Prognostic Significance of NOTCH1-ICD Expression in Renal Cell Carcinoma

Renal cell carcinoma (RCC) is a renal cortical tumor with high clinical incidence. The effect of glutathione peroxidases (GPXs) on RCC and the possible mechanism are still unclear. This study aims to explore the expression level of GPXs gene in RCC and its effect on the clinical prognosis of patients with RCC via bioinformatics analysis. The mRNA expressions of GPXs family genes were obtained from the public data of The Cancer Genome Atlas (TCGA) database. The Kruskal-Wails test was used to analyze the differences in mRNA expression of GPXs family genes between samples from patients with RCC and the normal population. UALAN databases were used to analyze the differences in protein expression of GPXs family genes between samples from patients with renal clear cell carcinoma and the normal population, and to evaluate the role of GPXs family genes in RCC. The Kaplan-Meier Plotter was used to analyze the correlation between different types of RCC and overall survival (OS), disease-free survival (DFS), disease-specific survival (DSS), and progression-free survival (PFS). Kaplan-Meier survival curve was drawn based on the GPX8 gene expression to study the relationship between GPX8 gene expression and prognosis of RCC patients. Based on the results of multivariate Cox regression analysis, a Nomogram scoring model for RCC prediction was established by introducing GPX8 gene. The mRNA expressions of GPX1 and GPX4 were higher in the sample of renal chromophobe cell carcinoma, renal clear cell carcinoma, and renal papillary cell carcinoma than those in the normal population (all P<0.01), and GPX7 and GPX8 were significantly over-expressed in patients with renal papillary cell carcinoma and renal clear cell carcinoma (all P<0.01). Compared with the normal group, the protein expressions of GPX1, GPX2, GPX7, and GPX8 were increased significantly in renal clear cell carcinoma (all P<0.01), while GPX3 and GPX4 expressions were decreased significantly (both P<0.01). The protein expressions of GPX1, GPX2, GPX7, and GPX8 were increased significantly in patients with renal clear cell carcinoma at different tumor grades (all P<0.01), while GPX3 and GPX4 expressions were decreased significantly (both P<0.01). Survival analysis showed that OS, DFS, DSS, and PFS were all decreased in patients with clear cell carcinoma compared with patients with papillary cell carcinoma and chromophobe cell carcinoma. According to the GPX8 level, patients were assigned into the low, medium, and high expression groups. Compared with the low GPX8 level group, the OS (P<0.01), DFS (P=0.03), DSS (P<0.01), and PFS (P=3.18×10-7) were significantly decreased in the high level group. Univariate Cox proportional regression analysis showed that the high level of GPX8 was associated with poor OS of 3 different types of renal cancer. Multifactorial analysis showed that GPX8 was an independent factor affecting the OS of patients with renal papillary cell carcinoma. Race and post tumor node metastasis (pTNM) typing were independent factors influencing the OS of patients with renal clear cell carcinoma. GPX8 and pTMN were independent factors influencing the OS of patients with renal chromophobe cell carcinoma. Based on these variables, the Nomogram risk models of 3 types of cell carcinoma were established, and the discrimination and calibration of the models were evaluated using the Consistency index (C-index) and calibration curves. The C-index of the risk model of renal papillary cell carcinoma was 0.62 (95% CI 0.51 to 1.00, P=0.03). The results of receiver operating characteristic (ROC) curve showed that the area under the curve (AUC) was 0.88. The C-index of the risk model of renal clear cell carcinoma was 0.72 (95% CI 0.52 to 1.00, P=0.03). The results of ROC curve showed that the AUC was 0.90. The C-index of the risk model of chromophobe cell carcinoma of kidney was 0.90 (95% CI 0.85 to 1.00, P<0.01). The results of ROC curve showed that the AUC was 0.59. GPXs family genes, especially GPX8, are potential markers for poor prognosis of RCC, and the occurrence and development of RCC can be predicted in clinical practice based on the expressions of GPXs family genes.

