Background:Ovarian cancer(OC)is a leading cause of gynecological cancer-linked deaths worldwide.Exosomal miR-1825 and its target gene C-type lectin domain family 5 member A(CLEC5A)are associated with tumorigenesis in ...Background:Ovarian cancer(OC)is a leading cause of gynecological cancer-linked deaths worldwide.Exosomal miR-1825 and its target gene C-type lectin domain family 5 member A(CLEC5A)are associated with tumorigenesis in cancers that was further probed.Methods:Exosomal miR-1825 expression in exosomes and its impact on overall survival(OS)prediction were determined using Gene Expression Omnibus(GEO)and The Cancer Genome Atlas(TCGA)data.Target genes of miR-1825 were searched in five prediction databases and prognostically significant differentially expressed genes were identified.Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analyses were carried out.The ability of CLEC5A to predict OS was evaluated using univariate and multivariate Cox regression analyses and Kaplan-Meier curves.The CLEC5A expression pattern in OC was validated using immunohistochemistry.The CIBERSORT algorithm was used to compare the immune cell landscape,and the results were validated in a GEO cohort.Finally,the predicted half maximal inhibitory concentration(IC50)values for five commonly used chemotherapy agents were also compared.Results:MiR-1825 level was higher in exosomes derived from OC cells and served as a tumor suppressor.The CLEC5A gene was found to be a target of miR-1825,the upregulation of which was correlated with a poor prognosis.M2 macrophage infiltration was significantly enhanced in the CLEC5A high expression group,while T follicular helper cell infiltration was reduced in it.While the predicted IC50 for cisplatin and doxorubicin was higher in the CLEC5A high expression group,that of docetaxel,gemcitabine,and paclitaxel was lower.Conclusion:MiR-1825,a promising OC biomarker,may promote OC progression by increasing CLEC5A expression via exosome-mediated efflux from tumor cells.展开更多
Background:TP53 mutations are common in breast cancer.There is currently no large-scale cohort study to investigate the TP53 landscape in breast cancer patients from China.The predictive value of TP53 mutations for th...Background:TP53 mutations are common in breast cancer.There is currently no large-scale cohort study to investigate the TP53 landscape in breast cancer patients from China.The predictive value of TP53 mutations for the efficacy of human epidermal growth factor receptor 2(HER2)-targeted therapy in breast cancer remains controversial.In the present study,we aimed to analyze the clinical spectrum and prognostic value of TP53 mutations in circulating tumor DNA(ctDNA)from breast cancer patients in China.Methods:We retrospectively analyzed the clinical data and TP53 mutation features in ctDNA samples from 804 patients withmetastatic breast cancer.TP53 mutations were detected by target region capture-based next-generation sequencing.The relationship between TP53 mutation status and disease-free survival(DFS)was analyzed in 444 patientswithmetastatic breast cancer.Moreover,the relationship between TP53 mutation status and progression-free survival(PFS)was analyzed in 55 HER2-positive patients treated with first-line trastuzumab-based therapy.Kaplan-Meier analysis was performed to estimate the survival curves of the different subgroups,and the log-rank test was used to compare the curves.A Cox regression model was used to estimate multivariable-adjusted hazard ratios and their 95%confidence intervals(CIs)associated with the DFS and PFS.Results:Among the 804 investigated patients,431(53.6%)patients harbored TP53 mutations.TP53 mutations were differentially distributed among different molecular subtypes of breast cancer(P<0.05).Patients with TP53 mutations had a shorter DFS than those with wild-type TP53(hazard ratio=1.32,95%CI=1.09-1.61,P=0.005).TP53 mutations in exons 5-8 were associated with worse outcome(hazard ratio=1.50,95%CI=1.11-2.03,P=0.009).However,TP53 mutation status was not significantly associated with PFS in HER2-positive patients who received firstline trastuzumab-based therapy(P=0.966).Interestingly,in the taxane combination group,patients with TP53 mutations exhibited longer PFS than those without TP53 mutations(hazard ratio=0.08,95%CI=0.02-0.30,P<0.001).However,in the nontaxane combination group,patients with TP53 mutations displayed shorter PFS than those with wild-type TP53(hazard ratio=4.84,95%CI=1.60-14.66,P=0.005).Conclusions:TP53 mutations in exons 5-8 may be an independent prognostic marker for short DFS in patients with metastatic breast cancer.TP53 mutations had opposite effects on trastuzumab-treated patients treated with and without taxanes.展开更多
