Recent advancements in understanding clear cell renal cell carcinoma (ccRCC) have underscored the critical role of the BAP1 gene in its pathogenesis and prognosis. While the von Hippel-Lindau (VHL) mutation has been extensively studied, emerging evidence suggests that mutations in BAP1 and other genes significantly impact patient outcomes. Radiogenomics with and without texture analysis based on CT imaging holds promise in predicting BAP1 mutation status and overall survival outcomes. However, prospective studies with larger cohorts and standardized imaging protocols are needed to validate these findings and translate them into clinical practice effectively, paving the way for personalized treatment strategies in ccRCC. This review aims to summarize the current knowledge on the role of BAP1 mutation in ccRCC pathogenesis and prognosis, as well as the potential of radiogenomics in predicting mutation status and clinical outcomes.

UNASSIGNED: Clear Cell Renal Cell Carcinoma (ccRCC) is the most common type of kidney cancer, characterized by high heterogeneity and complexity. Recent studies have identified mitochondrial defects and autophagy as key players in the development of ccRCC. This study aims to delve into the changes in mitophagic activity within ccRCC and its impact on the tumor microenvironment, revealing its role in tumor cell metabolism, development, and survival strategies.
UNASSIGNED: Comprehensive analysis of ccRCC tumor tissues using single cell sequencing and spatial transcriptomics to reveal the role of mitophagy in ccRCC. Mitophagy was determined to be altered among renal clear cells by gene set scoring. Key mitophagy cell populations and key prognostic genes were identified using NMF analysis and survival analysis approaches. The role of UBB in ccRCC was also demonstrated by in vitro experiments.
UNASSIGNED: Compared to normal kidney tissue, various cell types within ccRCC tumor tissues exhibited significantly increased levels of mitophagy, especially renal clear cells. Key genes associated with increased mitophagy levels, such as UBC, UBA52, TOMM7, UBB, MAP1LC3B, and CSNK2B, were identified, with their high expression closely linked to poor patient prognosis. Particularly, the ubiquitination process involving the UBB gene was found to be crucial for mitophagy and its quality control.
UNASSIGNED: This study highlights the central role of mitophagy and its regulatory factors in the development of ccRCC, revealing the significance of the UBB gene and its associated ubiquitination process in disease progression.

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Although sex differences have been reported in patients with clear cell renal cell carcinoma (ccRCC), biological sex has not received clinical attention and genetic differences between sexes are poorly understood. This study aims to identify sex-specific gene mutations and explore their clinical significance in ccRCC. We used data from The Cancer Genome Atlas-Kidney Renal Clear Cell Carcinoma (TCGA-KIRC), The Renal Cell Cancer-European Union (RECA-EU) and Korean-KIRC. A total of 68 sex-related genes were selected from TCGA-KIRC through machine learning, and 23 sex-specific genes were identified through verification using the three databases. Survival differences according to sex were identified in nine genes (ACSS3, ALG13, ASXL3, BAP1, JADE3, KDM5C, KDM6A, NCOR1P1, and ZNF449). Female-specific survival differences were found in BAP1 in overall survival (OS) (TCGA-KIRC, p = 0.004; RECA-EU, p = 0.002; and Korean-KIRC, p = 0.003) and disease-free survival (DFS) (TCGA-KIRC, p = 0.001 and Korean-KIRC, p = 0.000004), and NCOR1P1 in DFS (TCGA-KIRC, p = 0.046 and RECA-EU, p = 0.00003). Male-specific survival differences were found in ASXL3 (OS, p = 0.017 in TCGA-KIRC; and OS, p = 0.005 in RECA-EU) and KDM5C (OS, p = 0.009 in RECA-EU; and DFS, p = 0.016 in Korean-KIRC). These results suggest that biological sex may be an important predictor and sex-specific tailored treatment may improve patient care in ccRCC.

