ABSTRACT
OBJECTIVE: To stratify patients with copy-number low (CNL) endometrial cancer (EC) by clinicopathological characteristics. METHODS: EC patients who underwent surgery between June 2018 and June 2022 at Peking University People's Hospital were included and further classified according to TCGA molecular subtyping: POLE ultramutated, microsatellite instability high (MSI-H), CNL, and copy-number high (CNH). Clinicopathological characteristics and prognosis of CNL patients were retrospectively reviewed. The Cox proportional hazards regression model was applied to perform univariate and multivariate analysis, and independent risk factors were identified. Differentially expressed genes (DEGs) according to overall survival (OS) were screened based on the transcriptome of CNL cases from the TCGA program. Finally, a nomogram was established, with an accuracy analysis performed. RESULTS: (1) A total of 279 EC patients were included, of whom 168 (60.2%) were in the CNL group. A total of 21 patients had recurrence and 6 patients deceased, and no significant difference in recurrence-free survival (RFS) was exhibited among the four molecular subtypes (P = 0.104), but that in overall survival (OS) was statistically significant (P = 0.036). (2) CNL patients were divided into recurrence and non-recurrence groups, and significant differences (P < 0.05) were found between the two groups in terms of pathological subtype, FIGO stage, ER, PR, glycated hemoglobin (HbA1c), and high-density lipoprotein cholesterol (HDL-C). All the above factors were included in univariate and multivariate Cox regression models, among which pathological subtype, PR, and HDL-C were statistically different (P < 0.05), resulting in three independent risk factors for the prognosis of patients in the CNL group. (3) By comparing the transcriptome of tumor tissues between living and deceased CNL patients from the TCGA database, 903 (4.4%) DEGs were screened, with four lipid metabolism pathways significantly enriched. Finally, a nomogram was established, and internal cross-validation was performed, showing good discrimination accuracy with an AUC of 0.831 and a C-index of 0.748 (95% CI 0.444-1.052). (4) According to the established nomogram and the median total score (85.89), patients were divided into the high score group (n = 85) and low score group (n = 83), and the 8 patients with recurrence were all in the high score group. Survival analysis was performed between the two groups, and the difference in RFS was statistically significant (P = 0.010). CONCLUSION: In the CNL group of EC patients, pathological subtype, PR, and HDL-C were independent prognostic risk factors, the nomogram established based upon which had a good predictive ability for the recurrence risk of patients with CNL EC.
Subject(s)
Endometrial Neoplasms , Female , Humans , Retrospective Studies , Endometrial Neoplasms/genetics , Endometrial Neoplasms/surgery , Endometrial Neoplasms/pathology , Prognosis , Nomograms , Risk FactorsABSTRACT
Objective:To explore the application and clinical significance of the cancer genome atlas (TCGA) molecular classification in endometrial cancer (EC).Methods:Sixty-six EC patients collected from December 2018 to March 2021 from Peking University People′s Hospital were categorized into four subgroups based on TCGA molecular classification tested by next generation sequencing. The correlation among four molecular subgroups and the clinical-pathological features including prognosis were analyzed.Results:(1) Clinical and pathological features: median age at diagnosis was 56 years (range: 24-78 years). The cases were distributed as follows: 3 (5%) cases DNA polymerase epsilon (POLE) ultra-mutated, 11 (17%) cases high microsatellite instability (MSI-H) including 2 Lynch syndrome, 42 (64%) cases low copy-number (CN-L) and 10 (15%) cases high copy-number (CN-H). There were significant differences among four subtypes in the combination of other tumors, tumor family history, surgical method, International Federation of Gynecology and Obstetrics (FIGO, 2009) stage, depth of muscle invasion and lymph vascular space invasion (all P<0.05). The proportions of patients in CN-H subgroup with advanced FIGO stage (stage Ⅲ-Ⅳ), deep muscle invasion and positive lymph-vascular space invasion were significantly increased. There were no significant differences in age, menopausal status, body mass index, metabolic syndrome-related complications, preoperative serum CA 125 and human epididymis protein 4 levels, tumor size, pathological grade (only endometrioid cancer), and lymph node metastasis among the 4 TCGA molecular types (all P>0.05). (2) Immuno-related molecular analysis: among 66 EC patients, 27 patients underwent immunohistochemical analysis of programmed cell death 1 ligand 1 (PD-L1) protein, and 28 patients underwent tumor mutation burden (TMB) detection. POLE and MSI-H subgroups contained TMB than those in CN-L and CN-H ( P<0.05).(3) Prognosis: the median follow-up time was 10 months (range: 0-28 months). The progression-free survival rate of TCGA molecular types were 100% (POLE ultra-mutated), 100% (MSI-H), 98% (CN-L), and 80% (CN-H) respectively and had significant differences ( P=0.034). The overall survival were 100% (POLE ultra-mutated), 100% (MSI-H), 98% (CN-L), and 90% (CN-H) respectively, but there were not statistically significant difference ( P=0.361). POLE ultra-mutated and MSI-H subgroups had the best survival, while CN-H had the worst. Conclusion:TCGA molecular classification has feasibility and clinical value in clinical application of EC, which is helpful to identify the prognosis of patients.
