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
We aimed to evaluate the efficacy and safety of adding apatinib,to sintilimab and chemotherapy in the neoadjuvant treatment of early triple-negative breast cancer(TNBC).In the phase 2 NeoSAC trial,patients with early ...We aimed to evaluate the efficacy and safety of adding apatinib,to sintilimab and chemotherapy in the neoadjuvant treatment of early triple-negative breast cancer(TNBC).In the phase 2 NeoSAC trial,patients with early TNBC received six cycles of apatinib,sintilimab,nab-paclitaxel,and carboplatin followed by surgery.The primary endpoint was pathological complete response(pCR)rate.Specimens collected pre-neoadjuvant therapy and post-surgery were retained for comprehensive analysis of predictive biomarkers and the impact on the tumor microenvironment.Among 34 enrolled patients,24 achieved pCR(70.6%;95%confidence interval(CI),53.0-85.3),and 79.4%(95%CI,65.1-93.7)had residual cancer burden 0-I.Imaging evaluation showed 21 complete responses(61.8%)and 13 partial responses(38.2%).The most common grade 3-4 adverse events were leukopenia(47%),neutropenia(36%),and thrombocytopenia(24%).The 36-month disease-free survival rate stood at 94.1%with a median follow-up of 39.1 months.Notably,baseline high ImmuneScore,immune cell infiltration,and enrichment of interferon-related pathways correlated with pCR.Comparison of pre-neoadjuvant and post-surgery data revealed that the pCR group treated with this novel regimen exhibited an upregulation of distinct immune cell subsets,thereby activating the tumor microenvironment.Moreover,higher oxeiptosis scores were associated with an increased likelihood of achieving pCR.Following neoadjuvant therapy,the pCR group showed a decrease in oxeiptosis score,whereas the non-pCR group exhibited an increase.Our study suggests that apatinib,sintilimab combined with carboplatin and nab-paclitaxel chemotherapy showed a promising clinical activity and manageable safety profile in early TNBC and merits further study.ClinicalTrials.gov registration:NCT04722718.展开更多
Homologous recombination deficiency(HRD)has emerged as a critical prognostic and predictive biomarker in oncology.However,current test-ing methods,especially those reliant on targeted panels,are plagued by inconsisten...Homologous recombination deficiency(HRD)has emerged as a critical prognostic and predictive biomarker in oncology.However,current test-ing methods,especially those reliant on targeted panels,are plagued by inconsistent results from the same samples.This highlights the urgent need for standardized benchmarks to evaluate HRD assay performance.In phases lla and Ilb of the Chinese HRD Harmonization Project,we de-veloped ten pairs of well-characterized DNA reference materials derived from lung,breast,and melanoma cancer cell lines and their matched normal cell lines,keeping each paired with seven cancer-to-normal mass ratios.Reference datasets for allele-specific copy number variations(AsCNVs)and HRD scores were established and validated using three sequencing methods and nine analytical pipelines.The genomic instabil-ity scores(GISs)of the reference materials ranged from 11 to 96,enabling validation across various thresholds.The AsCNV reference datasets covered a genomic span of 2340 to 2749 Mb,equivalent to 81.2%to 95.4%of the autosomes in the 37d5 reference genome.These bench-marks were subsequently utilized to assess the accuracy and reproducibility of four HRD panel assays,revealing significant variability in both ASCNV detection and HRD scores.The concordance between panel-detected GISs and reference GISs ranged from 0.81 to 0.94,with only two assays exhibiting high overall agreement with Myriad MyChoice CDx for HRD classification.This study also identified specific challenges in ASCNV detection in HRD-related regions and the profound impact of high ploidy on consistency.The established HRD reference materials and datasets providea robust toolkit forobjective evaluation of HRD testing.展开更多
