where these short mtcfDNAs originate,and whether the length of mt-cfDNAs can be correlated with tumor burden and cancer progression.In this study,we first performed whole-genome sequencing analysis(WGS)of cfDNAs from a human tumor cell line-xenotransplantation mouse model and found that mt-cfDNAs released from transplanted tumor cells were shorter than the mouse counterpart.We next analyzed blood cfDNA samples from hepatocellular carcinoma and prostate cancer patients and found that mt-cfDNA lengths were inversely related to tumor size as well as the concentration of circulating tumor DNA.Our study suggested that monitoring the size of mt-cfDNAs in cancer patients would be a useful way to estimate tumor burden and cancer progression.
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 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.
文摘目的分析2019年广西恶性肿瘤流行情况与疾病负担特征,为广西恶性肿瘤防治提供参考。方法根据广西56个肿瘤登记地区上报的2019年肿瘤登记数据,计算2019年广西恶性肿瘤发病率、中国人口年龄标准化发病率(简称中标发病率)、死亡率、中国人口年龄标准化死亡率(简称中标死亡率),分析2019年广西恶性肿瘤发病和死亡情况;计算伤残调整生命年(disability adjusted life years,DALYs)、早死所致的寿命损失年(years of life lost,YLLs)等指标,评价2019年广西恶性肿瘤的疾病负担。结果2019年广西56个肿瘤登记地区报告恶性肿瘤新发病例数为71430例,粗发病率为219.87/10万,中标发病率为172.17/10万;报告恶性肿瘤死亡数为45485例,粗死亡率为140.01/10万,中标死亡率为105.25/10万。2019年广西全部恶性肿瘤合计损失的DALYs为660930.15人年,YLLs占DALYs的97.4%,DALYs率为2034.40/10万。2019年广西恶性肿瘤的发病率、死亡率及DALYs率呈现男性高于女性、城市地区高于农村地区的特点。此外,在广西5个地理区域中,恶性肿瘤发病率、死亡率及DALYs率最高的地区分别是桂北地区、桂南地区和桂西地区。2019年广西恶性肿瘤发病前10位癌种分别是肝癌、肺癌、女性乳腺癌、结直肠癌、子宫颈癌、胃癌、鼻咽癌、子宫体癌、前列腺癌和甲状腺癌,发病数占全部恶性肿瘤的75.3%;恶性肿瘤死亡前10位癌种分别是肝癌、肺癌、结直肠癌、胃癌、女性乳腺癌、子宫颈癌、鼻咽癌、食管癌、白血病和脑癌,死亡数占全部恶性肿瘤死亡的82.1%。结论2019年广西恶性肿瘤的疾病负担仍处于较高水平,具有明显的性别差异及地区差异。肝癌、肺癌、女性乳腺癌、结直肠癌、子宫颈癌以及鼻咽癌等仍是广西重点防控的恶性肿瘤。此外,甲状腺癌发病顺位上升到恶性肿瘤发病顺位第10位,应重点关注并及早采取措施加以防范。
文摘目的:研究可预测PD-1/PD-L1抑制剂治疗恶性肿瘤临床疗效的潜在生物标志物。方法:检索PubMed、Web of Science、CNKI、万方和维普数据库,检索时限为各数据库建库至2022年9月20日。由2名评价员独立筛选文献、提取资料并评价纳入研究的偏倚风险后,采用RevMan5.4和STATA16.0软件进行Meta分析。结果:共纳入18项研究,共计4018例患者。在随访的1年和2年内,发现高水平肿瘤突变负担(TMB)的肿瘤患者使用PD-1/PD-L1抑制剂的总生存率(OS)(P=0.003,P=0.01)和无进展生存率(PFS)(P=0.0002,P=0.04)更高。在不同的随访时间内,以1%为临界值,PD-L1表达高低作为预测PD-1/PD-L1抑制剂OS和PFS的生物标志物差异无统计学意义(P>0.05)。结论:TMB可以作为预测PD-1/PD-L1抑制剂治疗恶性肿瘤患者后2年内临床疗效的生物学指标,但其效用能否持续更长时间有待进一步研究;PD-L1单项检测目前不能成为预测应用PD-1/PD-L1抑制剂受益与否的生物学标志物。
