| Objectives:1.The study aimed to reveal the metabolic profile of Endometrial cancer(EC),as well as establish and validate the diagnostic model to identify EC patients from controls using urine and serum combined ultraperformance chromatography-mass spectrometry(UPLC-MS)based metabolomics.2.Urine and serum combined UPLC-MS based metabolomics were performed to explore the metabolic characteristics of different types of EC,as well as construct discover biomarker panels to distinguish high-risk EC from low-risk EC and type II from type I EC.3.Urinary metabolomics was applied to screen for potential biomarkers which could evaluate the efficacy of fertility-sparing treatment in EC patients.Metabolic pathways were analyzed to provide novel ideas for the treatment regimen.4.To evaluate the efficacy and safety of fertility-sparing treatment on obese women(BMI≥30 kg/m2)with EC or atypical endometrial hyperplasia(AEH).Methods:1.One hundred and forty-six EC patients and 59 control women were included in our study in the training and validation sets.Their serum and urine samples were collected and analyzed by performing UPLC-MS based metabolomics.Comparative analysis was applied to distinguish the metabolites and altered metabolic pathways.Receiver operating characteristic(ROC)analyses were used to discover and validate the potential biomarker models.2.Seventy-nine patients with stage IA,well-differentiated,endometrioid adenocarcinoma were assigned to the low-risk group,and the remaining 77 patients with high-risk factors were assigned to the high-risk group,including 22 type II patients.UPLC-MS based metabolomics was used to analyze the serum and urine samples.The statistical methods and pathway analysis were applied to discover potential biomarker panels and altered metabolic pathways.3.Sixty-six urine samples were collected from patients who received fertility-sparing treatment,including 24 patients prior to treatment(PT),18 patients with partial remission(PR)and 24 patients with complete remission(CR).Differential metabolites or metabolic pathways that could evaluate the treatment effect were screened using urinary metabolomics techniques.4.EC/AEH patients with obesity who received fertility-preserving therapy were included in our study.The treatment regimens included oral high-dose progestin therapy and GnRHa combined LNG-IUS/letrozole therapy.Data regarding clinical characteristics,treatment outcomes,adverse events,and reproductive outcomes were collected and analyzed.Results:1.One hundred and eighty-six urine metabolites and 85 serum metabolites were significantly different in EC and controls.Pathway analysis revealed abnormal amino acid and glucose metabolisms between cancer patients and controls.The panel of ADP-mannose and Docosatrienoic acid showed the best predictive ability with the AUC of 0.983(0.956-0.998).2.Two hundred and eighteen urine metabolites and 55 serum metabolites showed the difference in low-risk and high-risk EC,119 urine metabolites and 132 serum metabolites were different in type Ⅰ and type Ⅱ EC patients.Pathway enrichment analysis indicated disordered purine and glutamine metabolisms between high-risk and low-risk EC.Also,altered folic acid metabolism was found between type Ⅰ and type Ⅱ EC.The panel containing Ganglioside GM3 and Tri-n-acetylchitotriose could differentiate high-risk EC from low-risk EC with the AUC of 0.96(0.916-1.000)in discovering group and the metabolites panel including Mucronine D and Asp-leu could significantly discriminate type Ⅱ EC from type I EC with the AUC of 0.938(0.837-1.000).3.Among the patients who received fertility preservation treatment,169,136,and 22 different urine metabolites were identified between PT and PR group,PT and CR group,PR and CR group,respectively.The content of citric acid,fatty acid,PGE2 decreased significantly with the gradual remission of lesions.The differential metabolites were enriched in TCA cycle,fatty acid synthesis,steroid hormone biosynthesis,arachidonic acid metabolism,ascorbate and aladarate metabolism,as well as nicotinate and nicotinamide metabolism.Diagnostic models of combined metabolites were constructed,which could distinguish these three groups with a great diagnostic value.The AUC value of each group was 0.955,0.965,and 0.744,respectively.4.Among the 102 patients,88(86.3%)cases achieved CR,92.5%in AEH and 82.3%in EC,with the 6(3-12)months median CR time.High remission rates were found in patients who received GnRHa combined regimen,younger than 35 years old and lost more than 10%of their weight.Fifteen(17.0%)women had developed recurrence with the median recurrence time of 26(8-52)months.Patients who received GnRHa regimen,lost more than 10%weight,received maintenance therapy or conceived during the follow-up period had a low probability of recurrence.Of the patients with CR,57 women attempted to conceive and 16(28.1%)women became pregnant,7(12.3%)of them successfully delivered and 4(7.0%)were in pregnancy,while 5(8.8%)of them miscarried.Conclusions:1.This urine and serum combined metabolomics study revealed the metabolic profile of EC,and established a diagnostic model to differentiate EC from controls with great diagnostic value.2.Different metabolites between high-risk and low-risk EC,type Ⅰ and type Ⅱ EC patients were discovered using urine and serum combined metabolomics,which could be used as biomarkers for EC classification.3.Differential metabolites were screened for patients who received fertility preservation treatment through urinary metabolomics.Diagnostic panels were constructed to distinguish patients in PT,PR and CR groups with great predictive accuracy,which have potential value for evaluating the efficacy of fertility preservation treatment.4.For obese patients with EC/AEH,fertility-preserving treatment achieve a promising response.Weight loss of more than 10%has a positive influence on response,recurrence,as well as pregnancy rates.GnRHa could be an option for these women with obesity due to the less effect on weight gain compared to progestin therapy. |
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