The prognostic value of cyclin D1 in renal cell carcinoma

Introduction

Renal cell carcinoma (RCC) is a family of distinct tumors, and a variety of molecules have been evaluated as prognostic markers for RCC. Cyclin D1, a cell cycle regulator, is overexpressed in several primary tumors.

Objective

To evaluate cyclin D1 expression as a prognostic marker in RCC.

Method

In total, 109 tumor specimens from patients with RCC were obtained from 2005 to 2010 at Hospital das Clínicas—Ribeirão Preto School of Medicine—USP, Brazil, and submitted to immunohistochemical analysis along with seven normal kidney tissue samples.

Results

All of the normal kidney samples lacked cyclin D1 immunohistochemical staining. In addition, there was lower protein expression in the papillary and chromophobe RCC samples. Patients with cyclin D1^low tumors (≤30 % positive cells) showed worse clinical outcome (p = 0.03), lower survival without metastasis and/or death by RCC (p = 0.03), high nuclear grade (p = 0.001), larger tumor size (p = 0.01), presence of symptoms at diagnosis (p = 0.04), necrosis (p = 0.004) and sarcomatoid morphology (p = 0.04). After multivariate analysis, cyclin D1 was not an independent significant factor for worse outcome; however, it improved the accuracy of the adopted prognostic system. The analysis performed for clear cell RCC alone showed similar statistical significance to that of the total cases.

Conclusions

Cyclin D1 protein was overexpressed in RCC. The types of RCC appear to exhibit different immunohistochemical staining patterns for cyclin D1; high protein expression was related to good clinical outcome and to most known favorable prognostic factors. Further investigations are necessary to reveal which mechanisms lead to cyclin D1 accumulation in neoplastic cells.     

突变体p53蛋白与肾细胞癌患者预后

目的 探讨突变体ｐ５３蛋白与肾细胞癌患者预后关系。方法 对９７例根治性切除术的肾细胞癌石蜡包埋标本采用免疫组化ＬＳＡＢ法测定ｍｔｐ５３。结果要阳性者３３例，５年生存率６１．５％；阴性者６４例，５年生存率８１．３％。两组生存率差异有显著性（Ｐ〈０．０５），ＣＯＸ比例风险模型分析提示ｍｔｐ５３不是独立预后因素（Ｐ〉０．１０）。结论ｍｔｐ５３对判断肾细胞癌预后有价值，但不是独立预后指标。     

基于TCGA数据库分析BIRC5在肾透明细胞癌中的表达及预后

目的通过分析杆状病毒凋亡抑制蛋白5(BIRC5)在肾透明细胞癌(ccRCC)组织中的表达,阐明BIRC5对其早期诊断及作为预后预测因子的作用。方法利用GEO、TCGA数据库和HPA分析BIRC5在ccRCC组织中mRNA和蛋白质水平的变化。运用UALCAN和LinkedOmics数据库阐述BIRC5表达与ccRCC临床病理学参数的相关性及对预后的影响。采用GEPIA、Kaplan-Meier Plotter、SurvExpress分析BIRC5表达与ccRCC预后的关系。结果BIRC5 mRNA在ccRCC中高表达,并且与ccRCC患者TNM分期相关(P<0.05),与ccRCC进展高度相关,高表达BIRC5mRNA是ccRCC患者不良预后指标。免疫组织化学结果证实,与正常肾组织相比,ccRCC中BIRC5蛋白表达量显著升高。结论在ccRCC中,BIRC5高表达是一种重要的早期诊断及不良预后指标,有望成为ccRCC早期诊断和预后预测标志物。     

Development and validation of the prognostic value of the immune-related genes in clear cell renal cell carcinoma

