ABSTRACT
PURPOSE: Genetic susceptibility to nonsyndromic renal cell carcinoma (RCC) remains poorly understood, especially for different histological subtypes, as does variations in genetic predisposition in different populations. The objectives of this study were to identify risk genes for RCC in the Canadian population, investigate their clinical significance, and evaluate variations in germline pathogenic variants (PVs) among patients with RCC across the globe. MATERIALS AND METHODS: We conducted targeted sequencing of 19 RCC-related and 27 cancer predisposition genes for 960 patients with RCC from Canada and identified genes enriched in rare germline PVs in RCC compared with cancer-free controls. We combined our results with those reported for patients from Japan, the United Kingdom, and the United States to investigate PV variations in different populations. Furthermore, we evaluated the performance of referral criteria for genetic screening for including patients with rare PVs. RESULTS: We identified 39 germline PVs in 56 patients (5.8%) from the Canadian cohort. Compared with cancer-free controls, PVs in CHEK2 (odds ratio [OR], 4.8 [95% CI, 2.7 to 7.9], P = 3.94 × 10-5) and ATM (OR, 4.5 [95% CI, 2.0 to 8.7], P = .016) were significantly enriched in patients with clear cell, whereas PVs in FH (OR, 215.1 [95% CI, 64.4 to 597.8], P = 6.14 × 10-9) were enriched in patients with non-clear cell RCCs. PVs in BRCA1, BRCA2, and ATM were associated with metastasis (P = .003). Comparative analyses showed an enrichment of TP53 PVs in patients from Japan, of CHEK2 and ATM in patients from Canada, the United States and the United Kingdom, and of FH and BAP1 in the United States. CONCLUSION: CHEK2, ATM, and FH are risk genes for RCC in the Canadian population, whereas PVs in BRCA1/2 and ATM are associated with risk of metastasis. Globally, clinical guidelines for genetic screening in RCC fail to include more than 70% of patients with rare germline PVs.
Subject(s)
Carcinoma, Renal Cell , Genetic Predisposition to Disease , Genetic Testing , Germ-Line Mutation , Kidney Neoplasms , Humans , Carcinoma, Renal Cell/genetics , Genetic Testing/methods , Kidney Neoplasms/genetics , Kidney Neoplasms/pathology , Male , Female , Middle Aged , Aged , Adult , CanadaSubject(s)
Carcinoma, Renal Cell , Kidney Neoplasms , Humans , Kidney Neoplasms/genetics , Kidney Neoplasms/diagnosis , Kidney Neoplasms/pathology , Carcinoma, Renal Cell/genetics , Carcinoma, Renal Cell/diagnosis , Carcinoma, Renal Cell/pathology , Carcinoma, Transitional Cell/genetics , Carcinoma, Transitional Cell/diagnosis , Carcinoma, Transitional Cell/pathology , Incidental Findings , Urinary Bladder Neoplasms/genetics , Urinary Bladder Neoplasms/diagnosis , Urinary Bladder Neoplasms/pathology , Early Detection of Cancer , Urologic Neoplasms/genetics , Urologic Neoplasms/diagnosis , Urologic Neoplasms/pathologyABSTRACT
BACKGROUND: Increased activity of the transcription factor FOXC1 leads to elevated transcription of target genes, ultimately facilitating the progression of various cancer types. However, there are currently no literature reports on the role of FOXC1 in renal cell carcinoma. METHODS: By using RT-qPCR, immunohistochemistry and Western blotting, FOXC1 mRNA and protein expression was evaluated. Gain of function experiments were utilized to assess the proliferation and metastasis ability of cells. A nude mouse model was created for transplanting tumors and establishing a lung metastasis model to observe cell proliferation and spread in a living organism. Various techniques including biological analysis, CHIP assay, luciferase assay, RT-qRCR and Western blotting experiments were utilized to investigate how FOXC1 contributes to the transcription of ABHD5 on a molecular level. FOXC1 was assessed by Western blot for its impact on AMPK/mTOR signaling pathway. RESULTS: FOXC1 is down-regulated in RCC, causing unfavorable prognosis of patients with RCC. Further experiments showed that forced FOXC1 expression significantly restrains RCC cell growth and cell metastasis. Mechanically, FOXC1 promotes the transcription of ABHD5 to activate AMPK signal pathway to inhibit mTOR signal pathway. Finally, knockdown of ABHD5 recovered the inhibitory role of FOXC1 overexpression induced cell growth and metastasis suppression. CONCLUSION: In general, our study demonstrates that FOXC1 exerts its tumor suppressor role by promoting ABHD5 transcription to regulating AMPK/mTOR signal pathway. FOXC1 could serve as both a diagnostic indicator and potential treatment focus for RCC.
