Publications by authors named "Ding-Wei Ye"

212 Publications

Construction of a robust prognostic model for adult adrenocortical carcinoma: Results from bioinformatics and real-world data.

J Cell Mol Med 2021 Feb 24. Epub 2021 Feb 24.

Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China.

This study aims to construct a robust prognostic model for adult adrenocortical carcinoma (ACC) by large-scale multiomics analysis and real-world data. The RPPA data, gene expression profiles and clinical information of adult ACC patients were obtained from The Cancer Proteome Atlas (TCPA), Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA). Integrated prognosis-related proteins (IPRPs) model was constructed. Immunohistochemistry was used to validate the prognostic value of the IPRPs model in Fudan University Shanghai Cancer Center (FUSCC) cohort. 76 ACC cases from TCGA and 22 ACC cases from GSE10927 in NCBI's GEO database with full data for clinical information and gene expression were utilized to validate the effectiveness of the IPRPs model. Higher FASN (P = .039), FIBRONECTIN (P < .001), TFRC (P < .001), TSC1 (P < .001) expression indicated significantly worse overall survival for adult ACC patients. Risk assessment suggested significantly a strong predictive capacity of IPRPs model for poor overall survival (P < .05). IPRPs model showed a little stronger ability for predicting prognosis than Ki-67 protein in FUSCC cohort (P = .003, HR = 3.947; P = .005, HR = 3.787). In external validation of IPRPs model using gene expression data, IPRPs model showed strong ability for predicting prognosis in TCGA cohort (P = .005, HR = 3.061) and it exhibited best ability for predicting prognosis in GSE10927 cohort (P = .0898, HR = 2.318). This research constructed IPRPs model for predicting adult ACC patients' prognosis using proteomic data, gene expression data and real-world data and this prognostic model showed stronger predictive value than other biomarkers (Ki-67, Beta-catenin, etc) in multi-cohorts.
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http://dx.doi.org/10.1111/jcmm.16323DOI Listing
February 2021

Association Between Human Papillomavirus Infection and Outcome of Perioperative Nodal Radiotherapy for Penile Carcinoma.

Eur Urol Oncol 2020 Nov 13. Epub 2020 Nov 13.

San Raffaele Hospital and Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy; Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. Electronic address:

Background: Data on the impact of human papillomavirus (HPV) infection status and outcomes for perioperative treatments for patients with lymph node-involved penile squamous-cell carcinoma (PSCC) are lacking.

Objective: To analyze the benefit from perioperative radiotherapy (RT) for PSCC according to HPV infection status.

Design, Setting, And Participants: In an international multicenter database of 1254 patients with PSCC who received inguinal lymph node dissection (ILND), 507 had suitable clinical information.

Intervention: ILND, with or without chemotherapy or RT for involved lymph nodes.

Outcome Measurements And Statistical Analysis: Kaplan-Meier and restricted mean survival time (RMST) analyses for overall survival (OS) were performed for all patients and after propensity score-matching (PSM; n = 136), for which patient age, histology, type of penile surgical procedure, pathological tumor and nodal stage, ILND laterality, pelvic LND, and perioperative treatment were taken into account when assessing differences between HPV and HPV- patients. Finally, we looked at genomic alterations in PSCC using data from the Foundation Medicine database (n = 199) to characterize HPV PSCC.

Results And Limitations: Patients with HPV PSCC (n = 86; 17%) had lower clinical N stage (p < 0.001) and inguinal lymph node metastasis density (p < 0.001). Perioperative RT was delivered in 49 patients (9.7%), with the vast majority receiving adjuvant RT (n = 40). HPV patients had similar median OS (p = 0.1) but longer RMST than HPV- patients at different time points. Nevertheless, HPV patients treated with perioperative RT exhibited longer median OS (p = 0.015) and longer RMST compared to HPV- patients. In the PSM cohorts, HPV status remained significantly associated with longer OS after RT. The HPV- PSCC group had a higher frequency of TP53 mutations compared to HPV PSCC (75% vs 15%; p < 0.001). The results are limited by the retrospective nature of the data.

Conclusions: Perioperative RT was more effective in the HPV PSCC subgroup. Reasons for the enhanced radiosensitivity may be related to the lack of TP53 mutations.

Patient Summary: We analyzed data from a large multicenter database for patients with penile cancer who had received inguinal lymph node dissection, with or without chemotherapy or radiotherapy. We found that for tumors positive for human papillomavirus (HPV), use of radiotherapy resulted in prolonged survival compared to HPV-negative tumors. On the basis of these results we are inspired to design studies on the use of radiotherapy in HPV-selected patients.
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http://dx.doi.org/10.1016/j.euo.2020.10.011DOI Listing
November 2020

High Expression of CD39 is Associated with Poor Prognosis and Immune Infiltrates in Clear Cell Renal Cell Carcinoma.

Onco Targets Ther 2020 14;13:10453-10464. Epub 2020 Oct 14.

Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China.

Introduction: The cell-surface ectonucleotidase CD39 is a key molecule of the immunosuppressive adenosine pathway within the tumor microenvironment. However, the relationship between CD39 and clear cell renal cell carcinoma (ccRCC) is rarely reported and still remains unclear.

Methods: CD39 expression was first analyzed using the Oncomine and the Tumor IMmune Estimation Resource (TIMER) databases, and then examined in ccRCC patients (n=367) who had undergone radical nephrectomy using immunohistochemistry (IHC) and real-time quantitative PCR analysis (qPCR). The prognosis value of CD39 in ccRCC was evaluated by Cox proportional hazards analysis. Functional and gene set enrichment analysis (GSEA) was performed using transcriptomic data of ccRCC from TCGA. Correlation analysis between CD39 and tumor-infiltrating lymphocytes (TILs) was performed using the TISIDB database. The impact of CD39 on immune checkpoint therapy (ICT) was evaluated by two public cohorts.

Results: CD39 mRNA and protein expression was upregulated in tumor tissues from ccRCC patients and aberrant expression of CD39 was associated with advanced tumor stage and poor prognosis in ccRCC patients. EMT, IL-2/STAT5, inflammatory response, interferon gamma and KRAS hallmark gene sets were identified as CD39-related signaling pathway. The expression level of CD39 was significantly and positively correlated with high abundance of the regulatory TILs including NK cells, macrophages, Th cells and Treg cells. CD39 was correlated with expression of several immune checkpoints and higher CD39 expression was associated with better OS of ccRCC patients who received ICT.

Conclusion: CD39 is a powerful prognostic marker of ccRCC patients. Increased tumor expression of CD39 mRNA is significantly correlated with infiltrating levels of TILs, and better efficacy of ICT to ccRCC. CD39 could be a novel therapeutic target for ccRCC.
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http://dx.doi.org/10.2147/OTT.S272553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7569176PMC
October 2020

Prevalence of comprehensive DNA damage repair gene germline mutations in Chinese prostate cancer patients.

Int J Cancer 2021 Feb 16;148(3):673-681. Epub 2020 Oct 16.

Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China.