BackgroundClear cell renal cell carcinoma (ccRCC) is a highly heterogeneous tumor, resulting a challenge of developing target therapeutics. Not long ago, immune checkpoint blockade regimens combine with tyrosin kinase inhibitors have evolved frontline options in metastatic RCC, which implies arrival of the era of tumor immunotherapy. Studies have demonstrated immune-related genes (IRGs) could characterize tumor milieu and related to patient survival. Nevertheless, the clinical significance of classifier depending on IRGs in ccRCC has not been well established.MethodsThe R package limma, univariate and LASSO cox regression analysis were used to screen the prognostic related IRGs from TCGA database. Multivariate cox regression was utilized to establish a risk prediction model for candidate genes. Quantitative real-time PCR was used to confirm the expression of candidates in clinical samples from our institution. CIBERSORT algorithm and correlation analysis were applied to explore tumor-infiltrating immune cells signature between different risk groups. A clinical nomogram was also developed to predict OS by using the rms R package based on the risk prediction model and other independent risk factors. The ICGC data was used for external validation of either gene risk model or nomogram.ResultsWe identified 382 differentially expressed immune related genes. Four unique prognostic IRGs (CRABP2, LTB4R, PTGER1 and TEK) were finally affirmed to associate with tumor survival independently and utilized to establish the risk score model. All candidates’ expression was successfully laboratory confirmed by q-PCR. CIBERSORT analysis implied patients in unfavorable-risk group with high CD8 T cell, regulatory T cell and NK cell infiltration, as well as high expression of PD-1, CTLA4, TNFRSF9, TIGIT and LAG3. A nomogram combined IRGs risk score with age, gender, TNM stage, Fuhrman grade, necrosis was further generated to predict of 3- and 5-year OS, which exhibited superior discriminative power (AUCs were 0.811 and 0.795).ConclusionsOur study established and validated a survival prognostic model system based on 4 unique immune related genes in ccRCC, which expands knowledge in tumor immune status and provide a potent prediction tool in future.     

The prognostic value of the site of invasion in T3aN0M0 clear cell renal cell carcinoma

Background

The 7th Tumor-Node-Metastasis system for clear cell renal cell carcinoma (ccRCC) classified renal sinus fat invasion (SFI), perirenal fat invasion (PFI), or renal vein invasion (RVI) as stage pT3a. However, their close interactions and prognostic value of them remain controversial. The goal of this study is to further analyze their prognostic values for patients with T3aN0M0 ccRCC.

The use of prognostic factors in metastatic renal cell carcinoma

BackgroundOver the last decade, the treatment landscape of metastatic renal cell carcinoma (mRCC) has evolved tremendously. The outcome of patients with mRCC has been improved since the advent of targeted therapy.ObjectiveIn this review, we address the use of prognostic schema in the era of targeted treatment. This article summarizes the current available prognostic models and the evidence to support their use in clinical settings.ConclusionPrognostic models can help guide clinicians in their decision making, as they have been validated in the first- and second-line targeted therapy settings as well as in non–clear cell mRCC. Prognostic factors are important in patient counseling, clinical trial stratification, and therapy planning. Very selected favorable-risk patients with minimal bulk and slow-growing disease could potentially be observed before needing treatment. Patients with poor-risk disease may be eligible for treatment with temsirolimus. Patients with a very poor prognosis may not be suitable candidates for cytoreductive nephrectomy. New biomarkers are on the horizon, though their roles need to be validated and their additive contribution to improve existing prognostic models examined.     

血管内皮生长因子在肾细胞癌中的表达及意义

研究肾细胞癌血管内皮生长因子（ＶＥＧＦ）的表达及其与肿瘤转移、分期、病理类型及预后的关系。采用抗ＶＥＧＦ的多克隆抗体免疫组织化学技术染色（ＬｓＡＢ法）研究６１例肾癌组织切片。结果显示：４５９％（２８／６１）的肾癌ＶＥＧＦ表达阳性，淋巴结和（或）血行转移的ＶＥＧＦ表达率（７７８％）明显高于非转移者（３２６％，Ｐ＜００１）；阳性表达者五年生存率（２９１％）明显低于阴性表达者（８４６％，Ｐ＜００１）；Ⅰ、Ⅱ期阳性表达低于Ⅲ、Ⅳ期（Ｐ＜００５）；但与性别、年龄及肿瘤的病理类型无关。ＶＥＧＦ除在癌细胞胞浆和胞膜表达外，尚表达于肿瘤基质血管和邻近肿瘤的正常肾小管胞浆、肾小球和血管内皮及血管平滑肌胞膜。认为ＶＥＧＦ除由肿瘤细胞合成外，可能尚表达于邻近肿瘤的正常肾小管胞浆，ＶＥＧＦ表达有助于肾癌预后判断及指导治疗，ＶＥＧＦ可能是肿瘤血管的良好标记物，设法抑制ＶＥＧＦ可望成为肾癌治疗的有效方法。     