Background:Blood-based cell-free DNA(cfDNA)methylation testing has emerged as a promising approach for multi-cancer early detection(MCED),holding the potential to improve cancer survival rates.However,traditional bisu...Background:Blood-based cell-free DNA(cfDNA)methylation testing has emerged as a promising approach for multi-cancer early detection(MCED),holding the potential to improve cancer survival rates.However,traditional bisulfite-based methods often encounter sensitivity limitations in detecting early-stage malignancies or certain cancer types.In the INSPECTOR study,we developed a MCED and cancer signal origin(CSO)system specifically designed for early-stage or hard-to-detect cancers,including those of the lung,breast,colorectum,liver,esophagus,stomach,pancreas,and ovary.Methods:We established a comprehensive methylation marker discovery database(n=6,342)by integrating public datasets(n=4,699)and in-house samples(n=1,643),all processed using human TET(hTET)enzyme-assisted whole-methylome sequencing(GM-seq).This enabled the design of a targeted panel encompassing 155,362 methylated CpG sites.Leveraging hTET-assisted high-depth next-generation sequencing(NGS),our blood test achieved amedian unique depth of 1,093×.Multicenter case-control cohorts,including various pathological subtypes,were used for training,validation,and independent validation of MCED and CSO models,and to verify the clinical feasibility.Results:Clinical validation was conducted across multi-center case-control cohorts,including 1,071 participants in the training set,581 in the validation set,and 824 in the independent validation set.TheMCEDassay demonstrated robust performancewith a specificity of 99.1%and sensitivity of 83.2%in the training set,99.0%and 81.8%in the validation set,and comparable results in the independent validation set(99.0%specificity,81.9%sensitivity).Notably,sensitivity reached 65.5%for stage I cancers,79.7%for stage II,and 71.3%for stages I-II combined.The sensitivities for different cancer types were as follows:esophageal(79.2%),gastric(76.1%),colorectal(86.2%),pancreatic(66.7%),liver(100.0%),lung(72.9%),breast(88.9%),and ovarian(87.9%).The CSO model exhibited strong accuracy,with top-1 cancer origin prediction rates of 87.9%(validation)and 87.4%(independent validation),rising to 95.1%and 94.5%for top-2 predictions,respectively.For stage I cancers specifically,the top-1 accuracy was 85.5%.Conclusions:These findings underscore the efficacy of the hTET-assisted cfDNA methylation sequencing system across diverse cancer types,particularly in early stages.Enzyme-assisted NGS test of methylated cfDNA thus enhances the clinical utility of non-invasive blood-based screening.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
Acute myeloid leukemia(AML)is a common hematological malignancy with overall poor prognosis.Exploring novel targets is urgent and necessary to improve the clinical outcome of relapsed and refractory(RR)AML patients.Th...Acute myeloid leukemia(AML)is a common hematological malignancy with overall poor prognosis.Exploring novel targets is urgent and necessary to improve the clinical outcome of relapsed and refractory(RR)AML patients.Through clinical specimens,animal models and cell-level studies,we explored the specific mechanism of 3-hydroxy-3-methylglutaryl coenzyme A synthase 1(HMGCS1)in AML and the mechanism of targeting HMGCS1 to attenuate cell proliferation,increase chemotherapy sensitivity and improve the occurrence and development of AML.Here,we reveal that HMGCS1 is overexpressed in RR patients and negatively related to overall survival(OS).Knocking out HMGCS1 in AML cells attenuated cell proliferation and increased chemotherapy sensitivity,while stable overexpression of HMGCS1 had the opposite effects.Mechanistically,we identified that knockout of HMGCS1 suppressed mitogen-activated protein kinase(MAPK)pathway activity,while overexpression of HMGCS1 could remarkably enhance the pathway.U0126,a MEK1 inhibitor,offset the effects of HMGCS1 overexpression,indicating that HMGCS1 promotes RR AML through the MAPK pathway.Further,we verified that hymeglusin,a specific inhibitor of HMGCS1,decreases cell growth both in AML cell lines and primary bone marrow cells of AML patients.Furthermore,combination of hymeglusin and the common chemotherapeutic drug cytarabine and adriamycin(ADR)had synergistic toxic effects on AML cells.Our study demonstrates the important role of HMGCS1 in AML,and targeting this protein is promising for the treatment of RR AML.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funded by the Provincial-Level Clinical Key Specialty Construction in Qinghai Province in China.