BACKGROUND: Clear cell Renal Cell Carcinoma (ccRCC) has a poor prognosis once metastatic. However, certain metastatic sites have been reported to have a different impact on the patient prognosis. For example, patients with pancreatic metastases have a much more favorable prognosis than those with metastases to other organs. The biological basis for this observation remains poorly understood. The aim of this study was to characterize the immune landscape of pancreatic metastases and the corresponding primary tumors in order to identify possible immunological features that correlate with disease biology.
METHODS: A detailed assessment of immune cell populations was performed using a total of 1,700 microscopic images from ccRCCs from 11 patients, their corresponding pancreatic metastases and ccRCCs from 10 patients without pancreatic metastases. Tumor specimens were stained for CD45, CD8, CD163 and FOXP3 and the densities of the respective immune cells were assessed semiquantitatively in the intratumoral and extratumoral compartment. Multispectral imaging was performed in selected tumors.
RESULTS: We found that pancreatic metastases show the lowest intratumoral infiltration with CD8+ cytotoxic T lymphocytes of all tumor specimens analyzed. The frequency of CD8+ lymphocytes was on 1.9 fold lower in pancreatic metastases (median density 8.3 cells per field of view [FOV] = 1.23 mm2) when compared to the corresponding primary tumor (15.6 cells per FOV, P = 0.0002) and more than 3-fold lower when compared to ccRCCs without pancreatic metastases (27.2 cells per FOV, P = 0.0012). There was also a significantly reduced intratumoral infiltration with immunosuppressive FOXP3+ lymphocytes in pancreatic metastases (2.6 cells per FOV, P = 0.009) and corresponding primary tumors (2 cells per FOV, P = 0.028) when compared to ccRCCs without pancreatic metastases (5.6 cells per FOV).
CONCLUSIONS: In this proof-of-concept study, we show that pancreatic metastases of ccRCC present with unique immunological features including a low intratumoral density of CD8+ and FOXP3+ lymphocytes. The low counts of CD8+ and FOXP3+ lymphocytes may reflect less aggressive features of ccRCC with pancreatic metastasis that may result in a more favorable patient prognosis.

Renal cell carcinoma (RCC) is a malignant tumor originating from the epithelial cells of the renal tubules. The clear cell RCC subtype is closely linked to a poor prognosis due to its rapid progression. Circular RNA (circRNA) is a novel class of regulatory RNA molecules that play a role in the development of ccRCC, although their functions have not been fully elucidated. In this study, we identified a significant downregulation of circ-IP6K2 in ccRCC tissues based on data from the GSE100186 dataset. The decreased expression of circ-IP6K2 correlated with the progression of TNM stage and histological grade, and was also associated with decreased overall survival rates in ccRCC patients. Moreover, our findings revealed that circ-IP6K2 expression suppressed proliferation, migration, and invasion capabilities in vitro, and inhibited xenograft growth in vivo. Mechanistically, circ-IP6K2 acted as a sponge for miR-1292-5p in ccRCC cells, which in turn targeted the 3\'UTR of CAMK2N1, leading to a decrease in its expression. CAMK2N1 was identified as a tumor suppressor that negatively regulated the β-catenin/c-Myc oncogenic signaling pathway. Additionally, we confirmed a positive correlation between the expression of circ-IP6K2 and CAMK2N1 in ccRCC. Circ-IP6K2 functions to impede the progression of ccRCC by modulating the miR-1292-5p/CAMK2N1 axis. These findings shed new light on the molecular mechanisms driving ccRCC progression and suggest potential therapeutic targets for the treatment of ccRCC.

UNASSIGNED: This study introduces a novel prognostic tool, the Disulfidoptosis-Related lncRNA Index (DRLI), integrating the molecular signatures of disulfidoptosis and long non-coding RNAs (lncRNAs) with the cellular heterogeneity of the tumor microenvironment, to predict clinical outcomes in patients with clear cell renal cell carcinoma (ccRCC).
UNASSIGNED: We analyzed 530 tumor and 72 normal samples from The Cancer Genome Atlas (TCGA), employing k-means clustering based on disulfidoptosis-associated gene expression to stratify ccRCC samples into prognostic groups. lncRNAs correlated with disulfidoptosis were identified and used to construct the DRLI, which was validated by Kaplan-Meier and receiver operating characteristic curves. We utilized single-cell deconvolution analysis to estimate the proportion of immune cell types within the tumor microenvironment, while the ESTIMATE and TIDE algorithms were employed to assess immune infiltration and potential response to immunotherapy.
UNASSIGNED: The Disulfidoptosis-Related lncRNA Index (DRLI) effectively stratified ccRCC patients into high and low-risk groups, significantly impacting survival outcomes (P < 0.001). High-risk patients, marked by a unique lncRNA profile associated with disulfidoptosis, faced worse prognoses. Single-cell analysis revealed marked tumor microenvironment heterogeneity, especially in immune cell makeup, correlating with patient risk levels. In prognostic predictions, DRLI outperformed traditional clinical indicators, achieving AUC values of 0.779, 0.757, and 0.779 for 1-year, 3-year, and 5-year survival in the training set, and 0.746, 0.734, and 0.750 in the validation set. Notably, while the constructed nomogram showed exceptional predictive capability for short-term prognosis (AUC = 0.877), the DRLI displayed remarkable long-term predictive accuracy, with its AUC value reaching 0.823 for 10-year survival, closely approaching the nomogram\'s performance.
UNASSIGNED: The study introduces the DRLI as a groundbreaking molecular stratification tool for ccRCC, enhancing prognostic precision and potentially guiding personalized treatment strategies. This advancement is particularly significant in the context of long-term survival predictions. Our findings also elucidate the complex interplay between disulfidoptosis, lncRNAs, and the immune microenvironment in ccRCC, offering a comprehensive perspective on its pathogenesis and progression. The DRLI and the nomogram together represent significant strides in ccRCC research, highlighting the importance of molecular-based assessments in predicting patient outcomes.