Objective To analyze the clinicopathological features and prognostic factors of common subtypes of non-transparent renal cell carcinoma. Methods Retrospective analysis of 115 patients with pathologically confirmed non-transparent renal cell carcinoma from January 2003 to December 2017, including 67 males and 48 females, with a male to female ratio of 1.4∶1. The average age is (51.2±13.4) years old. 71 cases were asymptomatic renal cancer, 44 cases had clinical symptoms, including 10 cases of gross hematuria, 28 cases of low back pain, 4 cases of hematuria with low back pain, and 2 cases of abdominal mass. There were 49 open surgery and 66 laparoscopic surgery. 58 patients underwent radical nephrectomy and 57 underwent partial nephrectomy. Of the 115 patients, 17 (14.9%) had abnormal hemoglobin (Hb), 22 (19.1%) had abnormal platelet (PLT) count, 18 (15.7%) had abnormal alkaline phosphatase, and abnormal lactate dehydrogenase 16 cases (13.9%). The Kaplan-Meier survival analysis method was used to calculate the survival rate of patients, and the Cox proportional regression risk model was used to analyze the prognostic factors. Results The postoperative pathological stage was 57 cases in T1a stage, 38 cases in T1b stage, 12 cases in T2a stage, 8 cases in T2b stage, 2 cases of regional lymph node positive, and 113 cases negative; no distant metastasis. Pathological types: 42 cases of renal chromophobe cell carcinoma, 37 cases of papillary renal cell carcinoma type Ⅰ, 36 cases of type Ⅱ. The average follow-up time was 38.6 months, and the rate of loss of follow-up was 3.5% (4/115). The 1, 3, and 5 year overall survival rates of 115 patients with common subtypes of non-transparent renal cell carcinoma were 99.1%, 95.8%, and 81.1%, respectively. Multivariate Cox regression analysis found that the pathological type (OR=4.625, P=0.014), four indicators ≥3 abnormalities (OR=30.853, P=0.024), lymph node metastasis (OR=35.663, P=0.006) were the group. An independent factor in the survival time of patients with common subtypes of non-transparent renal cell carcinoma. Conclusions Compared with papillary renal cell carcinoma type Ⅰ and renal chromophobe cell carcinoma, papillary renal cell carcinoma type Ⅱ has a higher degree of malignancy and a poor prognosis. The pathological types of the common subtypes of non-transparent renal cell carcinoma, four indicators (Hb, PLT count, alkaline phosphatase, and lactate dehydrogenase)≥3 abnormalities and lymph node metastasis are independent prognostic factors for overall survival. Key words: Non-transparent renal cell carcinoma; Renal chromophobe cell carcinoma; Papillary renal cell carcinoma; Prognosis

Fuhrman Grade Provides Higher Prognostic Accuracy Than Nucleolar Grade for Papillary Renal Cell Carcinoma

Cytogenetic and molecular genetic techniques have been used in demonstrating the chromosomal abnormalities which characterize specific subtypes of renal cell carcinoma (RCC). The aim of this study was to determine the efficiency of fluorescent in situ hybridization (FISH) technique in characterizing various subtypes of RCC based on the presence of specific chromosome abnormalities found in each RCC subtype. FISH was performed on touch imprint smears from eight renal cell carcinomas histologically confirmed by established criteria. In four tumors with histologic features of chromophobe renal cell carcinoma (ChRCC), interphase FISH was performed using centromeric probes for chromosomes 1, 2, 6, 10, 12, 17 and 21. All four ChRCC tumors showed one FISH signal corresponding to one copy number for each of these chromosomes. Two papillary RCCs included in this study showed trisomy 7 and 17, and loss of chromosome Y, using the corresponding chromosome centromeric probes. Similarly, we tested two clear cell RCCs for chromosome 3 short arm deletion with DNA probe 3p21.3. Both tumors showed loss of 3p21.3 signal. We conclude that interphase FISH performed on touch imprint smears is a relatively simple, rapid and reliable method for detecting chromosome abnormalities which are specific for various subtypes of RCC.

Focus on kidney cancer

Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up†.

Objective To analyze the prognostic factors of adult nonclear cell renal cell carcinoma (nccRCC). Methods The clinical data of 286 patients with pathologically diagnosed one specific type of nccRCC after radical nephrectomy and nephron sparing surgery(NSS) in the affiliated hospital of Qingdao university followed up from January 2012 to January 2019 were retrospectively analyzed.There were 159 males and 127 females. Their age ranged from 17 to 81 years old, with an average age of 53. Based on the AJCC combination stage, 218 cases were in stage Ⅰ, 56 cases were in stage Ⅱ, 9 cases were in stage Ⅲ, 3 cases were in stage Ⅳ. Assay indicators were collected, including lymphocyte percentage(LY%)(31.5±10.5), neutrophil-lymphocyte ratio(NLR)(2.6±2.8), albumin(40.9±4.7)g/L, prealbumin(255.0±74.3)mg/L, lactate dehydrogenase (LDH)(201.0±174.0)U/L, creatine kinase isoenzyme (CK-MB)(20.0±62.1)U/L, total cholesterol(4.9±1.0)mmol/L, blood urea nitrogen/creatinine (BUN/Cr)(12.9±9.9), blood glucose(5.4±1.3)mmol/L, triglyceride(1.4±1.1)mmol/L, low-density lipoprotein cholesterol (LDL-C)(2.9±0.8)mmol/L. The optimal cut-off value of the above indexes were obtained by the receiver operating characteristic curve(ROC) in the SPSS software, and difference between high cut-off and low cut-off divided basing on the optimal cut-off value were evaluated respectively. The prognostic factors of adult nccRCC were evaluated by univariate and multivariate Cox proportional hazards regression analysis. Kaplan-Meier survival curve was used to study the survival relationship. The log-rank test were used to compare survival rate in two groups. The prognostic factors of nccRCC were analyzed after the results above were presented. Prognostic factors in renal chromophobe cell carcinoma and papillary cell carcinoma were analyzed by the same method. Results The 286patients were followed up from 1 to 87 months, with an average of 43.9 months. The 3-year and 5-year survival rates were 93.8% and 89.3%, respectively. Results of univariate and multivariate Cox regression model revealed that AJCC combined staging (HR=2.38, 95%CI1.48-3.83), LDH(HR=2.99, 95%CI1.16-7.69), blood glucose (HR=4.13, 95%CI 1.74-9.78), CK-MB (HR=3.85, 95%CI1.63-9.08) were independent prognostic factors of nccRCC. NLR(HR=8.28, 95%CI1.66-41.35) and LDH(HR=9.82, 95%CI2.94-32.82) were the independent prognostic factor in the renal chromophobe cell carcinoma subgroup and the papillary renal cell carcinoma subgroup, separately. Conclusions AJCC combination stage, LDH, blood glucose and CK-MB are independent prognostic factors of adult nccRCC. Patients with low LDH, hypoglycemia, CK-MB and early AJCC stage have better prognosis. NLR is an independent predictor of renal chromophobe cell carcinoma, and the low NLR group has a better prognosis and higher survival rate. LDH is an independent predictor of papillary renal cell carcinoma and low LDH is beneficial to patients' prognosis. NLR and LDH can be used as a prognostic indicator for clinical evaluation in renal chromophobe cell carcinoma and papillary renal cell carcinoma, respectively. Key words: Kidney neoplasms; Nonclear cell renal cell carcinoma; Pathology; Prognosis