文摘We aimed to evaluate the efficacy and safety of adding apatinib,to sintilimab and chemotherapy in the neoadjuvant treatment of early triple-negative breast cancer(TNBC).In the phase 2 NeoSAC trial,patients with early TNBC received six cycles of apatinib,sintilimab,nab-paclitaxel,and carboplatin followed by surgery.The primary endpoint was pathological complete response(pCR)rate.Specimens collected pre-neoadjuvant therapy and post-surgery were retained for comprehensive analysis of predictive biomarkers and the impact on the tumor microenvironment.Among 34 enrolled patients,24 achieved pCR(70.6%;95%confidence interval(CI),53.0-85.3),and 79.4%(95%CI,65.1-93.7)had residual cancer burden 0-I.Imaging evaluation showed 21 complete responses(61.8%)and 13 partial responses(38.2%).The most common grade 3-4 adverse events were leukopenia(47%),neutropenia(36%),and thrombocytopenia(24%).The 36-month disease-free survival rate stood at 94.1%with a median follow-up of 39.1 months.Notably,baseline high ImmuneScore,immune cell infiltration,and enrichment of interferon-related pathways correlated with pCR.Comparison of pre-neoadjuvant and post-surgery data revealed that the pCR group treated with this novel regimen exhibited an upregulation of distinct immune cell subsets,thereby activating the tumor microenvironment.Moreover,higher oxeiptosis scores were associated with an increased likelihood of achieving pCR.Following neoadjuvant therapy,the pCR group showed a decrease in oxeiptosis score,whereas the non-pCR group exhibited an increase.Our study suggests that apatinib,sintilimab combined with carboplatin and nab-paclitaxel chemotherapy showed a promising clinical activity and manageable safety profile in early TNBC and merits further study.ClinicalTrials.gov registration:NCT04722718.
基金supported by the National Key R&D Program of China(Grant No.2022YFF1202203)the NIFDC Fund for Key Technology Research,China(Grant No.GJJS-2022-2-1).
文摘Homologous recombination deficiency(HRD)has emerged as a critical prognostic and predictive biomarker in oncology.However,current test-ing methods,especially those reliant on targeted panels,are plagued by inconsistent results from the same samples.This highlights the urgent need for standardized benchmarks to evaluate HRD assay performance.In phases lla and Ilb of the Chinese HRD Harmonization Project,we de-veloped ten pairs of well-characterized DNA reference materials derived from lung,breast,and melanoma cancer cell lines and their matched normal cell lines,keeping each paired with seven cancer-to-normal mass ratios.Reference datasets for allele-specific copy number variations(AsCNVs)and HRD scores were established and validated using three sequencing methods and nine analytical pipelines.The genomic instabil-ity scores(GISs)of the reference materials ranged from 11 to 96,enabling validation across various thresholds.The AsCNV reference datasets covered a genomic span of 2340 to 2749 Mb,equivalent to 81.2%to 95.4%of the autosomes in the 37d5 reference genome.These bench-marks were subsequently utilized to assess the accuracy and reproducibility of four HRD panel assays,revealing significant variability in both ASCNV detection and HRD scores.The concordance between panel-detected GISs and reference GISs ranged from 0.81 to 0.94,with only two assays exhibiting high overall agreement with Myriad MyChoice CDx for HRD classification.This study also identified specific challenges in ASCNV detection in HRD-related regions and the profound impact of high ploidy on consistency.The established HRD reference materials and datasets providea robust toolkit forobjective evaluation of HRD testing.
基金the Ethics Committee of the Cancer Prevention Center,Sun Yat-sen University(SL-B2023-717-01)Chinese PLA General Hospital(S2021-427-01)+2 种基金The Sixth Affiliated Hospital of Sun Yat-sen University(2024ZSLYEC-361)Gansu Provincial Cancer Hospital(IRB-PJ-2024-043)Shenzhen Bao’an District Songgang People’s Hospital(PY202408020003).
