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Utility of EFEMP1 in the Prediction of Oncologic Outcomes of Urothelial Carcinoma.

ABSTRACT: Urothelial carcinoma (UC) of the upper tract (UTUC) and urinary bladder (UBUC) is a heterogeneous malignancy. Through transcriptomic profiling of the Gene Expression Omnibus UBUC dataset (GSE31684), we discovered that epidermal growth factor-containing fibulin-like extracellularmatrix protein 1 (EFEMP1) was the most upregulated gene during metastatic development. EFEMP1 is an important component of basement membranes and acts as an enzyme regulator in extracellular matrix biology. Initially, evaluation of EFEMP1 mRNA expression in 50 UBUCs showed significantly upregulated levels in high stage UC. We further validated the clinical significance of EFEMP1 in 340 UTUC and 295 UBUC using immunohistochemistry, evaluated by H-score. High EFEMP1 immunoexpression significantly correlated with high pathologic stage, high histological grade, lymph node metastasis, vascular invasion, perineural invasion and high mitosis (all p < 0.05). After adjusting for established clinicopathological factors, EFEMP1 expression status retained its prognostic impact on disease-specific survival and metastasis-free survival in UTUC and UBUC (all p < 0.01). Furthermore, Ingenuity Pathway Analysis showed that actin cytoskeleton signaling, tumor microenvironment pathway and mitochondrial dysfunction were significantly enriched by EFEMP1 dysregulation. In conclusion, high EFEMP1 expression was associated with adverse pathological features in UC and independently predicted worse outcomes, suggesting its roles in clinical decision-making and risk stratification.

SUBMITTER: Chen TJ

PROVIDER: S-EPMC8226762 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Utility of EFEMP1 in the Prediction of Oncologic Outcomes of Urothelial Carcinoma.

Chen Tzu-Ju TJ Chan Ti-Chun TC Li Wan-Shan WS Li Chien-Feng CF Ke Hung-Lung HL Wei Yu-Ching YC Wu Wen-Jeng WJ Li Wei-Ming WM

Genes 20210606 6

Urothelial carcinoma (UC) of the upper tract (UTUC) and urinary bladder (UBUC) is a heterogeneous malignancy. Through transcriptomic profiling of the Gene Expression Omnibus UBUC dataset (GSE31684), we discovered that epidermal growth factor-containing fibulin-like extracellularmatrix protein 1 (<i>EFEMP1</i>) was the most upregulated gene during metastatic development. EFEMP1 is an important component of basement membranes and acts as an enzyme regulator in extracellular matrix biology. Initial ...[more]

PMID: 34204134

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Project description:Background and objectiveRadical nephroureterectomy (RNU) represents the gold standard treatment for non-metastatic upper tract urothelial cancer. We sought to provide a comprehensive review of reported oncologic outcomes of the RNU procedure and of factors that might impact these outcomes.MethodsA non-systematic review of the literature was conducted by performing an electronic literature search using PubMed with "radical nephroureterectomy" and "oncologic outcomes" as free text search terms. Both original articles and systematic reviews were considered. Search was limited to articles in English that were published in the last 20 years.Key content and findingsOpen and laparoscopic RNU offer comparable oncologic outcomes. In more recent years, the discussion has de facto shifted towards the "oncological safety" of robotic RNU, which also seems to offer comparable oncologic outcomes. Several studies have looked at the impact of different treatment-, patient- and tumor-related factors. Among treatment-related factors, attention has been given to diagnostic ureteroscopy and the risk of intravesical recurrence. Surgical wait time and perioperative blood transfusion have also been studied. Perioperative chemotherapy, specifically adjuvant therapy, was shown to improve survival. Among patient-related factors, baseline chronic kidney disease, diabetes mellitus, body mass index, and systemic inflammation have gained recent attention. Some tumor related factors, such as stage, grade, location, and multifocality may negatively impact survival outcomes. Lymphovascular invasion and histologic variants are clinically significant pathological findings.ConclusionsRNU is a procedure with measured long-term oncologic outcomes. Minimally invasive techniques have gained an established role as they seem to offer comparable oncologic "safety", although special attention is needed in relation to the method of bladder cuff excision. Robotic RNU is gaining popularity, and while evidence remains limited, the current literature supports the oncologic safety of this procedure. Several factors, which can be categorized as treatment-related, patient-related, and tumor-related, might impact the oncologic outcomes of UTUC patients undergoing RNU. These factors can provide crucial information to stratify patients based on their relative risk of disease recurrence and mortality which may guide clinical decision-making.

Project description:Cigarette smoking is a common risk factor for developing upper tract urothelial carcinoma (UTUC).To assess the impact of cigarette smoking status, cumulative smoking exposure, and time from cessation on oncologic UTUC outcomes in patients treated with radical nephroureterectomy (RNU).A total of 864 patients underwent RNU at five institutions. The median follow-up in this retrospective study was 50 mo. Smoking history included smoking status, quantity of cigarettes per day (CPD), duration in years, and years from smoking cessation. The cumulative smoking exposure was categorized as light-short-term (? 19 CPD and ? 19.9 yr), moderate (all combinations except light-short-term and heavy-long-term), and heavy-long-term (? 20 CPD and ? 20 yr).RNU with or without lymph node dissection. No patient received neoadjuvant chemotherapy.Univariable and multivariable logistic regression and competing risk regression analyses assessed the effects of smoking on oncologic outcomes.A total of 244 patients (28.2%) never smoked; 297 (34.4%) and 323 (37.4%) were former and current smokers, respectively. Among smokers, 87 (10.1%), 331 (38.3%), and 202 (23.4%) were light-short-term, moderate, and heavy-long-term smokers, respectively. Current smoking status, smoking ? 20 CPD, ? 20 yr, and heavy-long-term smoking were associated with advanced disease (p values ? 0.004), greater likelihood of disease recurrence (p values ? 0.01), and cancer-specific mortality (p values ? 0.05) on multivariable analyses that adjusted for standard features. Patients who quit smoking ? 10 yr prior to RNU did not differ from never smokers regarding advanced tumor stages, disease recurrence, and cancer-specific mortality, but they had better oncologic outcomes then current smokers and those patients who quit smoking <10 yr prior to RNU. The study is limited by its retrospective nature.Cigarette smoking is significantly associated with advanced disease stages, disease recurrence, and cancer-specific mortality in patients treated with RNU for UTUC. Current smokers and those with a heavy and long-term smoking exposure have the highest risk for poor oncologic outcomes. Smoking cessation >10 yr prior to RNU seems to mitigate some detrimental effects. These results underscore the need for smoking cessation and prevention programs.

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Utility of EFEMP1 in the Prediction of Oncologic Outcomes of Urothelial Carcinoma.

Publications

Utility of EFEMP1 in the Prediction of Oncologic Outcomes of Urothelial Carcinoma.

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