Assessment of the prognostic value of SPOCK1 in clear cell renal cell carcinoma: a bioinformatics analysis

BackgroundClear cell renal cell carcinoma (ccRCC) is one of the most common urological malignancies, and once metastasis occurs, it often has a poor prognosis and lacks effective treatment. Therefore, there is an urgent need to screen some new biomarkers and explore their molecular mechanisms to improve the early clinical diagnosis and targeted therapy of ccRCC. SPOCK1 (SPARC/osteonectin, CWCV and Kazal-like domains proteoglycan 1) is a conserved multi-domain proteoglycan that plays an important role in the development of multiple cancer types; however, its prognostic value in ccRCC has not been investigated. The study of the prognostic value of SPOCK1 in ccRCC is a good complement to the study of ccRCC biomarkers.MethodsDatabases of this study included Oncomine, Kaplan-Meier Plotter, GEPIA, GeneMANIA, cBioPortal, and TIMER. Student’s t-test was used to analyze the differences in SPOCK1 expression in ccRCC tissues compared with tumor-adjacent normal tissues. Kaplan-Meier curves for survival analysis were used to assess the correlation between the expression of SPOCK1 and the prognostic outcomes. Correlation module drew the expression scatterplots between SPOCK1 and immune cell infiltration in ccRCC, together with the Spearman’s rho value and estimated statistical significance.ResultsThe SPOCK1 mRNA expression was significantly higher in ccRCC tissues (mean expression ± SD: 920.2±195.2) than in normal tissues (mean expression ± SD: 358.4±29.1, P=0.008), and high SPOCK1 expression significantly and positively correlated with the pathological stage of ccRCC patients (F value =10.2, P<0.001). Higher expression of SPOCK1 was also associated with significantly shorter overall survival (OS) and disease-free survival (DFS) in ccRCC patients (GEPIA: P=0.046, P<0.001, respectively; Kaplan-Meier Plotter: P=0.002, P=0.0022, respectively). The function of SPOCK1 is mainly related to tumor development and extracellular matrix remodeling, and it may participate in the epithelial-mesenchymal transition process. SPOCK1 expression significantly and positively correlated with infiltration of several immune cells in ccRCC, including cancer-associated fibroblasts (CAFs) (Rho =0.333, P=2.16×10⁻¹³), tumor-associated macrophages (TAMs) (Rho =0.18, P=1.02×10⁻⁴), and tumor-associated neutrophils (TANs) (Rho =0.165, P=3.83×10⁻⁴). Conversely, there was a significant and negative correlation between SPOCK1 expression and infiltration of CD4⁺ T cells (Rho =−0.113, P=0.015).ConclusionsSPOCK1 may be a potential prognostic biomarker in ccRCC.     

肾癌预后分子标记物的研究进展

肾癌是泌尿系统常见的恶性肿瘤之一。肾癌患者初诊时约45％已有肿瘤转移，50％的肾癌患者术后有肿瘤复发。应用分子免疫治疗、基因治疗以及抗肿瘤血管形成的分子靶向治疗，对晚期或转移性肾癌已取得令人满意的疗效。但是肾癌生物学行为极为多变，近年许多肿瘤标记物相继被发现并用于肾癌的预后判断。其中G250-MN／CAIX、Ki-67、p53、B7-H1、PTEN等被证实是独立于TNM分期、分级和ECOG评分等临床信息之外的显著的预后因素。现综述肾癌预后相关性较强的肿瘤分子标记物的研究近况。     

CD44v6和PCNA在肾透明细胞癌的表达及其预后价值

目的　探讨CD4 4v6和PCNA与肾透明细胞癌 (CCRCC)分级、分期和预后的关系 ,以及两者相互之间的关系。方法　采用免疫组化技术检测 5 8例CCRCC标本中CD4 4v6和PCNA的表达 ,比较两者同Fuhrman分级、病理分期和预后的关系 ,以及两者相互之间的关系。结果　CD4 4v6表达阳性率为 4 4 .8% (2 6 / 5 8) ,为细胞膜染色 ;PCNA表达阳性率为 5 6 .9% (33/ 5 8) ,为细胞核染色。两者表达与分级 (P <0 .0 0 1)和患者生存率 (P <0 .0 1和P <0 .0 5 )均显著相关 ,与病理分期无关 (P >0 .0 5 )。两者相互之间亦无关 (P >0 .0 5 )。结论　CD4 4v6和PCNA表达可能在CCRCC进展中发挥作用 ,并为判断预后提供了有用的信息     