Solid Renal Masses in Transplanted Allograft Kidneys: A Closer Look at the Epidemiology and Management.

Diagnostic and Prognostic Molecular Markers in Renal Cell Carcinoma

Expression of Pax2 in Human Renal Tumor-Derived Endothelial Cells Sustains Apoptosis Resistance and Angiogenesis

Characterization of Patients With Metastatic Renal Cell Carcinoma Experiencing Complete Response to First-line Therapies: Results From the International Metastatic Renal Cell Carcinoma Database Consortium.

Outcome prediction for renal cell carcinoma: evaluation of prognostic factors for tumours divided according to histological subtype

Histopathology of Surgically Treated Renal Cell Carcinoma: Survival Differences by Subtype and Stage

Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Introduction: Renal cell carcinoma (RCC) accounts for 90% of all kidney cancers. It comprises a heterogeneous group of renal tumors with distinct genetic and molecular characteristics including clear cell RCC (ccRCC), papillary RCC (pRCC) and chromophobe RCC (chRCC). The differential diagnosis of RCC subtypes relies on distinct morphology which is not always accurate. Accurate classification of RCC subtypes is critical since each exhibits different clinical behaviour, prognosis and response to therapy. The purpose of this study is to determine whether a limited number of miRNAs can classify RCC subtypes with high accuracy. Experimental Design: We extracted RNA from 90 formalin-fixed paraffin-embedded (FFPE) tissues including 27 clear cell RCC, 29 papillary RCC, 19 chromophobe RCC, 4 unclassified RCC tumors and 11 oncocytomas. We measured the absolute expression of six miRNAs by qRT-PCR. Receiver operator characteristic curves were constructed and the area under the curve (AUC) was calculated to assess diagnostic performance. We also tested miRNA expression by in situ hybridization (ISH) in an independent set of ninety-eight FFPE renal tumors. Results: We developed a two-step miRNA classifier. In the first step, expressions of selected miRNAs were found to discriminate clear cell RCC and papillary RCC from chromophobe RCC and renal oncocytoma. Two miRNAs were able to discriminate clear cell RCC and papillary RCC from chromophobe RCC and oncocytoma. miR-221 was significantly overexpressed in chromophobe RCC and oncocytoma compared to clear cell RCC and papillary RCC (4.49-fold change, p= 6.398e-010) and was able to discriminate between the two groups (AUC: 0.9637, 95% CI: 0.9132 to 1.014, p&amp;lt;0.0001). In the second step, the absolute expression of two miRNAs could distinguish clear cell RCC from papillary RCC (10.4-fold change, p = 1.243e-013). Moreover, an additional two miRNAs could differentiate chromophobe RCC from renal oncocytoma (3.30- fold change, p = 1.751e-006). In situ hybridization revealed that miRNAs display a nuclear staining pattern that was able to distinguish clear cell RCC from papillary RCC (p&amp;lt;0.001) and chromophobe RCC from renal oncocytoma (p =0.009). Conclusion: miRNA expressions were able to distinguish between RCC subtypes and renal oncocytoma. miRNA assessment by in situ hybridization is a clinically useful diagnostic tool that can complement current methods for RCC classification. Citation Format: Ashley Di Meo, Mereet Hanna, Rola Saleeb, Samantha Wala, Adriana Krizova, Manal Gabril, Haiyan Zhai, Maria Pasic, Andrew Evans, Fadi Brimo, George Yousef. A microRNA signature for the classification of renal cell carcinoma subtypes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5447. doi:10.1158/1538-7445.AM2017-5447