Germline DNA damage repair (DDR) deficiency has been associated with increased cancer risk, poor prognosis and therapeutic opportunity for prostate cancer (PCa) patients. However, the landscape of germline mutations in PCa covering comprehensive DDR genes has not been reported. We performed whole-exome sequencing in 246 patients who meet the National Cancer Center Network guidelines for genetic testing and analyzed variants in 276 DDR genes, which was from the Cancer Genome Atlas. A total of 79 deleterious germline alterations in 60 DDR genes were identified in 31% (76/246) patients. Mutations were found in nine DDR pathways, including 11.8% men in homologous recombination repair (HR) pathways, 2.4% men in mismatch repair (MMR) pathway and 16.7% (41/246) patients in non-HR/MMR pathways. In HRR and MMR pathways, mutations were mostly identified in BRCA2 (5.3%), HFM1 (0.8%), ZSWIM7 (0.8%), MSH2 (0.8%) and MSH3 (0.8%). When compared with the cancer-free cohort, POLN and POLG conferred high risk to PCa with odds ratio 6.9 and 20.5, respectively. We provided a comprehensive view of germline DDR gene mutations in PCa patients. We also identified two potential PCa predisposition genes: POLN and POLG, which have not been reported in the Western population, confirming the necessity of customizing a multigene panel for Chinese PCa patients.
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http://dx.doi.org/10.1002/ijc.33324DOI Listing
February 2021

Identification and validation of novel metastasis-related signatures of clear cell renal cell carcinoma using gene expression databases.

Am J Transl Res 2020 15;12(8):4108-4126. Epub 2020 Aug 15.

Department of Urology, Fudan University Shanghai Cancer Center Shanghai 200032, P. R. China.

Patients with clear cell renal cell carcinoma (ccRCC) typically face aggressive disease progression when metastasis occurs. Here, we screened and identified differentially expressed genes in three microarray datasets from the Gene Expression Omnibus database. We identified 112 differentially expressed genes with functional enrichment as candidate prognostic biomarkers. Lasso Cox regression suggested 10 significant oncogenic hub genes involved in earlier recurrence and poor prognosis of ccRCC. Receiver operating characteristic curves validated the specificity and sensitivity of the Cox regression penalty used to predict prognosis. The area under the curve indexes of the integrated genes scores were 0.758 and 0.772 for overall and disease-free survival, respectively. The prognostic values of , and were validated through an analysis of 10 hub genes in 380 patients with ccRCC from a real-world cohort. The expression levels of were of high prognostic value for predicting metastatic potential. These findings will likely significantly contribute to our understanding of the underlying mechanisms of ccRCC, which will enhance efforts to optimize therapy.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7476160PMC
August 2020

Locoregional surgical treatment improves the prognosis in patients with primary metastatic testicular cancer with a single bone or brain metastasis.

Mol Clin Oncol 2020 Aug 3;13(2):146-154. Epub 2020 Jun 3.

Department of Urology, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China.

The present study investigated the clinical significance afforded by locoregional surgery in improving the prognosis of primary metastatic testicular cancer (pMTC). The population-based Surveillance, Epidemiology and End Results database was used as the primary source of data in the present study. Stratification analysis was employed to identify the effects of testicular surgery on testicular cancer-specific survival and overall survival. Propensity score matching and Cox regression models were then employed to find and evaluate the extent of improvements to the survival of patients with pMTC by testicular surgery. The median testicular cancer-specific survival and overall survival in the surgery group were 10% higher than those in the group without surgery. Testicular surgery was demonstrated to have provided a survival advantage for patients with a single metastasis in the bone or brain, but not in the liver or lung. When combined with radiotherapy and chemotherapy, surgery significantly improved the survival of patients. However, according to the surgical outcome based on molecular subtypes, when deciding on the surgery for patients with metastatic testicular cancer, only human chorionic gonadotropin and lactate dehydrogenase, and not α-fetoprotein should be considered. Surgery serves a significant role in the management of non-seminoma, whereas its role in the management of seminoma is far more limited. The effects of locoregional surgery have been neglected when treating patients with pMTC. Surgical procedures should be considered more seriously when planning combination treatments for patients with pMTC with a single bone or brain metastasis.
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http://dx.doi.org/10.3892/mco.2020.2057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7366240PMC
August 2020

A risk calculator predicting recurrence in lymph node metastatic penile cancer.

BJU Int 2020 11 7;126(5):577-585. Epub 2020 Aug 7.

Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.

Objectives: To develop and externally validate a risk calculator for prediction of any cancer recurrence in patients with penile squamous cell carcinoma (pSCC) and inguinal lymph node metastases (ILNM), as to date no validated prognostic tool is available for patients with pSCC and ILNM.

Patients And Methods: The development cohort included 234 patients from seven referral centres. The external validation cohort included 273 patients from two additional referral centres. Cox regression identified predictors of any recurrence, which were used to develop a risk calculator. The risk-calculator grouped the development and the validation cohorts according to the individual risk of any recurrence at 24 months (24m-R). Adjuvant treatment effects were tested on overall survival (OS) according to the derived tertiles, within the development and validation cohorts.

Results: Positive surgical margins, pN , and ILNM ratio were associated with higher recurrence rate. The 2-year OS rates were lower for patients with high (>37%) and intermediate (19-37%) compared to low (<19%) 24m-R risk of recurrence, for both the development (43% and 58% vs 83%, P < 0.001) and validation cohort (44% and 50% vs 85%, P < 0.001). Results were confirmed in the subgroup of patients who did not receive adjuvant treatment (P < 0.001), but not in patients who did receive adjuvant treatments in both the development and validation cohorts (P > 0.1).

Conclusion: Adjuvant treatment planning is crucial in patients with pSCC with ILNM, where only weak evidence is available. The current tool proved to successfully stratify patients according to their individual risk, potentially allowing better tailoring of adjuvant treatments.
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http://dx.doi.org/10.1111/bju.15177DOI Listing
November 2020

Large-scale transcriptome profiles reveal robust 20-signatures metabolic prediction models and novel role of G6PC in clear cell renal cell carcinoma.

J Cell Mol Med 2020 08 21;24(16):9012-9027. Epub 2020 Jun 21.

Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China.