Dear editor,Breast cancer has been considered as the most common malignancy and the leading cause of death in women worldwide[1].Triple-negative breast cancer(TNBC)accounts for 10%-20%of breast cancers,which are chara...Dear editor,Breast cancer has been considered as the most common malignancy and the leading cause of death in women worldwide[1].Triple-negative breast cancer(TNBC)accounts for 10%-20%of breast cancers,which are characterized by the absence of estrogen receptor(ER),progesterone receptor(PR),and amplification of human epidermal growth factor receptor 2(HER2)[2].TNBC is well known for its rapid progressiveness,high rate of distant organ recurrence,and poor prognosis.Metastasis remains the major cause of death for patients with TNBCs.Up to date,the only direct treatment for metastatic TNBCs is chemotherapy,which has been challenged by tumor heterogeneity and drug resistance.Lack of effective targeted therapy for metastatic TNBCs impels researchers to focus on discovering potentially actionable targets through mutational profiling.展开更多
Circulating tumor DNA(ctDNA)is a potential biomarker of prognosis and therapeutic response.We conducted this study to explore the role of the molecular tumor burden index(mTBI)in ctDNA as a therapeutic response and pr...Circulating tumor DNA(ctDNA)is a potential biomarker of prognosis and therapeutic response.We conducted this study to explore the role of the molecular tumor burden index(mTBI)in ctDNA as a therapeutic response and prognostic biomarker in a larger cohort prospective phase III randomized multicenter study.We collected 291 plasma samples from 125 metastatic breast cancer patients from the CAMELLIA study(NCT01917279).Target-capture deep sequencing of 1021 genes was performed to detect somatic variants in ctDNA from the plasma samples.The pretreatment mTBI value was correlated with tumor burden(P=0.025).Patients with high-level pretreatment mTBI had shorter overall survival than patients with low-level pretreatment mTBI,and the median overall survival was 40.9 months and 68.4 months,respectively(P=0.011).Patients with mTBI decrease to less than 0.02%at the first tumor evaluation had longer progression-free survival and overall survival(P<0.001 and P=0.007,respectively).The mTBI has good sensitivity to identify complete response/partial response and progressive disease based on computed tomography scans(88.5%and 87.5%,respectively).The patients classified as molecular responders had longer progression-free survival and overall survival than the nonmolecular responders in the overall cohort(P<0.001 and P=0.036,respectively),as well as in the cohort in which computed tomography scans were defined as representing stable disease(P=0.027 and P=0.015,respectively).The mTBI in ctDNA detected in liquid biopsies is a potential biomarker of therapeutic response and prognosis in patients with metastatic breast cancer.展开更多
Dear editor,Lung cancer is the leading cause of cancer-related death worldwide,with the predominant pathological type being non-small cell lung cancer(NSCLC)[1,2].Next-gener-ation sequencing(NGS)analysis is increasing...Dear editor,Lung cancer is the leading cause of cancer-related death worldwide,with the predominant pathological type being non-small cell lung cancer(NSCLC)[1,2].Next-gener-ation sequencing(NGS)analysis is increasingly used to help clinicians select appropriate target therapies,such as epidermal growth factor receptor-tyrosine kinase inhibitors(EGFR-TKIs)for EGFR-mutant patients[3].Both pericarcinomatous tissues and peripheral blood lymphocytes are widely used as normal control for NGS analysis.However,whether pericarcinomatous tissue is suitable for background filtering in mutation analysis remains controversial.According to the whole-genome sequencing data from The Cancer Genome Atlas(TCGA)database,there were some genomic variations in peri-carcinomatous tissue from NSCLC patients,but no driver gene mutation was detected[4,5].Therefore,deep sequencing of pericarcinomatous and tumor tissues is necessary to confirm whether pericarcinomatous tissue harbors low-frequency mutations.展开更多
基金funded by a grant from the National Natural Science Foundation of China(81873045)the Natural Science Foundation of Fujian Province of China(2020J011115)+1 种基金the Medicine Innovation Project of Fujian Province of China(2020CXB007)the Joint Funds for the Innovation of Science and Technology(2021Y9209).
