Exploring Value Of Folic And Folic Receptor In Endometrial Cancer Based On Machine Learning

Objective : Endometrial cancer(EC),a common malignancy of the female reproductive system,is increasing in incidence and mortality each year.Although most patients have a good prognosis,20% to 30% of patients with advanced disease still have a poor prognosis.Currently,there are no reliable biomarkers for early diagnosis and effective prognostic improvement of this disease.Folic acid(FA)plays an important role in normal life activities by entering cells mainly as a methyl donor and participating in methylation reactions and deoxynucleotide synthesis through endocytosis mediated by the folate receptor(FOLR).The aim of this study was to explore the effects of folic acid and folic acid receptors on EC using bibliometrics,the National Health and Nutrition Examination Survey(NHANES)database and The Cancer Genome Atlas(TCGA)database.The impact of folic acid and folate receptors on EC occurrence and the value of clinical applications.Methods:(1)A comprehensive bibliometric assessment of studies on folic acid and folate receptors in EC in the Web of Science core database from 1993 to January2023 was first performed,including country,author,publication institution,journal,and keywords.Bibliometric analysis was performed using VOSviewer and Cite Space software.(2)8,809 female subjects aged ≥ 20 years from the NHANES database from 2011-2018,including 8,738 non-oncology patients and 71 EC patients,were included,using a 1:1 propensity score matching(Propensity score matching(PSM)method to reduce selection bias,and Restricted cubic spline(RCS)plotting to explore the non-linear relationship between different forms of folic acid and EC.(3)Using the TCGA database,Human Protein Atlas(HPA),the c Bio Portal database,Tumor Immune Estimation Resource(TIMER),Gene MANIA database and Kyoto Encyclopedia of Genes and Genomes(KEGG)for analysis of FOLR1,FOLR2 and FOLR3 expression,immunity and prognosis in EC.Results:(1)A total of 91 papers were searched from the Web of Science core database,including 75 reviews and theses and 74 in English.In total,23 publishing countries and 156 institutions participated in the study,with the US ranking first in terms of number of publications,followed by China,with the main publishing journals located in Q1/Q2.(2)Data from the NHANES database from 2011-2018 were analyzed to assess the association between folic acid and EC risk,with 1:1propensity score matching(PSM)results showing 68 each for EC patients and non-oncology participants.Serum total folic acid,5-methyltetrahydrofolate,5-formyltetrahydrofolate,tetrahydrofolate and 5,10-methylenetetrahydrofolate were significantly associated with EC(P <0.05).In addition,the RCS showed a significant non-linear correlation between 5-formyltetrahydrofolate,tetrahydrofolate,and5,10-methylenetetrahydrofolate and EC.(3)Analysis of the TCGA database revealed that FOLR1 and FOLR3 expression was significantly increased in EC tissues,while FOLR2 expression was significantly decreased in EC tissues compared to normal tissues.Among them,increased expression of FOLR1 in cancer tissues was associated with poorer overall survival(OS)and disease-specific survival(DSS)(P <0.05);increased expression of FOLR3 in cancer tissues was associated with poorer DSS(P<0.05).FOLR1,FOLR2 and FOLR3 were significantly associated with immune cell infiltration and were enriched in multiple pathways such as adenosine triphosphate binding cassette(ATP Binding Cassette),fatty acid degradation and pyruvate metabolism.Conclusion:(1)Folic acid and folate receptors had important research value in EC.(2)The results of this study showed that changes in serum concentrations of total folic acid,5-methyltetrahydrofolate,5-formyltetrahydrofolate,tetrahydrofolate and5,10-methylenetetrahydrofolate are closely related to EC.(3)FOLR1 may become a novel marker for EC diagnosis and prognosis in future studies.