Clear cell renal cell carcinoma (ccRCC) is the most common and highly malignant pathological type of kidney cancer. We sought to establish a metabolic signature to improve post-operative risk stratification and identify novel targets in the prediction models for ccRCC patients. A total of 58 metabolic differential expressed genes (MDEGs) were identified with significant prognostic value. LASSO regression analysis constructed 20-mRNA signatures models, metabolic prediction models (MPMs), in ccRCC patients from two cohorts. Risk score of MPMs significantly predicts prognosis for ccRCC patients in TCGA (P < 0.001, HR = 3.131, AUC = 0.768) and CPTAC cohorts (P = 0.046, HR = 2.893, AUC = 0.777). In addition, G6PC, a hub gene in PPI network of MPMs, shows significantly prognostic value in 718 ccRCC patients from multiply cohorts. Next, G6Pase was detected high expressed in normal kidney tissues than ccRCC tissues. It suggested that low G6Pase expression significantly correlated with poor prognosis (P < 0.0001, HR = 0.316) and aggressive progression (P < 0.0001, HR = 0.414) in 322 ccRCC patients from FUSCC cohort. Meanwhile, promoter methylation level of G6PC was significantly higher in ccRCC samples with aggressive progression status. G6PC significantly participates in abnormal immune infiltration of ccRCC microenvironment, showing significantly negative association with check-point immune signatures, dendritic cells, Th1 cells, etc. In conclusion, this study first provided the opportunity to comprehensively elucidate the prognostic MDEGs landscape, established novel prognostic model MPMs using large-scale ccRCC transcriptome data and identified G6PC as potential prognostic target in 1,040 ccRCC patients from multiply cohorts. These finding could assist in managing risk assessment and shed valuable insights into treatment strategies of ccRCC.
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http://dx.doi.org/10.1111/jcmm.15536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7417710PMC
August 2020

Diagnostic Performance of Confocal Laser Endomicroscopy for the Detection of Bladder Cancer: Systematic Review and Meta-Analysis.

Urol Int 2020 18;104(7-8):523-532. Epub 2020 Jun 18.

Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China,

Objective: To systematically evaluate the diagnostic efficacy of confocal laser endomicroscopy (CLE) in detection of bladder cancer.

Methods: A systematic literature search on CLE in diagnosing bladder cancer in PubMed, Embase, and the Cochrane Library databases was performed. A bivariate meta-regression model was used for meta-analysis to evaluate the pooled diagnostic value of CLE.

Results: A total of 5 eligible studies involving 302 lesions were available for this meta-analysis. In a per-lesion analysis, pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and summary receiver-operating curve (SROC) area under the curve (AUC) of CLE for malignant lesions were 0.90 (95% confidence interval [CI]: 0.85-0.94), 0.72 (95% CI: 0.59-0.82), 3.20 (95% CI: 2.14-4.79), 0.14 (95% CI: 0.09-0.21), 23.27 (95% CI: 11.71-46.25), and 0.91 (95% CI: 0.89-0.94), respectively. For low-grade urothelial carcinomas, pooled sensitivity, specificity, PLR, NLR, DOR, and AUC for CLE were 0.72 (95% CI: 0.57-0.84), 0.87 (95% CI: 0.77-0.93), 5.48 (95% CI: 3.12-9.62), 0.32 (95% CI: 0.20-0.50), 17.19 (95% CI: 8.01-36.89), and 0.85 (95% CI: 0.82-0.88), respectively. For high-grade urothelial carcinomas, pooled sensitivity, specificity, PLR, NLR, DOR, and AUC for CLE were 0.82 (95% CI: 0.62-0.92), 0.84 (95% CI: 0.73-0.91), 4.96 (95% CI: 2.58-9.54), 0.22 (95% CI: 0.09-0.52), 22.49 (95% CI: 5.33-94.85), and 0.89 (95% CI: 0.86-0.91), respectively.

Conclusion: CLE is a promising endoscopy technique for real-time tumor grading of bladder cancer.
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http://dx.doi.org/10.1159/000508417DOI Listing
June 2020

Development and validation of a nomogram including lymphocyte-to-monocyte ratio for initial prostate biopsy: a double-center retrospective study.

Asian J Androl 2021 Jan-Feb;23(1):41-46

Department of Urology, The Affiliated Hospital of Qingdao University, Qingdao 266003, China.

Here, we developed a prostate cancer (PCa) risk nomogram including lymphocyte-to-monocyte ratio (LMR) for initial prostate biopsy, and internal and external validation were further conducted. A prediction model was developed on a training set. Significant risk factors with P < 0.10 in multivariate logistic regression models were used to generate a nomogram. Discrimination, calibration, and clinical usefulness of the model were assessed using C-index, calibration plot, and decision curve analysis (DCA). The nomogram was re-examined with the internal and external validation set. A nomogram predicting PCa risk in patients with prostate-specific antigen (PSA) 4-10 ng ml was also developed. The model displayed good discrimination with C-index of 0.830 (95% confidence interval [CI]: 0.812-0.852). High C-index of 0.864 (95% CI: 0.840-0.888) and 0.871 (95% CI: 0.861-0.881) was still reached in the internal and external validation sets, respectively. The nomogram exhibited better performance compared to the nomogram with PSA only (C-index: 0.763, 95% CI: 0.746-0.780, P < 0.001) and the nomogram with LMR excluded (C-index: 0.824, 95% CI: 0.804-0.844, P < 0.010). The calibration curve demonstrated good agreement in the internal and external validation sets. DCA showed that the nomogram was useful at the threshold probability of >4% and <99%. The nomogram predicting PCa risk in patients with PSA 4-10 ng ml also displayed good calibration and discrimination performance (C-index: 0.734, 95% CI: 0.708-0.760). This nomogram incorporating age, PSA, digital rectal examination, abnormal imaging signals, PSA density, and LMR could be used to facilitate individual PCa risk prediction in initial prostate biopsy.
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http://dx.doi.org/10.4103/aja.aja_19_20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7831838PMC
June 2020

[Attitudes of prostate cancer patients towards postoperative penile rehabilitation and their influencing factors].

Zhonghua Nan Ke Xue 2019 Apr;25(5):329-332

Department of Urology, Shanghai Cancer Center; Shanghai Medical College, Fudan University, Shanghai 200025, China.

Objective: To investigate the attitudes of prostate cancer (PCa) patients towards postoperative penile rehabilitation and their influencing factors.

Methods: Seventy-nine PCa patients underwent radical prostatectomy from January through June 2017 and all received a questionnaire investigation before surgery on IIEF-5 and their attitudes towards postoperative penile rehabilitation. We analyzed the reasons for the patients' rejection of postoperative penile rehabilitation.

Results: Totally 56 (71%) of the patients accepted and the other 23 (29%) refused postoperative penile rehabilitation. The factors influencing their attitudes towards penile rehabilitation mainly included age (P = 0.023), income (P = 0.040), tumor stage (P = 0.044), and preoperative sexual activity (P = 0.004). The patients who accepted penile rehabilitation had significantly higher IIEF-5 scores than those who refused it (14.75 ± 0.88 vs 8.48 ± 1.16, P = 0.000 2). During the follow-up period, only 29 (36.7%) of the patients bought the vacuum erection device but not the other 50 (63.3%). The tumor stage (P = 0.004), income (P < 0.01) and preoperative androgen-deprivation therapy (P = 0.039) significantly influenced the patients' decision on the purchase of the device. Relevant admission education achieved a 45% decrease in the number of the patients unwilling to accept penile rehabilitation for worrying about its negative effect on cancer treatment, a 25% decrease in those rejecting penile rehabilitation because of age, and a 20% decrease in those refusing it due to the tumor stage. The cost of treatment was an important reason for the patients' rejection of postoperative penile rehabilitation.

Conclusions: The tumor stage and income are the main factors influencing PCa patients' decision on postoperative penile rehabilitation. Relevant admission education and reduced cost of rehabilitation are important for popularization of postoperative penile rehabilitation in PCa patients.
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April 2019

Optimising the selection of candidates for neoadjuvant chemotherapy amongst patients with node-positive penile squamous cell carcinoma.