Subject(s)
1-Acylglycerol-3-Phosphate O-Acyltransferase , AMP-Activated Protein Kinases , Carcinoma, Renal Cell , Cell Proliferation , Forkhead Transcription Factors , Kidney Neoplasms , Mice, Nude , Signal Transduction , TOR Serine-Threonine Kinases , Carcinoma, Renal Cell/genetics , Carcinoma, Renal Cell/metabolism , Carcinoma, Renal Cell/pathology , Humans , Animals , Forkhead Transcription Factors/metabolism , Forkhead Transcription Factors/genetics , Kidney Neoplasms/genetics , Kidney Neoplasms/pathology , Kidney Neoplasms/metabolism , Cell Line, Tumor , TOR Serine-Threonine Kinases/metabolism , TOR Serine-Threonine Kinases/genetics , Cell Proliferation/genetics , Mice , AMP-Activated Protein Kinases/metabolism , AMP-Activated Protein Kinases/genetics , 1-Acylglycerol-3-Phosphate O-Acyltransferase/metabolism , 1-Acylglycerol-3-Phosphate O-Acyltransferase/genetics , Gene Expression Regulation, Neoplastic , Disease Progression , Male , Female , Mice, Inbred BALB CSubject(s)
Carcinoma, Renal Cell , Kidney Neoplasms , Humans , Carcinoma, Renal Cell/pathology , Carcinoma, Renal Cell/genetics , Carcinoma, Renal Cell/metabolism , Kidney Neoplasms/pathology , Kidney Neoplasms/genetics , Kidney Neoplasms/metabolism , Male , Middle Aged , Female , Aged , Retrospective Studies , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/genetics , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism , PAX8 Transcription Factor/metabolism , PAX8 Transcription Factor/genetics , PAX2 Transcription Factor/metabolism , PAX2 Transcription Factor/genetics , Racemases and Epimerases/metabolism , Racemases and Epimerases/genetics , Nephrectomy , Follow-Up StudiesSubject(s)
Carcinoma, Renal Cell , Epithelial-Mesenchymal Transition , Kidney Neoplasms , Methyltransferases , Carcinoma, Renal Cell/genetics , Carcinoma, Renal Cell/metabolism , Carcinoma, Renal Cell/pathology , Humans , Kidney Neoplasms/genetics , Kidney Neoplasms/pathology , Kidney Neoplasms/metabolism , Methyltransferases/metabolism , Methyltransferases/genetics , Methylation , Adenosine/analogs & derivatives , Adenosine/metabolism , Epigenesis, Genetic , Drug Resistance, Neoplasm , Neoplasm Invasiveness , RNA-Binding Proteins/metabolism , RNA-Binding Proteins/genetics , Prognosis , Apoptosis , Gene Expression Regulation, Neoplastic , RNA Splicing Factors/genetics , RNA Splicing Factors/metabolismABSTRACT
Objective: To investigate the clinicopathological characteristics, immunophenotypes, molecular features, and differential diagnosis of BAP1 mutated clear cell renal cell carcinoma (CCRCC) for better understanding this entity. Methods: Clinical data, histological morphology, immunophenotypes and molecular characteristics of 18 BAP1 mutated CCRCC cases diagnosed at the Department of Pathology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China from January 2020 to December 2022 were analyzed. The patients were followed up. Results: There were 17 males and 1 female patients, aged from 39 to 72 years, with an average age of 56.3 years. Sixteen patients with primary CCRCC were followed up for an average of 24 months, 7 patients had metastases occurred from 4 to 22 months postoperatively. Thirteen of the 16 patients were alive at the time of the last follow-up while 3 patients died 12, 15, and 20 months after the surgery, respectively. One patient underwent retroperitoneal mass resection, but had lung metastasis 32 months after surgery. One case received cervical tumor resection and died at 22 months after the surgery. Characteristic CCRCC regions were identified in 11 of the 18 cases. The tumor cells were arranged in papillary, alveolar, and large nest patterns. Abundant lymphoid tissue, necrosis, and psammoma bodies were seen. Tumor cells showed abundant eosinophilic cytoplasm, and sometimes exhibited rhabdoid differentiation. Round eosinophilic globules were located in the cytoplasm and extracellular matrix. There were 9 cases with WHO/International Society of Urological Pathology grade 3, and 9 cases with grade 4. PAX8 (18/18), carbonic anhydrase 9 (CA9, 16/18), CD10 (18/18), and vimentin (18/18) were positive in the vast majority of tumors.TFE3 was expressed in 5 cases, with strong expression in only 1 case. Eighteen cases were all positive for P504s. Twelve cases harbored a BAP1 mutation combined with von Hippel-Lindau (VHL) mutation, and 2 cases had mutations in BAP1, VHL and PBRM1 simultaneously. SETD2 mutation was not found in any of the cases. Conclusions: BAP1 mutated CCRCC contained papillary, alveolar, and large nest patterns, eosinophilic cytoplasm, high-grade nucleoli, and collagen globules, with P504s positivity. In practical work, when encountering CCRCC containing these features, pathologists should consider the possibility of BAP1 mutations and conduct related molecular tests.