文摘Background:Ovarian cancer(OC)is a leading cause of gynecological cancer-linked deaths worldwide.Exosomal miR-1825 and its target gene C-type lectin domain family 5 member A(CLEC5A)are associated with tumorigenesis in cancers that was further probed.Methods:Exosomal miR-1825 expression in exosomes and its impact on overall survival(OS)prediction were determined using Gene Expression Omnibus(GEO)and The Cancer Genome Atlas(TCGA)data.Target genes of miR-1825 were searched in five prediction databases and prognostically significant differentially expressed genes were identified.Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analyses were carried out.The ability of CLEC5A to predict OS was evaluated using univariate and multivariate Cox regression analyses and Kaplan-Meier curves.The CLEC5A expression pattern in OC was validated using immunohistochemistry.The CIBERSORT algorithm was used to compare the immune cell landscape,and the results were validated in a GEO cohort.Finally,the predicted half maximal inhibitory concentration(IC50)values for five commonly used chemotherapy agents were also compared.Results:MiR-1825 level was higher in exosomes derived from OC cells and served as a tumor suppressor.The CLEC5A gene was found to be a target of miR-1825,the upregulation of which was correlated with a poor prognosis.M2 macrophage infiltration was significantly enhanced in the CLEC5A high expression group,while T follicular helper cell infiltration was reduced in it.While the predicted IC50 for cisplatin and doxorubicin was higher in the CLEC5A high expression group,that of docetaxel,gemcitabine,and paclitaxel was lower.Conclusion:MiR-1825,a promising OC biomarker,may promote OC progression by increasing CLEC5A expression via exosome-mediated efflux from tumor cells.
基金supported by the grants from the Chinese Academy of Medical Sciences(CAMS)Initiative for InnovativeMedicine(CAMS-12 M-1-010,2017-I2M-3-004)the National Natural Science Foundation of China(81874122).
文摘Background:TP53 mutations are common in breast cancer.There is currently no large-scale cohort study to investigate the TP53 landscape in breast cancer patients from China.The predictive value of TP53 mutations for the efficacy of human epidermal growth factor receptor 2(HER2)-targeted therapy in breast cancer remains controversial.In the present study,we aimed to analyze the clinical spectrum and prognostic value of TP53 mutations in circulating tumor DNA(ctDNA)from breast cancer patients in China.Methods:We retrospectively analyzed the clinical data and TP53 mutation features in ctDNA samples from 804 patients withmetastatic breast cancer.TP53 mutations were detected by target region capture-based next-generation sequencing.The relationship between TP53 mutation status and disease-free survival(DFS)was analyzed in 444 patientswithmetastatic breast cancer.Moreover,the relationship between TP53 mutation status and progression-free survival(PFS)was analyzed in 55 HER2-positive patients treated with first-line trastuzumab-based therapy.Kaplan-Meier analysis was performed to estimate the survival curves of the different subgroups,and the log-rank test was used to compare the curves.A Cox regression model was used to estimate multivariable-adjusted hazard ratios and their 95%confidence intervals(CIs)associated with the DFS and PFS.Results:Among the 804 investigated patients,431(53.6%)patients harbored TP53 mutations.TP53 mutations were differentially distributed among different molecular subtypes of breast cancer(P<0.05).Patients with TP53 mutations had a shorter DFS than those with wild-type TP53(hazard ratio=1.32,95%CI=1.09-1.61,P=0.005).TP53 mutations in exons 5-8 were associated with worse outcome(hazard ratio=1.50,95%CI=1.11-2.03,P=0.009).However,TP53 mutation status was not significantly associated with PFS in HER2-positive patients who received firstline trastuzumab-based therapy(P=0.966).Interestingly,in the taxane combination group,patients with TP53 mutations exhibited longer PFS than those without TP53 mutations(hazard ratio=0.08,95%CI=0.02-0.30,P<0.001).However,in the nontaxane combination group,patients with TP53 mutations displayed shorter PFS than those with wild-type TP53(hazard ratio=4.84,95%CI=1.60-14.66,P=0.005).Conclusions:TP53 mutations in exons 5-8 may be an independent prognostic marker for short DFS in patients with metastatic breast cancer.TP53 mutations had opposite effects on trastuzumab-treated patients treated with and without taxanes.