BJU Int 2020 06 1;125(6):867-875. Epub 2020 Apr 1.

University Hospital Rostock, Rostock, Germany.

Objectives: To identify predictors of poor overall survival (OS) amongst patients with penile squamous cell carcinoma (pSCC) with clinical inguinal lymphadenopathy (cN+), in order to define the best candidates for neoadjuvant chemotherapy (NAC).

Patients And Methods: Using an international, multicentre database of 924 patients with pSCC, we identified 334 men who harboured cN+ with available clinical and follow-up data. Lymph node involvement was defined either by the presence of palpable inguinal node disease or by preoperative computed tomography (CT) assessment. Fluorine-18 fluorodeoxyglucose positron-emission tomography ( F-FDG-PET)/CT scan was performed based on clinical judgment of the treating physician. Regression-tree analysis generated a risk stratification tool for prediction of 24-month overall mortality (OM). Kaplan-Meier explored the OS benefit related to the use of NAC according to the regression-tree-stratified subgroups.

Results: Overall, 120 (35.9%), 152 (45.5%), and 62 (18.6%) patients harboured cN1, cN2, and cN3 disease. F-FDG-PET/CT was performed in 48 (14.4%) patients, and 16 (4.8%) had inguinal and pelvic nodal PET detection. The median OS was 107 months, with a 24-month OS of 66%. At regression-tree analysis (area under the curve = 70%), patients with cN3 and cN2 with PET/CT-detected inguinal and pelvic nodal activity had a higher risk of 24-month OM (>50%). NAC was associated with improved 24-month OS rates (54% vs 33%) only in this subgroup of patients (P = 0.002), which was also confirmed after multivariable adjustment (hazard ratio 0.28, 95% confidence interval 0.13-0.62; P = 0.002).

Conclusion: Patients with pSCC with cN3 or cN2 and inguinal and pelvic 18F-FDG-PET/CT scan detected disease had higher 24-month OM rates according to our regression-tree model. NAC was associated with improved OS only in these subgroups of patients. Our novel decision model may help to stratify cN+ patients, and identify those who most likely will benefit from NAC prior to radical surgical resection.
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http://dx.doi.org/10.1111/bju.15054DOI Listing
June 2020

Prognostic value of primary tumor surgery in seminoma patients with distant metastasis at diagnosis: a population-based study.

Asian J Androl 2020 Nov-Dec;22(6):602-607

Department of Urology, Fudan University Shanghai Cancer Center, Shanghai 200032, China.

The aims of this study were to determine the prognostic value of primary tumor surgery and identify optimal candidates for such surgery among patients with seminoma and distant metastasis at diagnosis. We identified 521 patients with seminoma and distant metastasis at diagnosis between 2004 and 2014 from the Surveillance, Epidemiology, and End Results database. Among these patients, 434 had undergone surgery, whereas 87 had not. The prognostic value of primary tumor surgery was assessed by Kaplan-Meier methods, log-rank analyses, and multivariate Cox's proportional hazards model. Survival curves and forest plots were also plotted. Survival analysis indicated that patients who underwent surgery had a better 5-year overall survival and cancer-specific survival than those who did not. Multivariate analyses demonstrated that primary tumor surgery is an independent prognostic factor for overall survival and cancer-specific survival, along with age at diagnosis, M stage, and marital status. In addition, primary tumor surgery still had considerable prognostic value in the subgroup of patients with lymph node metastasis. Further, forest plots demonstrated that patients with M1a stage, N1 or N2-3 stage, and a younger age at diagnosis (<60 years) may benefit from primary tumor surgery. In conclusion, our findings indicate that primary tumor surgery is correlated with improved survival in patients with seminoma and distant metastasis. Furthermore, primary tumor surgery is an independent prognostic indicator for patients with seminoma and distant metastasis.
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http://dx.doi.org/10.4103/aja.aja_140_19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7705971PMC
February 2020

Development and validation of a robust multigene signature as an aid to predict early relapse in stage I-III clear cell and papillary renal cell cancer.

J Cancer 2020 1;11(5):997-1007. Epub 2020 Jan 1.

Department of Urology, Fudan University Shanghai Cancer Center, Shanghai 200032, China.

Multi-gene signature can be used as prognostic indicator in many types of cancer, but the association with early-relapse in patients with stage I-III clear cell and papillary renal cell cancer (RCC) is unknown. We aim to establish a mRNAs signature for improving prediction of early-relapse in patients with stage I-III clear cell and papillary RCC. The data of 610 patients with stage I-III RCC from The Cancer Genome Atlas (TCGA) and 270 patients from Fudan University Shanghai Cancer Center (FUSCC) were extracted. Propensity score matching analysis, linear models for microarray data VOOM method, least absolute shrinkage and selection operation Cox regression modeling analysis was conducted in turn for selecting multi-mRNA signature. Survival differences were assessed by Kaplan-Meier estimate and compared using log-rank test. Multivariable Cox regression and time-dependent receiver operating characteristic curves were used to evaluate the association of mRNAs signature with relapse-free survival (RFS). Seventeen mRNAs were identified to constitute the early-relapse signature. Among patients with stage I-III RCC, those with high-risk score calculated from 17 mRNAs signature showed shorter RFS than those with low-risk score, both in TCGA discovery and internal validation sets, and in FUSCC discovery and internal validation sets (all p < 0.05). In multivariable Cox regression analysis, the 17 mRNAs signature remained an independent prognostic factor both in TCGA discovery (HR 2.43, 95%CI 1.98-2.96) and internal validation sets (HR 1.66, 95%CI 1.19-2.30), and FUSCC discovery (HR 1.28, 95%CI 1.13-1.43) and internal validation sets (HR 1.65, 95%CI 1.11-2.48). Additionally, the 17 mRNAs signature achieved a higher accuracy for RFS estimation beyond clinical indicator. The 17 mRNAs signature could classify stage I-III RCC patients into low- or high-risk of early-relapse, and will help to guide interventions to optimize survival outcomes.
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http://dx.doi.org/10.7150/jca.38274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6959077PMC
January 2020

Prostate volume does not provide additional predictive value to prostate health index for prostate cancer or clinically significant prostate cancer: results from a multicenter study in China.

Asian J Androl 2020 Sep-Oct;22(5):539-543

Department of Urology, Shanghai Changhai Hospital, The Second Military Medical University, Shanghai 200433, China.

