Xi Cheng

An miRNA signature associated with tumor mutation burden in endometrial cancer

AbstractTumor mutation burden (TMB) is an essential biomarker to predict immunotherapy response. TMB measurement was mainly evaluated by whole-exome sequencing (WES), which was costly and difficult to be widely applied. In the present study, we aimed to establish and validate a miRNA signature to predict TMB level in endometrial cancer using The Cancer Genome Atlas (TCGA) database. MiRNA expression and somatic mutation profiles of uterine corpus endometrial carcinoma (UCEC) were downloaded from TCGA database. Total 518 patients with UCEC were randomly classified into training set (n=311) and validation set (n=207). Thirty-five differentially expressed miRNAs between high-TMB and low-TMB group were identified in training set. Least absolute shrinkage and selection operator (LASSO) method was performed to select out 26 miRNAs to establish the optimal signature. The accuracy of the miRNA signature for predicting TMB level was 0.833 for training set, 0.749 for validation set and 0.799 for total set. Moreover, the miRNA signature had significant correlation with immune checkpoints related genes (PD-1, PD-L1, CTLA-4) and mismatch repair related genes (BRCA1, BRCA2, MLH1, MSH6) expression. In conclusion, this miRNA signature could predict TMB level in endometrial cancer and might have some merits in providing guidance for immunotherapy in endometrial cancer.

Integrated analysis of tumor mutation burden and immune infiltrates in endometrial cancer

To explore the prognostic value of tumor mutation burden (TMB) and its correlation with immune infiltrates in endometrial cancer. Transcriptome and somatic mutation profiles of Uterine Corpus Endometrial Carcinoma (UCEC) were downloaded from TCGA database. Somatic mutations were analyzed by "maftools" and visualized in waterfall plot. We calculated TMB of each patients and divided all patients into the high-TMB group and the low-TMB group by the median threshold. Survival analysis and Wilcoxon test were used to investigate the prognostic value of TMB and its association with clinical variables. Differentially expressed genes (DEGs) were identified in 2 TMN groups and functional analysis was performed to find out significant biological pathways. A TMB-related signature was conducted by multivariate analysis, receiver operating characteristic (ROC) curve was performed to predict accuracy of the model, meanwhile, a validation cohort from Fudan University Shanghai Cancer Center (FUSCC) was obtained to verify the signature. Then we estimated association between TMB and immune infiltrates by CIBERSORT algorithm and figured out prognostic immune cells of UCEC in TIMER database. Total 575 samples including 25 normal tissues and 552 tumor samples were enrolled from TCGA database. PTEN mutations accounted for the most and single nucleotide polymorphism and C>T transitions were most frequent forms of somatic mutations in UCEC. The low-TMB group possessed worse survival than the high-TMB group (P = 0.004). DEGs in 2 TMB groups were mostly enriched in adaptive immune response and immunoglobulin/immune receptor component. A TMB-related signature consisting of GFAP, EDN3, CXCR3, PLXNA4, SST presented good predictability with area under the curve (AUC) = 0.686. In FUSCC validation cohort, the high-risk group possessed worse survival outcome than the low-risk group (P = 0.015). Immune infiltrates was correlated to survival in UCEC and low TMB were associated with less immune infiltrates, which suggested poor immune response. TMB was not only related to overall survival but also immune infiltrates in UCEC. The TMB-related signature (GFAP, EDN3, CXCR3, PLXNA4, SST) had good predictability for overall survival in endometrial cancer. Our study might have some merits in elucidating potential mechanism of TMB and immune infiltrates in UCEC and providing guidance of immunotherapy for endometrial cancer.

Significant prognostic value of cell-cycle proteins in early-stage small cell carcinoma of cervix

Small cell carcinoma of cervix (SCCC) was a highly aggressive tumor with dismal prognosis. Current treatment strategies manifested poor survival outcomes and novel treatment options were needed exploration. We aimed to investigate several prognostic biomarkers for SCCC and conducted a novel risk-score system to predict cancer specific survival (CSS) in early-stage SCCC. Seven cell-cycle proteins were detected by immunohistochemistry in 88 SCCCs. Univariate and multivariate analysis were performed to identify prognostic proteins and establish a predicting model. Total patients were divided into two groups by the median risk-score: the high-risk group and the low-risk group. Logistic regression and Wilcoxon test were used to investigate the association between clinical variables and the risk-score system. Seven cell cycle proteins were overexpressed in SCCC. The expression of CDC20, MAD2L1, MCM2 and BUBR1 were correlated to survival outcomes with P < 0.05. A novel risk-score system consisting of CDC20, MAD2L1 and BUBR1 was significantly an independent prognostic factor for CSS and the high-risk group possessed worse survival (P < 0.001). The c-indexes for clinical model, risk-score system and the combined model were 0.668, 0.718 and 0.727, respectively. The AUCs for these three models were 0.730, 0.775 and 0.823, respectively. Furthermore, we discovered that patients with high-risk scores were inclined to possessing older age, parametrial invasion and higher FIGO stage (IIA vs IA/IB) with P < 0.05. This risk-score system consisting of CDC20, MAD2L1 and BUBR1 presented good discrimination and predictability for SCCC. Novel biomarkers in this study might have some merits in providing guidance of novel treatment strategies for SCCC.