The value of tumor nephrectomy in metastatic renal cell carcinoma

In the case of an organ-confined RCC, tumor nephrectomy is the undisputed therapy of choice even though overall 5-year survival has not surpassed the 60% threshold. Further improvement will most likely have to await the development of more effective systemic treatment strategies. For an exclusively surgical therapy of metastatic RCC, tumor nephrectomy, sometimes in combination with metastasectomy, can be applied. However, more commonly used is a multimodality approach consisting of a cytoreductive operation followed by immunotherapy. Alternatively, one may select immunotherapy first followed by adjuvant nephrectomy in the case of a response, or one may proceed directly to immunotherapy only. Long-term survival does not exceed 5-10%, and patient selection appears to have a higher prognostic impact than any treatment strategy available. Concepts and progress in the field clearly are of increasing value for modern oncologic urologists. The current standard, a multimodality treatment of metastatic RCC, in which an operation becomes necessary at a certain point in time, easily justifies a central role for the urologic surgeon.     

影响肾功能癌患者预后的因素分析

目的　通过多因素分析 ,探讨影响肾癌预后的因素。　方法　对 316例肾癌进行回顾性分析 ,采用Kaplan Meier法对确定的单因素进行生存率的描述 ,应用Log Rank检验对有意义的单因素进行筛选 ,通过Cox比例风险模型对预后因素进行评价。　结果　平均随访时间 (40 3± 18 5 )个月 ,5年生存率 6 2 3%。通过多因素分析最终进入Cox比例风险模型的有 9个因素 ,远隔转移是最重要的影响预后的因素 (P =0 0 0 13) ,其他因素依次是分期 (P =0 0 182 )、年龄 (P =0 0 34 7)、机体表现状态 (P =0 0 42 3)、淋巴转移 (P =0 0 471)、淋巴结清扫 (P =0 0 5 42 )、细胞分级 (P =0 0 775 )、血浆白蛋白 (P =0 15 36 )、血肌酐 (P =0 45 43)。　结论　肾癌的TNM分期是最重要的影响预后的因素 ;年龄、机体表现状态对预后产生影响 ,淋巴结清扫对相对早期肾癌是有意义的。     

The incidence and prognostic significance of humoral hypercalcemia in renal cell carcinoma

This retrospective study was conducted to evaluate the incidence and prognostic significance of humoral hypercalcemia in 218 renal cell carcinoma patients during the last 20 years. Of 218 patients 20 (9.2%) were hypercalcemic, with serum calcium levels ranging from 10.7 to 16.0 mg./dl. The respective incidence of humoral hypercalcemia was 3% in patients with stage I, 5.9% with stage II, 14.1% with stage III and 18.9% with stage IV disease without bone metastasis. The survival curves between the hypercalcemic and eucalcemic groups among stages I to III cancer patients showed no statistical significance (p greater than 0.05). The survival curve deteriorated significantly in stage IV cancer patients with humoral hypercalcemia (p less than 0.005), with a median survival of 45.0 +/- 39.7 days versus 286.4 +/- 27.6 days in eucalcemic patients. No specific correlation was found between pathological cell type and humoral hypercalcemia.     

长链非编码 RNA MIAT 在肾透明细胞癌中的表达情况和预后意义

目的 探讨长链非编码RNAMIAT在肾透明细胞癌中的表达情况及与患者临床指标的相关性,分析其作为肾透明细胞癌分子标记物的可能性。方法 通过荧光定量PCR方法 检测MIAT在40例肾透明细胞癌组织和40例癌旁正常组织中的表达情况,同时结合TCGA数据库分析MIAT表达水平与肾透明细胞癌患者临床指标和预后的关系。结果 MIAT在肾透明细胞癌组织中的表达明显高于癌旁正常组织,在肾癌细胞系中的表达明显高于正常肾小管上皮细胞,差异均具有统计学意义（P<0.05）。TCGA数据库资料分析表明,MIAT表达水平与肾癌患者T分期（P<0.001）、M分期呈正相关（P<0.05）。Kaplan-Meier生存分析表明,高表达MIAT的肾癌患者总体生存时间明显低于低表达MIAT的肾癌患者（Log-rankP<0.05）。结论 MIAT在肾透明细胞癌组织和肾癌细胞系中高表达,有可能成为肾透明细胞癌的分子标记物。     