To evaluate whether prostate volume (PV) would provide additional predictive utility to the prostate health index (phi) for predicting prostate cancer (PCa) or clinically significant prostate cancer, we designed a prospective, observational multicenter study in two prostate biopsy cohorts. Cohort 1 included 595 patients from three medical centers from 2012 to 2013, and Cohort 2 included 1025 patients from four medical centers from 2013 to 2014. Area under the receiver operating characteristic curves (AUC) and logistic regression models were used to evaluate the predictive performance of PV-based derivatives and models. Linear regression analysis showed that both total prostate-specific antigen (tPSA) and free PSA (fPSA) were significantly correlated with PV (all P < 0.05). [-2]proPSA (p2PSA) was significantly correlated with PV in Cohort 2 (P< 0.001) but not in Cohort 1 (P= 0.309), while no significant association was observed between phi and PV. When combining phi with PV, phi density (PHID) and another phi derivative (PHIV, calculated as phi/PV) did not outperform phi for predicting PCa or clinically significant PCa in either Cohort 1 or Cohort 2. Logistic regression analysis also showed that phi and PV were independent predictors for both PCa and clinically significant PCa (all P < 0.05); however, PV did not provide additional predictive value to phi when combining these derivatives in a regression model (all models vs phi were not statistically significant, all P > 0.05). In conclusion, PV-based derivatives (both PHIV and PHID) and models incorporating PV did not improve the predictive abilities of phi for either PCa or clinically significant PCa.
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http://dx.doi.org/10.4103/aja.aja_136_19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523603PMC
January 2020

Prognostic value of epithelial-mesenchymal transition markers in clear cell renal cell carcinoma.

Aging (Albany NY) 2020 01 8;12(1):866-883. Epub 2020 Jan 8.

Department of Urology, Fudan University Shanghai Cancer Center, Shanghai 200032, China.

Epithelial-to-mesenchymal transition (EMT) is important in tumor invasiveness and metastasis. We aimed to determine prognostic value of six key EMT markers (, , , , , ) in clear cell renal cell carcinoma (ccRCC). A total of 533 ccRCC patients with RNASeq data from The Cancer Genome Atlas (TCGA) cohort were included for analysis. Gene expression of these EMT markers was compared between tumor and normal tissues based on Oncomine database and TCGA cohort. Their correlations with progression-free survival (PFS) and overall survival (OS) were also examined in both TCGA cohort and FUSCC (Fudan University Shanghai Cancer Center) cohort. Cox proportional hazards regression model and Kaplan-Meier plot were used to assess the relative factors. Functional enrichment analyses were utilized to describe biologic function annotations and significantly involved hallmarks pathways of each gene. We found that Epithelial marker, expression was lower, while mesenchymal markers (, , , ) expression was higher in ccRCC primary tumors. In the TCGA cohort, we found that patients with higher expression of , or lower expression of had worse prognosis. Further, in the FUSCC cohort, we confirmed the predictive ability of mesenchymal markers and epithelial marker expression in PFS and OS of ccRCC patients. After generating Cox regression models, EMT markers (, , , and ) were independent prognostic factors of both PFS and OS in ccRCC patients. Our preliminary EMT prediction model can facilitate further screening of EMT biomarkers and cast a better understanding of EMT gene function in ccRCC.
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http://dx.doi.org/10.18632/aging.102660DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6977664PMC
January 2020

Prognostic implication and functional annotations of Rad50 expression in patients with prostate cancer.

J Cell Biochem 2020 06 30;121(5-6):3124-3134. Epub 2019 Dec 30.

Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China.

Increasing evidence has shown that Rad50, a protein involved in the DNA damage repair process, significantly correlated with tumor prognosis. This study focused on Rad50 expression in tumor samples and its prognostic value for patients with prostate cancer (PCa). In this study, significantly elevated Rad50 expression in PCa tissues compared to normal tissues (P < .01). Five independent Oncomine databases validated significant differential expression of Rad50 (P < .001). Hence, 80 patients with PCa from Fudan University Shanghai Cancer Center (FUSCC) and 351 patients with PCa with available protein expression data from The Cancer Genome Atlas (TCGA) were included to investigate the survival benefit. Univariate and multivariate Cox regression analyses were performed to investigate the significance of clinicopathological factors on disease-free survival (DFS) and overall survival (OS). Kaplan-Meier analysis indicated that elevated Rad50 protein expression levels significantly correlated with unfavorable DFS (P = .005) in the FUSCC cohort and poorer OS (P = .04) in TCGA cohort. Furthermore, coregulation analysis of proteins indicated that 76 coregulated proteins were associated with Rad50, while 11 most highly involved hub proteins, including Rad50, MRE11A, DUT, POLR3A, MCM3AP, RECQL, PNPT1, RANBP3, DDX1, SNRPB, and UGN, were significantly coregulated in the protein-protein interaction network. Functional enrichment analysis consecutively indicated significant functions and signaling pathways including DNA replication, spliceosome, DNA geometric change, homologous recombination, and G2M checkpoint. This study first reveals that elevated Rad50 expression is significantly associated with aggressive progression and poor survival for patients with PCa. Together, these data suggest that Rad50 may act as an oncoprotein, guide the molecular diagnosis, and may shed light on novel individual therapeutic strategies for progressive PCa patients.
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http://dx.doi.org/10.1002/jcb.29580DOI Listing
June 2020

Extended versus non-extended lymphadenectomy during radical cystectomy for patients with bladder cancer: a meta-analysis of the effect on long-term and short-term outcomes.

World J Surg Oncol 2019 Dec 21;17(1):225. Epub 2019 Dec 21.

Department of Urology, Fudan University Shanghai Cancer Center, No. 270 Dong an Road, Shanghai, 200032, People's Republic of China.

Background: Pelvic lymphadenectomy (PLND) is an integral part of curative surgery for high-risk non-muscle invasive and muscle-invasive bladder cancer. The therapeutic value of extended PLND is controversial.

Methods: We conducted a comprehensive online search in PubMed, EMBASE, and the Cochrane Library databases for relevant literature directly comparing extended PLND (e-PLND) with non-extended PLND (ne-PLND) from database inception to June 2019. We performed the meta-analysis to evaluate the impact of PLND templates on recurrence-free survival (RFS), disease-specific survival (DSS), overall survival (OS), rates of postoperative major complications, and mortality within 90 days of surgery.

Results: A total of 10 studies involving 3979 patients undergoing either e-PLND or ne-PLND were included. The results showed that e-PLND was significantly associated with better RFS (HR 0.74, 95% CI 0.62-0.90, p = 0.002) and DSS (HR 0.66, 95% CI 0.55-0.79, p < 0.001). However, no correlation was found between e-PLND template and a better OS (HR 0.93, 95% CI 0.55-1.58, p = 0.79). Postoperative major complications were similar between e-PLND group and ne-PLND group, as was mortality within 90 days of surgery.

Conclusion: e-PLND template is correlated with favorable RFS and DSS outcomes for patients with bladder cancer. e-PLND did not have more postoperative major complications than did ne-PLND.
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http://dx.doi.org/10.1186/s12957-019-1759-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6925870PMC
December 2019

The Role of Serine Peptidase Inhibitor Kazal Type 13 (SPINK13) as a Clinicopathological and Prognostic Biomarker in Patients with Clear Cell Renal Cell Carcinoma.

Med Sci Monit 2019 Dec 11;25:9458-9470. Epub 2019 Dec 11.

Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China (mainland).