基金This work was supported by the National Key R&D Program of China(2018YFC1312101)Chinese Academy of Medical Sciences(CAMS)Initiative for Innovative Medicine(CAMS-12M-1-010,2017-12M-3-004)+2 种基金Major Project of Beijing Municipal Science and Technology Commission(D161100000816004)National Science and Technology Major Project of the Ministry of Science and Technology,China(2015ZX09101007)Beijing Municipal Science and Technology Project(D161100000816004).
文摘Dear editor,Breast cancer has been considered as the most common malignancy and the leading cause of death in women worldwide[1].Triple-negative breast cancer(TNBC)accounts for 10%-20%of breast cancers,which are characterized by the absence of estrogen receptor(ER),progesterone receptor(PR),and amplification of human epidermal growth factor receptor 2(HER2)[2].TNBC is well known for its rapid progressiveness,high rate of distant organ recurrence,and poor prognosis.Metastasis remains the major cause of death for patients with TNBCs.Up to date,the only direct treatment for metastatic TNBCs is chemotherapy,which has been challenged by tumor heterogeneity and drug resistance.Lack of effective targeted therapy for metastatic TNBCs impels researchers to focus on discovering potentially actionable targets through mutational profiling.
基金This work was supported by‘National Natural Science Foundation of China’(Grant Number:81874122)‘CAMS Initiative for Innovative Medicine’(Grant Number:2017-I2M-3-004)‘Major Project of the Beijing Municipal Science and Technology Commission’(Grant Number:D161100000816004).
文摘Circulating tumor DNA(ctDNA)is a potential biomarker of prognosis and therapeutic response.We conducted this study to explore the role of the molecular tumor burden index(mTBI)in ctDNA as a therapeutic response and prognostic biomarker in a larger cohort prospective phase III randomized multicenter study.We collected 291 plasma samples from 125 metastatic breast cancer patients from the CAMELLIA study(NCT01917279).Target-capture deep sequencing of 1021 genes was performed to detect somatic variants in ctDNA from the plasma samples.The pretreatment mTBI value was correlated with tumor burden(P=0.025).Patients with high-level pretreatment mTBI had shorter overall survival than patients with low-level pretreatment mTBI,and the median overall survival was 40.9 months and 68.4 months,respectively(P=0.011).Patients with mTBI decrease to less than 0.02%at the first tumor evaluation had longer progression-free survival and overall survival(P<0.001 and P=0.007,respectively).The mTBI has good sensitivity to identify complete response/partial response and progressive disease based on computed tomography scans(88.5%and 87.5%,respectively).The patients classified as molecular responders had longer progression-free survival and overall survival than the nonmolecular responders in the overall cohort(P<0.001 and P=0.036,respectively),as well as in the cohort in which computed tomography scans were defined as representing stable disease(P=0.027 and P=0.015,respectively).The mTBI in ctDNA detected in liquid biopsies is a potential biomarker of therapeutic response and prognosis in patients with metastatic breast cancer.
基金This work was supported by the National Key R&D Program of China(Grant No.2016YFC0905500,2016YFC0905503)Science and Technology Program of Guangdong(Grant No.2017B020227001,2016A020215084)+3 种基金Science and Technology Program of Guangzhou(Grant No.201607020031,201400000001-2)Chinese National Natural Science Foundation Project(Grant No.81772476,81572659,81602011)Pearl River Nova Program of Guangzhou(Grant No.201610010048)National Natural Science Funds for Young Scholars of China(Grant No.81502355).
文摘Dear editor,Lung cancer is the leading cause of cancer-related death worldwide,with the predominant pathological type being non-small cell lung cancer(NSCLC)[1,2].Next-gener-ation sequencing(NGS)analysis is increasingly used to help clinicians select appropriate target therapies,such as epidermal growth factor receptor-tyrosine kinase inhibitors(EGFR-TKIs)for EGFR-mutant patients[3].Both pericarcinomatous tissues and peripheral blood lymphocytes are widely used as normal control for NGS analysis.However,whether pericarcinomatous tissue is suitable for background filtering in mutation analysis remains controversial.According to the whole-genome sequencing data from The Cancer Genome Atlas(TCGA)database,there were some genomic variations in peri-carcinomatous tissue from NSCLC patients,but no driver gene mutation was detected[4,5].Therefore,deep sequencing of pericarcinomatous and tumor tissues is necessary to confirm whether pericarcinomatous tissue harbors low-frequency mutations.