Identification of genes that correlate clear cell renal cell carcinoma and obesity and exhibit potential prognostic value

BackgroundRenal cell carcinoma (RCC) is a common urologic malignancy. Although the relationship between clear cell RCC (ccRCC) and obesity has been well-established by several large-scale retrospective studies, the molecular mechanisms and genetic characteristics behind this correlation remains unclear. In the current study, several bioinformatics tools were used to identify the key genes in ccRCC related to obesity.MethodsMicroarray data comparing ccRCC with normal renal tissues in patients with and without obesity were downloaded from the GEO database for screening of differentially expressed genes (DEGs). The DEGs were verified with expression level and survival analysis using several online bioinformatics tools.ResultsIn the current study, the differential expression of five genes correlated with both ccRCC and obesity; IGHA1 and IGKC as oncogenes, and MAOA, MUC20 and TRPM3 as tumor suppressor genes. These genes were verified by comparing the relationship between the expression levels and survival outcomes from open-source data in The Cancer Genome Atlas (TCGA) dataset.ConclusionsIn conclusion, the five genes differentially expressed in ccRCC and obesity are related to disease progression and prognosis, and therefore could provide prognostic value for patients with ccRCC.     

Analysis of CD44 isoform v10 expression and its prognostic value in renal cell carcinoma

OBJECTIVE: To examine the expression of CD44 isoform v10 (CD44v10) in patients with renal cell carcinoma (RCC), analyse its role in RCC and its relationship with conventional clinical-histopathological experience. Materials and methods Sixty-four RCC specimens and five metastatic specimens were analysed immunohistochemically using a CD44v10 specific antibody. The expression of CD44v10 was compared with the histological grade and clinical or pathological stage of the tumours. RESULTS: Of the 64 primary tumour specimens, 22 (34%) expressed CD44v10 protein; all of these positive specimens were clear-cell and mixed-cell RCC. Staining was also positive in four of five metastatic specimens and negative in all four cases of granular cell carcinoma. CD44v10 expression was significantly correlated with the histological grade (P<0.0001), clinical stage (P = 0.0050) and pathological stage (P = 0.0143) of the tumours. The prognosis for patients with clear-cell RCC who were CD44v10-positive was worse than for patients who were CD44v10-negative (P<0.0001). In subgroups with different tumour stage (< or =pT2 or > or =pT3), the prognosis for patients with positive CD44v10 expression was also worse than for those with no expression (P<0.05). CONCLUSION: The expression of CD44v10 correlated significantly with histological grade, clinical and pathological stage, and with survival in patients with clear-cell RCC. CD44v10 protein may play a role in the progression of clear-cell and mixed-cell RCC, and thus the analysis of CD44v10 expression may provide useful prognostic information.     

A critical assessment of the prognostic value of clear cell,papillary and chromophobe histological subtypes in renal cell carcinoma: a population‐based study

OBJECTIVE

To assess the magnitude of the effect of histological subtype (HS, the three most common being clear cell, papillary and chromophobe) on cause‐specific mortality (CSM) from renal cell carcinoma (RCC).

PATIENTS AND METHODS

Univariable and multivariable Cox regression models included data from 11 618 patients treated with nephrectomy between 1988 and 2004 in nine Surveillance Epidemiology and End Results registries. We tested whether HS represents an independent predictor of CSM, and whether HS adds to the ability of other variables to predict CSM. The covariates comprised age, year of surgery, T stage, nodal status, M stage and Fuhrman grade.

RESULTS

In a multivariable model predicting CSM, HS was an independent predictor (P = 0.03), but failed to improve the accuracy of the model (+0.1% gain when HS was included in the model).

CONCLUSION

Although we confirmed that HS is an independent predictor for CSM, there was no gain in accuracy when HS was added to standard predictors of CSM. From a practical perspective, this implies that patients with clear cell, papillary and chromophobe HS share similar natural histories after nephrectomy, provided that other cancer characteristics are accounted for. From a statistical perspective, in multivariable models of CSM, the clear cell, papillary and chromophobe HS might be included as a single entity.