BACKGROUND The serine peptidase inhibitor Kazal type 13 (SPINK13) gene has tumor suppressor activity, but its role in renal cell carcinoma (RCC) remains unknown. This study aimed to investigate mRNA expression of SPINK13 in clear cell renal cell carcinoma (CCRCC) in human tissue and to use bioinformatics data to investigate the role of SPINK13 expression as a clinicopathological and prognostic biomarker for patients with CCRCC. MATERIAL AND METHODS Patients with CCRCC (N=533) with available RNA sequence data from The Cancer Genome Atlas (TCGA)-CCRCC database were analyzed with patients who had a tissue diagnosis of CCRCC (N=305) at the Fudan University Shanghai Cancer Center (FUSCC). Differential transcriptional and proteome expression profiles were obtained from the ONCOMINE cancer microarray database, TCGA, and the Human Protein Atlas (HPA) database. Quantitative reverse transcription-polymerase chain reaction (RT-qPCR) measured SPINK13 mRNA expression in 305 samples of CCRCC tissue from the FUSCC. The effects of clinicopathological parameters on progression-free survival (PFS) and overall survival (OS) were analyzed using the Kaplan-Meier and log-rank test. RESULTS Transcriptional and proteome expression of SPINK13 were significantly increased CCRCC tissue samples. Increased SPINK13 mRNA expression was significantly associated with reduced PFS and OS in 838 patients with CCRCC patients from the two independent cohorts, the FUSCC and the TCGA-CCRCC cohorts (p<0.01). Gene set enrichment analysis (GSEA) showed that SPINK13 expression was involved in complement, apical junction, epithelial-mesenchymal transition (EMT), glycolysis, hypoxia, and inflammation signaling pathways. CONCLUSIONS Increased expression of SPINK13 was associated with poor prognosis in patients with CCRCC.
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http://dx.doi.org/10.12659/MSM.917754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6926094PMC
December 2019

The Prognostic Value of Programmed Death-Ligand 1 in a Chinese Cohort With Clear Cell Renal Cell Carcinoma.

Front Oncol 2019 25;9:879. Epub 2019 Nov 25.

Department of Urology, Fudan University Shanghai Cancer Center, Institutes of Biomedical Sciences, and School of Life Sciences, Fudan University, Shanghai, China.

To investigate the association between tumor PD-L1 expression and patient survival to determine whether PD-L1 represents an independent prognostic feature for patients with non-metastatic clear cell renal cell carcinoma (RCC). The tissue bank of the Fudan University Shanghai Cancer Center was queried to identity tissue samples of patients treated with radical nephrectomy, for non-metastatic sporadic clear cell RCC (ccRCC) between 2008 and 2015. Real-time polymerase chain reaction and immunohistochemistry staining was performed to detect the expression level of PD-L1 in paired cancer tissue and paracancerous tissue. Three-hundred-and-thirty patients were enrolled in this study, with a mean age of 55.0 years at surgery and a mean tumor size of 5.2 cm. Two-hundred-and-forty-two (73.3%) and 88 (26.7%) patients showed a high and low expression of PD-L1 mRNA, respectively, while 254 patients had positive PD-L1 immunohistochemistry staining. Two-hundred-and-ninety-two patients had consistent results for mRNA and the PD-L1 protein based on these different detection methods. Patients with high PD-L1 expression were more likely to exhibit adverse pathologic features including an advanced T stage ( = 0.002) and lymph node metastasis ( = 0.044). The Kaplan-Meier curves of PFS and OS stratified by PD-L1 expression had a statistically significant difference. PD-L1 expression maintained a significant predictive role for PFS and OS in the multivariate cox model. Our data suggests that PD-L1 correlates with prognosis in RCC and targeting the PD-1/PD-L1 pathway should be considered in the treatment of RCC patients.
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http://dx.doi.org/10.3389/fonc.2019.00879DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6886562PMC
November 2019

C-Reactive Protein Levels and Survival Following Cytoreductive Nephrectomy in 118 Patients with Metastatic Renal Cell Carcinoma Treated with Sunitinib: A Retrospective Study.

Med Sci Monit 2019 Nov 26;25:8984-8994. Epub 2019 Nov 26.

Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China (mainland).

BACKGROUND This study aimed to evaluate the factors associated with a survival benefit for patients with metastatic renal cell carcinoma (mRCC) treated with sunitinib, with and without cytoreductive nephrectomy (CN). MATERIAL AND METHODS This retrospective clinical study included 118 patients with mRCC who were treated with CN and sunitinib (CN-sunitinib) (N=70) and with sunitinib-alone (N=48). Categorical clinicopathological variables were compared with hypothesis tests using contingency tables and a chi-squared test. Independent indicators for progression-free survival (PFS) and overall survival (OS) were analyzed with univariate and multivariate Cox regression models. The Kaplan-Meier method and log-rank test were used to evaluate patient survival. RESULTS The median PFS and OS for the 118 patients were 8.38 and 15.48 months, respectively. There were no significant differences between the CN-sunitinib group and the sunitinib-alone group for either PFS (7.2 months vs. 11.6 months; P=0.525) or OS (16.7 months vs. 15.2 months; P=0.839). Stratification of patients based on clinicopathological characteristics showed that CN was significantly associated with reduced PFS and OS for patients with lymph node metastasis (PFS, P<0.001; OS, P<0.001) and high International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk scores (PFS, P=0.003; OS, P=0.011). However, CN was associated with a significant survival benefit for patients with low levels of serum C-reactive protein (CRP<10 mg/L) (PFS, P=0.026; OS, P=0.007). CONCLUSIONS Sunitinib-alone without CN improved the survival of patients with mRCC who had high IMDC risk scores or lymph node metastasis. CN and sunitinib resulted in significantly improved survival in patients with low serum CRP.
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http://dx.doi.org/10.12659/MSM.918635DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6897293PMC
November 2019

Genetic variants in influencing telomere length are associated with prostate cancer risk.

J Cancer 2019 15;10(24):6170-6174. Epub 2019 Oct 15.

Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China.

Telomere length measured in lymphocytes has been evaluated as a potential biomarker for prostate cancer (PCa) risk. Identifying genetic variants that affect telomere length and testing their association with disease could clarify any causal role. We therefore investigated associations between genetic variants in three telomere length-related genes and PCa risk in a case-control study. The influence of these variants on the leukocyte telomere lengths was then appraised by real-time PCR. rs2297441 [odds ratio (OR): 1.23; 95% confidence interval (CI): 1.03-1.46, = 0.021] and rs3208008 (OR: 1.23; 95% CI: 1.03-1.46) were associated with PCa risk. These two risk single nucleotide polymorphisms (SNPs) (OR: 0.59; 95% CI: 0.39-0.89, = 0.012 and OR: 0.58; 95% CI: 0.38-0.87, = 0.009, respectively) and another SNP rs1136410 (OR: 1.53; 95% CI: 1.01-2.31, = 0.043) were also associated with leukocyte telomere length. These findings support that genetic determinants of telomere length may influence PCa risk.
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http://dx.doi.org/10.7150/jca.35917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6856594PMC
October 2019

Prognostic implications of Aquaporin 9 expression in clear cell renal cell carcinoma.

J Transl Med 2019 11 8;17(1):363. Epub 2019 Nov 8.