BACKGROUND: To develop a novel nomogram for predicting 2-year and 5-year disease-free survival (DFS) and overall survival (OS) in patients with cT1-clear cell renal cell carcinoma (ccRCC) undergoing partial nephrectomy (PN).
METHODS: A retrospective study was conducted across five urological centers, including 940 patients who underwent PN for cT1N0M0-ccRCC. Four centers were randomly selected to constitute the training group, while the remaining center served as the testing group. We employed the LASSO and multivariate Cox regression to develop new nomograms. The 1,000 bootstrap-corrected c-index, net reclassification improvement (NRI) and receiver operating characteristic curve were employed to compare the predictive abilities of new nomograms with the widely used UUIS and SSIGN models. Finally, the novel nomograms underwent external validation.
RESULTS: The training group included 714 patients, while the testing group consisted of 226 patients. The bootstrap-corrected c-indexes for the DFS and OS model were 0.870 and 0.902, respectively. In the training cohort, the AUC for the DFS and OS models at 2 years and 5 years were 0.953, 0.902, 0.988, and 0.911, respectively. These values were also assessed in the testing cohort. The predictive capabilities of the new nomograms surpassed those of the UUIS and SSIGN models (NRI > 0). Decision curve analysis demonstrated that the novel nomograms provide greater net benefits compared to the UUIS and SSIGN models.
CONCLUSIONS: Our novel nomograms demonstrated strong predictive ability for forecasting oncological outcomes in cT1-ccRCC patients after PN. These user-friendly nomograms are simple and convenient for clinical application, providing tangible clinical benefits.

Clear cell renal cell carcinoma (ccRCC) is the most common subtype of kidney cancer characterized by metabolic reprogramming. Glutamine metabolism is pivotal in metabolic reprogramming, contributing to the significant heterogeneity observed in ccRCC. Consequently, developing prognostic markers associated with glutamine metabolism could enhance personalized treatment strategies for ccRCC patients. This study obtained RNA sequencing and clinical data from 763 ccRCC cases sourced from multiple databases. Consensus clustering of 74 glutamine metabolism related genes (GMRGs)- profiles stratified the patients into three clusters, each of which exhibited distinct prognosis, tumor microenvironment, and biological characteristics. Then, six genes (SMTNL2, MIOX, TMEM27, SLC16A12, HRH2, and SAA1) were identified by machine-learning algorithms to develop a predictive signature related to glutamine metabolism, termed as GMRScore. The GMRScore showed significant differences in clinical prognosis, expression profile of immune checkpoints, abundance of immune cells, and immunotherapy response of ccRCC patients. Besides, the nomogram incorporating the GMRScore and clinical features showed strong predictive performance in prognosis of ccRCC patients. ALDH18A1, one of the GRMGs, exhibited elevated expression level in ccRCC and was related to markedly poorer prognosis in the integrated cohort, validated by proteomic profiling of 232 ccRCC samples from Fudan University Shanghai Cancer Center (FUSCC). Conducting western blotting, CCK-8, transwell, and flow cytometry assays, we found the knockdown of ALDH18A1 in ccRCC significantly promoted apoptosis and inhibited proliferation, invasion, and epithelial-mesenchymal transition (EMT) in two human ccRCC cell lines (786-O and 769-P). In conclusion, we developed a glutamine metabolism-related prognostic signature in ccRCC, which is tightly linked to the tumor immune microenvironment and immunotherapy response, potentially facilitating precision therapy for ccRCC patients. Additionally, this study revealed the key role of ALDH18A1 in promoting ccRCC progression for the first time.

UNASSIGNED: While immune checkpoint inhibitors represent the mainstream treatment for metastatic renal cell carcinoma, a standardized approach following immune checkpoint inhibitors remains unclear. We report a case of metastatic renal cell carcinoma treated with nivolumab rechallenge.
UNASSIGNED: A 60-year-old male with metastatic melanoma was referred to the urology division due to right renal cancer. He was undergoing nivolumab treatment for metastatic melanoma. Radical nephrectomy revealed clear cell renal cell carcinoma, pT3a. Two months post-surgery, multiple metastases were identified. Despite subsequent administration of interferon-α, axitinib, and temsirolimus, the metastases progressed. Consequently, nivolumab rechallenge and palliative radiotherapy were initiated, resulting in a durable response for 20 months. However, disease progression occurred, and he died of cancer 4 years after nephrectomy.
UNASSIGNED: This is the first report of nivolumab rechallenge in metastatic renal cell carcinoma. Although the utility remains unclear, this case suggests that some patients may benefit from nivolumab rechallenge.