BACKGROUND Ferroptosis has recently been associated with multiple degenerative diseases.Ferroptosis induction in cancer cells is a feasible method for treating neoplastic diseases.However,the association of iron proli...BACKGROUND Ferroptosis has recently been associated with multiple degenerative diseases.Ferroptosis induction in cancer cells is a feasible method for treating neoplastic diseases.However,the association of iron proliferation-related genes with prognosis in HER2+breast cancer(BC)patients is unclear.AIM To identify and evaluate fresh ferroptosis-related biomarkers for HER2+BC.METHODS First,we obtained the mRNA expression profiles and clinical information of HER2+BC patients from the TCGA and METABRIC public databases.A four gene prediction model comprising PROM2,SLC7A11,FANCD2,and FH was subsequently developed in the TCGA cohort and confirmed in the METABRIC cohort.Patients were stratified into high-risk and low-risk groups based on their median risk score,an independent predictor of overall survival(OS).Based on these findings,immune infiltration,mutations,and medication sensitivity were analyzed in various risk groupings.Additionally,we assessed patient prognosis by combining the tumor mutation burden(TMB)with risk score.Finally,we evaluated the expression of critical genes by analyzing single-cell RNA sequencing(scRNA-seq)data from malignant vs normal epithelial cells.RESULTS We found that the higher the risk score was,the worse the prognosis was(P<0.05).We also found that the immune cell infiltration,mutation,and drug sensitivity were different between the different risk groups.The highrisk subgroup was associated with lower immune scores and high TMB.Moreover,we found that the combination of the TMB and risk score could stratify patients into three groups with distinct prognoses.HRisk-HTMB patients had the worst prognosis,whereas LRisk-LTMB patients had the best prognosis(P<0.0001).Analysis of the scRNAseq data showed that PROM2,SLC7A11,and FANCD2 were significantly differentially expressed,whereas FH was not,suggesting that these genes are expressed mainly in cancer epithelial cells(P<0.01).CONCLUSION Our model helps guide the prognosis of HER2+breast cancer patients,and its combination with the TMB can aid in more accurate assessment of patient prognosis and provide new ideas for further diagnosis and treatment.展开更多
Background:This study aimed to investigate the mutation spectrum of the QDPR gene,to determine the effect of mutations on dihydropteridine reductase(DHPR)structure/function,to discuss the potential genotype-phenotype ...Background:This study aimed to investigate the mutation spectrum of the QDPR gene,to determine the effect of mutations on dihydropteridine reductase(DHPR)structure/function,to discuss the potential genotype-phenotype correlation,and to evaluate the clinical outcome of Chinese patients after treatment.Methods:Nine DHPR-deficient patients were enrolled in this study and seven of them underwent neonatal screening.QDPR gene mutations were analyzed and confi rmed by routine methods.The potential pathogenicity of missense variants was analyzed using Clustal X,PolyPhen program and Swiss-PDB Viewer 4.04_OSX software,respectively.The clinical outcomes of the patients were evaluated after long-term treatment.Results:In 10 mutations of the 9 patients,4 were novel mutations(G20V,V86D,G130S and A175R),4 were reported by us previously,and 2 known mutations were identified.R221X was a hotspot mutation(27.7%)in our patients.Eight missense mutations probably had damage to protein.Six patients in this series were treated with a good control of phenylalanine level.The height and weight of the patients were normal at the age of 4 months to 7.5 years.Four patients,who underwent a neonatal screening and were treated early,showed a normal mental development.In 2 patients diagnosed late,neurological symptoms were signifi cantly improved.Conclusions:The mutation spectrum of the QDPR gene is different in the Chinese population.Most mutations are related to severe phenotype.The determination of DHPR activity should be performed in patients with hyperphenylalaninemia.DHPR-defi cient patients who were treated below the age of 2 months may have a near normal mental development.展开更多
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.
基金supported by grants from the Major Program of Shanghai Committee on Science and Technology(11dz1950300)the National Key Technology R&D Program(2012BAI09B04).
文摘Background:This study aimed to investigate the mutation spectrum of the QDPR gene,to determine the effect of mutations on dihydropteridine reductase(DHPR)structure/function,to discuss the potential genotype-phenotype correlation,and to evaluate the clinical outcome of Chinese patients after treatment.Methods:Nine DHPR-deficient patients were enrolled in this study and seven of them underwent neonatal screening.QDPR gene mutations were analyzed and confi rmed by routine methods.The potential pathogenicity of missense variants was analyzed using Clustal X,PolyPhen program and Swiss-PDB Viewer 4.04_OSX software,respectively.The clinical outcomes of the patients were evaluated after long-term treatment.Results:In 10 mutations of the 9 patients,4 were novel mutations(G20V,V86D,G130S and A175R),4 were reported by us previously,and 2 known mutations were identified.R221X was a hotspot mutation(27.7%)in our patients.Eight missense mutations probably had damage to protein.Six patients in this series were treated with a good control of phenylalanine level.The height and weight of the patients were normal at the age of 4 months to 7.5 years.Four patients,who underwent a neonatal screening and were treated early,showed a normal mental development.In 2 patients diagnosed late,neurological symptoms were signifi cantly improved.Conclusions:The mutation spectrum of the QDPR gene is different in the Chinese population.Most mutations are related to severe phenotype.The determination of DHPR activity should be performed in patients with hyperphenylalaninemia.DHPR-defi cient patients who were treated below the age of 2 months may have a near normal mental development.