Cancer Institute, Fudan University Shanghai Cancer Center, No. 270 Dong'an Road, Shanghai, 200032, People's Republic of China.

Background: Growing evidence has demonstrated immune reactivity as a confirmed important carcinogenesis and therapy efficacy for clear cell renal cell carcinoma (ccRCC). Aquaporin 9 (AQP9) is involved in many immune-related signals; however, its role in ccRCC remains to be elucidated. This study investigated AQP9 expression in tumor tissues and defined the prognostic value in ccRCC patients.

Methods: A total of 913 ccRCC patients with available RNA-sequence data from the Cancer Genome Atlas (TCGA) database and Fudan University Shanghai Cancer Center (FUSCC) were consecutively recruited in analyses. Differential transcriptional and proteome expression profiles were obtained and validated using multiple datasets. A partial likelihood test from Cox regression analysis was developed to address the influence of independent factors on progression-free survival (PFS) and overall survival (OS). The Kaplan-Meier method and log-rank test were performed to assess survival. Receiver operating characteristic (ROC) curves were used to describe binary classifier value of AQP9 using area under the curve (AUC) score. Functional enrichment analyses and immune infiltration analysis were used to describe significantly involved hallmark pathways of hub genes.

Results: Significantly elevated transcriptional and proteomic AQP9 expressions were found in ccRCC samples. Increased AQP9 mRNA expression was significantly associated with advanced clinicopathological parameters and correlated with shorter PFS and OS in TCGA and FUSCC cohorts (p < 0.001). ROC curves suggested the significant diagnostic and prognostic ability of AQP9 (PFS, AUC = 0.823; OS, AUC = 0.828). Functional annotations indicated that AQP9 is involved in the most significant hallmarks including complement, coagulation, IL6/JAK-STAT3, inflammatory response and TNF-alpha signaling pathways.

Conclusion: Our study revealed that elevated AQP9 expression was significantly correlated with aggressive progression, poor survival and immune infiltrations in ccRCC patients, and we validated its prognostic value in a real-world cohort. These data suggest that AQP9 may act as an oncogene and a promising prognostic marker in ccRCC.
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http://dx.doi.org/10.1186/s12967-019-2113-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6842264PMC
November 2019

Inactivation of the AMPK-GATA3-ECHS1 Pathway Induces Fatty Acid Synthesis That Promotes Clear Cell Renal Cell Carcinoma Growth.

Cancer Res 2020 01 5;80(2):319-333. Epub 2019 Nov 5.

Department of Urology, Fudan University Shanghai Cancer Center, the Obstetrics and Gynecology Hospital of Fudan University, State Key Lab of Genetic Engineering and School of Life Sciences, Fudan University, Shanghai, P.R. China.

The tumorigenic role and underlying mechanisms of lipid accumulation, commonly observed in many cancers, remain insufficiently understood. In this study, we identified an AMP-activated protein kinase (AMPK)-GATA-binding protein 3 (GATA3)-enoyl-CoA hydratase short-chain 1 (ECHS1) pathway that induces lipid accumulation and promotes cell proliferation in clear cell renal cell carcinoma (ccRCC). Decreased expression of ECHS1, which is responsible for inactivation of fatty acid (FA) oxidation and activation of FA synthesis, positively associated with ccRCC progression and predicted poor patient survival. Mechanistically, ECHS1 downregulation induced FA and branched-chain amino acid (BCAA) accumulation, which inhibited AMPK-promoted expression of GATA3, a transcriptional activator of ECHS1. BCAA accumulation induced activation of mTORC1 and FA synthesis, and promoted cell proliferation. Furthermore, GATA3 expression phenocopied ECHS1 in predicting ccRCC progression and patient survival. The AMPK-GATA3-ECHS1 pathway may offer new therapeutic approaches and prognostic assessment for ccRCC in the clinic. SIGNIFICANCE: These findings uncover molecular mechanisms underlying lipid accumulation in ccRCC, suggesting the AMPK-GATA3-ECHS1 pathway as a potential therapeutic target and prognostic biomarker.
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http://dx.doi.org/10.1158/0008-5472.CAN-19-1023DOI Listing
January 2020

Screening and Identification of Potential Prognostic Biomarkers in Adrenocortical Carcinoma.

Front Genet 2019 11;10:821. Epub 2019 Sep 11.

Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China.

Adrenocortical carcinoma (ACC) is a rare but aggressive malignant cancer that has been attracting growing attention over recent decades. This study aims to integrate protein interaction networks with gene expression profiles to identify potential biomarkers with prognostic value . Three microarray data sets were downloaded from the Gene Expression Omnibus (GEO) database to identify differentially expressed genes (DEGs) according to the normalization annotation information. Enrichment analyses were utilized to describe biological functions. A protein-protein interaction network (PPI) of the DEGs was developed, and the modules were analyzed using STRING and Cytoscape. LASSO Cox regression was used to identify independent prognostic factors. The Kaplan-Meier method for the integrated expression score was applied to analyze survival outcomes. A receiver operating characteristic (ROC) curve was constructed with area under curve (AUC) analysis to determine the diagnostic ability of the candidate biomarkers. A total of 150 DEGs and 24 significant hub genes with functional enrichment were identified as candidate prognostic biomarkers. LASSO Cox regression suggested that , , , and were independent prognostic factors in ACC. In multivariate Cox analysis, the integrated expression scores of the modules showed statistical significance in predicting . Meanwhile, ROC curves were generated to validate the ability of the Cox model to predict prognosis. The AUC index for the integrated genes scores was 0.861 ( < 0.0001). In conclusion, the present study identifies DEGs and hub genes that may be involved in poor prognosis and early recurrence of ACC. The expression levels of , , , and are of high prognostic value, and may help us understand better the underlying carcinogenesis or progression of ACC. Further studies are required to elucidate molecular pathogenesis and alteration in signaling pathways for these genes in ACC.
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http://dx.doi.org/10.3389/fgene.2019.00821DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6749084PMC
September 2019

Elevated CD36 expression correlates with increased visceral adipose tissue and predicts poor prognosis in ccRCC patients.

J Cancer 2019 25;10(19):4522-4531. Epub 2019 Jul 25.

Department of Urology, Fudan University Shanghai Cancer Center, Shanghai 200032.