ABSTRACT
BACKGROUND: Human umbilical cord mesenchymal stem cells (UC-MSCs), characterized by great differentiation potential, strong proliferation ability and low immunogenicity, exert an immeasurable role in wound repair and vascular regeneration in ischemic tissues.OBJECTIVE: To investigate the effect of intraventricularly injected UC-MSCs on expression of granulocyte-colony stimulating factor (GM-CSF) and transforming growth factor-β1 (TGF-β1) in the myocardium of myocardial infarction rats.METHODS: 120 adult male Sprague-Dawley rats were selected randomly, among which, 20 healthy rats were randomly selected as controls and the rest rats were subcutaneously injected with isoproterenol to establish the myocardial infarction model. Model rats were randomized into model group, UC-MSC supernatant group, UC-MSC low-dose group,middle-dose group and high-dose group, with 20 rats in each group. Twenty-four hours after modeling, normal saline,UC-MSC supernatant, UC-MSC suspensions containing 0.25×106, 1.0×106, 4.0×106 cells (2 mL) were injected intraventricularly into the rats in the corresponding groups, respectively. Left ventricular ejection fraction (LVEF),end-systolic left ventricular volume (LVESV) and left ventricular end-diastolic volume (LVEDV) were measured by echocardiography at 2 weeks after treatment. Serum lactate dehydrogenase (LDH), creatine kinase (CK) and pro-brain natriuretic peptide (Pro-BNP) were measured by enzyme-linked immunosorbent assay (ELISA). At the end of the experiment, 10 rats were killed by dislocation and the cardiac specimens were taken. The myocardial infarct size was determined by nitroblue tetrazolium staining. The expressions of GM-CSF and TGF-β in the myocardium of rats in each group were determined by western blot method.RESULTS AND CONCLUSION: (1) Higher LVEF levels and lower LVESV and LVEDV were found in the low-, middleand high-dose UC-MSC groups than the model group and UC-MSC supernatant group (P < 0.05). LVEF, LVEDV and LVEDV in the middle- and high-dose UC-MSC group were lower than those in the low-dose UC-MSC group (P < 0.05). (2)The levels of serum LDH, CK, Pro-BNP and myocardial tissue GM-CSF and TGF-β1 in the low-, middle- and high-dose UC-MSC group were significantly lower than those in the model group and UC-MSC supernatant group (P < 0.05).Compared with the low-dose UC-MSC group, the levels of serum LDH, CK, Pro-BNP and myocardial tissue GM-CSF and TGF-β1 were significantly lower in the middle- and high-dose UC-MSC groups (P < 0.05). (3) The myocardial infarct sizes of the low-, middle- and high-dose UC-MSC groups were significantly lower than those of the model and UC-MSC supernatant groups (P < 0.05), while the myocardial infarct sizes of middle- and high-dose UC-MSC groups were significantly lower than that of low-dose UC-MSC group (P < 0.05). To conclude, UC-MSCs can significantly reduce the expression of GM-CSF and TGF-β1 in the rat myocardium after myocardial infarction, effectively protect myocardial tissues, and improve cardiac function.
