Explore The Relationship Between Amino Acid And Chemotherapy-related Cognitive Dysfunction In Breast Cancer Patients And The Value Of Related Proteins In Breast Cancer Based On Metabonomics

ObjectiveThe changes of amino acid metabolism in breast cancer patients before and after chemotherapy were analyzed to explore the relationship between amino acid metabolism and cognitive impairment in breast cancer and the value of different amino acid-related genes(proteins)in breast cancer.MethodsA total of 139 patients with pathologically confirmed breast cancer who met the inclusion and exclusion criteria from the Hospital during 2021-2022 were collected,including 74 patients before chemotherapy and 65 patients with cognitive dysfunction after chemotherapy.Their cognitive function was evaluated by Montreal cognitive assessment Scale(MoCA),and 23 amino acid metabolic profiles were obtained by LC-MS/MS method.Univariate analysis and multivariate statistical analysis including T-test,principal component analysis(PCA)and orthogonal partial least squares discriminant analysis(OPLS-DA)were performed using MetbraAnalyst5.0 to identify differential metabolites,namely,arginine,cysteine,glutamine,lysine,ornithine,glutamic acid,and proline.Logistic regression diagnosis model was established for different amino acids to select the amino acids that had influence on cognitive dysfunction of patients before and after chemotherapy.Evaluating the diagnostic capability of the model using ROC.The differential amino acids were substituted into MetbraAnalyst5.0 for metabolic enrichment analysis and metabolic pathway analysis to find the proteins involved in the differential metabolic pathway,namely GPT,GLUD1,CPS1,NAGS and GLUL.The value of these proteins in breast cancer was analyzed using TIMER,Ualcan,Kaplan-Meier,GEPIA and other databases.ResultsThe PLS-DA model showed that there were metabolic differences between the two groups before and after chemotherapy,and the metabolism of 7 amino acids was significantly different between the two groups(P<0.05).Compared with before chemotherapy,the levels of arginine,cysteine,glutamine,lysine and ornithine increased after chemotherapy,while the levels of glutamic acid and proline decreased.logistic regression diagnostic model showed that there were two amino acids,namely arginine(Arg)and glutamic acid(Glu),which had an impact on cognitive dysfunction of patients before and after chemotherapy.The area under ROC curve(AUC)of the two amino acids were 0.741 and 0.353,respectively.Analysis of the above proteins in the database found that:Compared with normal breast tissues,the expression levels of GPT,GLUD1 and CPS1 in breast cancer tissues are down-regulated,while the expression levels of NAGS and GLUL are up-regulated.Compared with normal tissues,the expression levels of GPT are reduced in luminal,HER-2 overexpression and triple-negative breast cancer,and the most obvious decline is in Luminal.NAGS are significantly different in various types of breast cancer,which is increased in Luminal,decreased in HER-2 overexpression and triple-negative breast cancer,and most significantly decreased in HER-2 overexpression types.GLUD1 was significantly reduced in all types of tissues compared with normal tissues,most notably in Luminal types.GLUL decreased significantly in HER-2 overexpression and triple-negative breast cancer,and the decrease was most obvious in HER-2 overexpression types.The reduction of CPS1 was most significant in triple negative breast cancer,but the difference was not statistically significant in other types.Low NAGS expression was associated with poor OS(P=0.026)and GLUL expression was associated with poor RFS at 150 months of follow-up(P=0.029).GLUD1 was closely related to the stage of breast cancer(P=0.0476),and other metabolites were not related to the stage.Conclusions1.Changes in arginine and glutamate levels are associated with the occurrence of cognitive dysfunction.2.The change of arginine level can detect the occurrence of cognitive dysfunction in the early stage of chemotherapy.3.Among all subtypes of breast cancer,only triple-negative breast cancer showed statistically significant expression of all related differential metabolites,suggesting that arginine biosynthesis may be related to triple-negative breast cancer.