Growing evidence has proved obesity one of the confirmed important etiologic indicators for renal cell carcinoma (RCC). is underpinned to be involved in adipose absorption, but its role in clear cell renal cell carcinoma (ccRCC) remains unclear. This study aimed to investigate the mRNA expression of in anthropometric measures of adipose tissue and defining its value in predicting prognosis in ccRCC patients. Real-Time qPCR gene expression analysis was detected from 367 paired ccRCC and adjacent normal tissues. Distributions of categorical clinical-pathological data together with levels of expression were compared with χ-test in a contingency table. Subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) were measured by magnetic resonance imaging (MRI) and identified at the level of the umbilicus. Pearson's correlation coefficient was utilized to quantify relations between body mass index (BMI), VAT%, SAT and expression respectively. Partial likelihood test from univariate and multivariate Cox regression analysis were developed to address the influence of independent factors on progression-free survival (PFS) and overall survival (OS). The Kaplan-Meier method and log-rank test were performed to assess the survival benefits between discrete levels. In the current study, mRNA was demonstrated highly expressed in ccRCC compared with normal tissues. In addition, mRNA expression was significantly increased in patients with advanced TNM stage (=0.003, <0.001, <0.001), and high VAT% (=0.004). Pearson's correlation coefficient indicated that amplification positively correlated with BMI (=0.117, =0.025), VAT% (=0.465, <0.001), while negatively associated with SAT (=-0.296, =0.002). Median PFS was 60 months and OS was 99 months. Meanwhile, ccRCC patients with elevated expression held shorter PFS and OS, with hazard ratios [HR; 95% confidence interval (CI)] of 4.873 (3.300-7.196, <0.001) and 4.610 (2.956-7.189, <0.001). In 104 cases with available MRI scans, VAT was significantly correlated with poor PFS and OS, with HR of 2.556 (1.036-6.310, <0.042) and 3.291 (1.034-10.477, <0.044). A total of 100 significant genes were obtained from GSEA, and was found involved in the most significant pathways including fatty acid metabolism, UV response, angiogenesis and transforming growth factor beta (TGF-β) signaling pathways. In conclusion, our study first reveal that elevated mRNA expression is positively correlated to distribution of abdominal adipose, particularly VAT%, which, in addition, notably predicts poor prognosis in ccRCC patients.
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http://dx.doi.org/10.7150/jca.30989DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6746135PMC
July 2019

Decreased SPTLC1 expression predicts worse outcomes in ccRCC patients.

J Cell Biochem 2020 02 12;121(2):1552-1562. Epub 2019 Sep 12.

Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China.

Objective: Serine palmitoyltransferase, long chain base subunit 1 (SPTLC1) catalyzes the first step in sphingolipid synthesis and has been implicated in the progression of various cancers. However, its role in clear cell renal cell carcinoma (ccRCC) remains unclear. Here, we investigated the expression and prognostic value of SPTLC1 in ccRCC.

Methods: Three ccRCC patient cohorts were studied. ccRCC and adjacent normal kidney tissue samples were obtained from 183 patients at the Fudan University Shanghai Cancer Center (FUSCC) and subjected to immunohistochemical staining and quantitative reverse-transcription polymerase chain reaction to evaluate SPTLC1 protein and messenger RNA (mRNA) expression. Two validation cohorts consisting of mRNA and clinicopathological data sets from patients with ccRCC were obtained from the Cancer Genome Atlas (TCGA, n = 429) and Oncomine (n = 178) databases. Associations between low and high SPTLC1 mRNA and protein expression and survival were evaluated using the Kaplan-Meier method and log-rank test. Independent prognostic factors were identified using univariate and multivariate Cox regression analysis.

Results: SPTLC1 mRNA or protein were expressed at significantly lower levels in ccRCC tissues compared with normal kidney tissues in all three patient cohorts (P < .001). Low SPTLC1 expression was significantly associated with shorter overall survival in the FUSCC (P = .041) and Oncomine (P < .001) cohorts, and was significantly associated with shorter overall survival (P < .0001) and progression-free survival (P < .001) in the TCGA cohort. Bioinformatics analysis identified 10 genes significantly coregulated with SPTLC1 in ccRCC, most of which contributed to sphingomyelin metabolism (SPTLC2, SPTLC3, SPTSSA, SPTSSB, ORMDL1, ORMDL2, ORMDL3, ZDHHC9, GOLGA7B, and KDSR). Functional enrichment analysis predicted that SPTLC1 and its network play significant roles in inflammatory, hypoxia, and interferon gamma responses, and in allograft rejection pathways.

Conclusion: Low SPTLC1 expression is significantly associated with disease progression and poor survival in patients with ccRCC, suggesting that SPTLC1 may function as a tumor suppressor. Thus, SPTLC1 could be a potential new biomarker and/or therapeutic target for ccRCC.
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http://dx.doi.org/10.1002/jcb.29390DOI Listing
February 2020

Prognostic value and immune infiltration of novel signatures in clear cell renal cell carcinoma microenvironment.

Aging (Albany NY) 2019 09 7;11(17):6999-7020. Epub 2019 Sep 7.

Department of Urology, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China.

Growing evidence has highlighted the immune response as an important feature of carcinogenesis and therapeutic efficacy in clear cell renal cell carcinoma (ccRCC). This study categorized ccRCC cases into high and low score groups based on their immune/stromal scores generated by the ESTIMATE algorithm, and identified an association between these scores and prognosis. Differentially expressed tumor environment (TME)-related genes extracted from common upregulated components in immune and stromal scores were described using functional annotations and protein-protein interaction (PPI) networks. Most PPIs were selected for further prognostic investigation. Many additional previously neglected signatures, including , exhibited significant prognostic potential. In addition, multivariate Cox analysis indicated that and were the most significant prognostic signatures, and were closely related to immune infiltration in TCGA cohort. External prognostic validation of and was undertaken in 380 ccRCC cases from a real-world cohort. These findings indicate the relevance of monitoring and manipulation of the microenvironment for ccRCC prognosis and precision immunotherapy.
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http://dx.doi.org/10.18632/aging.102233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6756904PMC
September 2019

Procollagen-lysine, 2-oxoglutarate 5-dioxygenases 1, 2, and 3 are potential prognostic indicators in patients with clear cell renal cell carcinoma.

Aging (Albany NY) 2019 08 25;11(16):6503-6521. Epub 2019 Aug 25.

Department of Urology, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China.

Intratumoral fibrosis is a frequent histologic finding in highly vascularized clear cell renal cell carcinoma (ccRCC). Here, we investigated the expression of a family of collagen-modifying enzymes, procollagen-lysine, 2-oxoglutarate 5-dioxygenases 1, 2, and 3 (PLOD1/2/3), in ccRCC tissues and assessed the prognostic value of wild-type and genetically mutated PLOD1/2/3 for ccRCC patients. Normal kidney and ccRCC mRNA and protein expression datasets were obtained from Oncomine, The Cancer Genome Atlas, and Human Protein Atlas databases. Associations between PLOD1/2/3 expression, clinicopathological variables, and patient survival were evaluated using Cox regression and Kaplan-Meier analyses. PLOD1/2/3 mRNA and protein expression levels were significantly elevated in ccRCC tissues compared with normal kidney. Increased PLOD1/2/3 mRNA expression was significantly associated with advanced tumor stage, high pathological grade, and shorter progression-free and overall survival (all <0.01). Genetic mutation of PLOD1/2/3 was present in ~3% of ccRCC patients and was associated with significantly poorer prognosis compared with expression of wild-type PLOD1/2/3 (<0.001). This study thus identifies tumor expression of wild-type or mutated PLOD1/2/3 mRNA as a potential predictive biomarker for ccRCC patients and sheds light on the underlying molecular pathogenesis of ccRCC.
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http://dx.doi.org/10.18632/aging.102206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6738415PMC
August 2019