Different surgical methods for FIGO stage IVB cervical cancer patients receiving chemotherapy: a population-based study

To assess survival differences between non-extensive surgery (NES) and extensive surgery (ES) in International Federation of Gynecology and Obstetrics (FIGO) stage IVB cervical cancer patients receiving chemotherapy from a population-based database, the Surveillance, Epidemiology and End Results. Propensity matching was conducted to minimize heterogeneity. Survival analysis was performed by the Kaplan-Meier method, log-rank test, and Cox proportional hazards model. A total of 154 patients met screening criteria, among whom 84 patients (84/154) underwent NES while 70 patients (70/154) underwent ES. After matching, no survival advantage was observed in ES group compared with NES group (p=0.066; hazard ratio [HR]=1.54; 95% confidence interval [CI]=0.97-2.42). Stratified analyses suggested ES prolonged overall survival in patients with histology other than squamous cell carcinoma and adenocarcinoma (p=0.028; HR=0.36; 95% CI=0.15-0.89) and American Joint Committee on Cancer (AJCC) T stage T1 (p=0.009; HR=0.18; 95% CI=0.05-0.66). Despite no survival benefit after regional lymph node surgery (p=0.629; HR=0.88; 95% CI=0.53-1.47), subgroup analyses demonstrated that patients younger than 50 (p=0.006; HR=0.21; 95% CI=0.07-0.64), with AJCC T stage T1 (p=0.002; HR=0.09; 95% CI=0.02-0.42), T3 (p=0.001; HR=0.02; 95% CI=0.00-0.21), hematogenous metastasis (p=0.036; HR=0.27; 95% CI=0.08-0.92) and without surgery of other sites (p In conclusion, ES or regional lymph node surgery may provide survival advantage for certain subgroup of FIGO IVB cervical cancer patients receiving chemotherapy. However, it deserves large scale prospective clinical trials to confirm.

FBP1 regulates proliferation, metastasis, and chemoresistance by participating in C-MYC/STAT3 signaling axis in ovarian cancer

AbstractFructose-1,6-bisphosphatase (FBP1) is a rate-limiting enzyme in gluconeogenesis and an important tumor suppressor in human malignancies. Here, we aimed to investigate the expression profile of FBP1 in ovarian cancer, the molecular mechanisms that regulate FBP1 expression and to examine how the FBP1 regulatory axis contributes to tumorigenesis and progression in ovarian cancer. We showed that FBP1 expression was significantly decreased in ovarian cancer tissues compared with normal ovarian tissues, and low-FBP1 expression predicted poor prognosis in patients with ovarian cancer. The enhanced expression of FBP1 in ovarian cancer cell lines suppressed proliferation and 2-D/3-D invasion, reduced aerobic glycolysis, and sensitized cancer cells to cisplatin-induced apoptosis. Moreover, DNA methylation and C-MYC binding at the promoter inhibited FBP1 expression. Furthermore, through physical interactions with signal transducer and activator of transcription 3 (STAT3), FBP1 suppressed nuclear translocation of STAT3 and exerted its non-metabolic enzymatic activity to induce the dysfunction of STAT3. Thus, our study suggests that FBP1 may be a valuable prognostic predictor for ovarian cancer. C-MYC-dependent downregulation of FBP1 acted as a tumor suppressor via modulating STAT3, and the C-MYC/FBP1/STAT3 axis could be a therapeutic target.

Surgery of primary sites for stage IVB cervical cancer patients receiving chemoradiotherapy: a population-based study

The purpose of this study was to analyze the impact of surgery of primary sites on stage IVB cervical cancer patients from a population-based database, the Surveillance, Epidemiology and End Results (SEER). Propensity score matching was performed to minimize heterogeneity in patient between with-surgery group and without-surgery group. Clinicopathological characteristics were compared using the χ² or Fisher's exact test. Survival analysis included the Kaplan-Meier method, log-rank test, and Cox proportional hazards model. Between 2010-2015, a total of 1,139 International Federation of Gynecology and Obstetrics (FIGO) stage IVB cervical cancer patients receiving chemoradiotherapy (CRT) were included in this retrospective study. Within post-matching cohort, the median duration of overall survival (OS) in stage IVB cervical cancer patients receiving CRT was 22 months. The overall 5-year survival rate was 25.7%. The increasing American Joint Committee on Cancer T stage (T1 vs. T2, p=0.033, hazard ratio [HR]=1.79, 95% confidence interval [CI]=1.05-3.05; T1 vs. T3, p=0.003, HR=2.20, 95% CI=1.31-3.67; T1 vs. T4, p=0.037, HR=2.75, 95% CI=1.06-7.12) and visceral metastasis (with vs. without, p=0.038, HR=1.60, 95% CI=1.03-2.49) was reported as independent risk factors of OS. Surgery of primary sites combined with CRT tended to prolong the survival of stage IVB cervical cancer patients (p<0.001, HR=0.36, 95% CI=0.21-0.61) compared with CRT, especially for patients without visceral metastasis (p=0.005, HR=0.31, 95% CI=0.14-0.70). In conclusion, patients with stage IVB cervical cancer may achieve their best outcomes through CRT combined with surgery of primary sites. However, it deserves large scale prospective clinical trials to confirm.