文摘Background:Blood-based cell-free DNA(cfDNA)methylation testing has emerged as a promising approach for multi-cancer early detection(MCED),holding the potential to improve cancer survival rates.However,traditional bisulfite-based methods often encounter sensitivity limitations in detecting early-stage malignancies or certain cancer types.In the INSPECTOR study,we developed a MCED and cancer signal origin(CSO)system specifically designed for early-stage or hard-to-detect cancers,including those of the lung,breast,colorectum,liver,esophagus,stomach,pancreas,and ovary.Methods:We established a comprehensive methylation marker discovery database(n=6,342)by integrating public datasets(n=4,699)and in-house samples(n=1,643),all processed using human TET(hTET)enzyme-assisted whole-methylome sequencing(GM-seq).This enabled the design of a targeted panel encompassing 155,362 methylated CpG sites.Leveraging hTET-assisted high-depth next-generation sequencing(NGS),our blood test achieved amedian unique depth of 1,093×.Multicenter case-control cohorts,including various pathological subtypes,were used for training,validation,and independent validation of MCED and CSO models,and to verify the clinical feasibility.Results:Clinical validation was conducted across multi-center case-control cohorts,including 1,071 participants in the training set,581 in the validation set,and 824 in the independent validation set.TheMCEDassay demonstrated robust performancewith a specificity of 99.1%and sensitivity of 83.2%in the training set,99.0%and 81.8%in the validation set,and comparable results in the independent validation set(99.0%specificity,81.9%sensitivity).Notably,sensitivity reached 65.5%for stage I cancers,79.7%for stage II,and 71.3%for stages I-II combined.The sensitivities for different cancer types were as follows:esophageal(79.2%),gastric(76.1%),colorectal(86.2%),pancreatic(66.7%),liver(100.0%),lung(72.9%),breast(88.9%),and ovarian(87.9%).The CSO model exhibited strong accuracy,with top-1 cancer origin prediction rates of 87.9%(validation)and 87.4%(independent validation),rising to 95.1%and 94.5%for top-2 predictions,respectively.For stage I cancers specifically,the top-1 accuracy was 85.5%.Conclusions:These findings underscore the efficacy of the hTET-assisted cfDNA methylation sequencing system across diverse cancer types,particularly in early stages.Enzyme-assisted NGS test of methylated cfDNA thus enhances the clinical utility of non-invasive blood-based screening.
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supported by the National Natural Science Foundation of China to H.Z.(Grant Nos.81770184,81970143,and 82270167)and L.Z.(Grant No.81800174)the Talent Young Program of Guangdong Province(2021B1515020017),and the Leading Talents Program from The First Affiliated Hospital of Jinan University to H.Z.
文摘Acute myeloid leukemia(AML)is a common hematological malignancy with overall poor prognosis.Exploring novel targets is urgent and necessary to improve the clinical outcome of relapsed and refractory(RR)AML patients.Through clinical specimens,animal models and cell-level studies,we explored the specific mechanism of 3-hydroxy-3-methylglutaryl coenzyme A synthase 1(HMGCS1)in AML and the mechanism of targeting HMGCS1 to attenuate cell proliferation,increase chemotherapy sensitivity and improve the occurrence and development of AML.Here,we reveal that HMGCS1 is overexpressed in RR patients and negatively related to overall survival(OS).Knocking out HMGCS1 in AML cells attenuated cell proliferation and increased chemotherapy sensitivity,while stable overexpression of HMGCS1 had the opposite effects.Mechanistically,we identified that knockout of HMGCS1 suppressed mitogen-activated protein kinase(MAPK)pathway activity,while overexpression of HMGCS1 could remarkably enhance the pathway.U0126,a MEK1 inhibitor,offset the effects of HMGCS1 overexpression,indicating that HMGCS1 promotes RR AML through the MAPK pathway.Further,we verified that hymeglusin,a specific inhibitor of HMGCS1,decreases cell growth both in AML cell lines and primary bone marrow cells of AML patients.Furthermore,combination of hymeglusin and the common chemotherapeutic drug cytarabine and adriamycin(ADR)had synergistic toxic effects on AML cells.Our study demonstrates the important role of HMGCS1 in AML,and targeting this protein is promising for the treatment of RR AML.
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.