Subject(s)
Carcinoma, Renal Cell , Kidney Neoplasms , Mutation , Tumor Suppressor Proteins , Ubiquitin Thiolesterase , Humans , Carcinoma, Renal Cell/genetics , Carcinoma, Renal Cell/pathology , Carcinoma, Renal Cell/surgery , Carcinoma, Renal Cell/metabolism , Ubiquitin Thiolesterase/genetics , Ubiquitin Thiolesterase/metabolism , Male , Female , Middle Aged , Tumor Suppressor Proteins/genetics , Tumor Suppressor Proteins/metabolism , Kidney Neoplasms/genetics , Kidney Neoplasms/pathology , Kidney Neoplasms/surgery , Aged , Adult , Histone-Lysine N-Methyltransferase/genetics , Histone-Lysine N-Methyltransferase/metabolism , Transcription Factors/genetics , Transcription Factors/metabolism , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , PAX8 Transcription Factor/genetics , PAX8 Transcription Factor/metabolism , Diagnosis, DifferentialSubject(s)
Adenocarcinoma of Lung , Carcinoma, Renal Cell , Kidney Neoplasms , Lung Neoplasms , Mutation , Humans , Carcinoma, Renal Cell/genetics , Carcinoma, Renal Cell/pathology , Kidney Neoplasms/genetics , Kidney Neoplasms/pathology , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Adenocarcinoma of Lung/genetics , Adenocarcinoma of Lung/pathology , Male , Adenocarcinoma/genetics , Adenocarcinoma/pathology , Adenocarcinoma/diagnosisABSTRACT
OBJECTIVE: Kidney renal clear cell carcinoma (KIRC, ccRCC) is the most common type of renal cancer with high recurrence and mortality. It has long been recognized that Antizyme inhibitor 1 (AZIN1) serves as a pro-oncogenic molecule in multiple cancers. However, the clinicopathological features of AZIN1 in KIRC remain unexplored. MATERIALS AND METHODS: The Cancer Genome Atlas (TCGA, TIMER, and GEPIA) were employed for pan-cancer expression and survival analysis of AZIN1, indicating the unique anti-tumor role of AZIN1 in KIRC. The expression and clinical characteristics of AZIN1 in KIRC were further proven via Human Protein Atlas and TCGA. single-sample GSEA was employed to investigate the immune infiltration of AZIN1. Then the downstream pathways were illustrated via the LinkedOmics, Metascape, and Cytoscape databases. The possible upper regulating noncoding RNAs (ncRNAs) were analyzed from five programs-TargetScan, StarBase, miRanda, PITA, and miRmap. RESULTS: AZIN1 is downregulated in KIRC patients. Lower levels of AZIN1 were linked with unfavorable outcomes in KIRC patients. The AZIN1 expression was positively related to immune cell infiltration in KIRC. We also elucidated a possible upstream regulatory ncRNA of AZIN1 in KIRC namely STK4-AS1/AC068338.2-miR-106b-5p-AZIN1 axis as well as the downstream signaling pathways. CONCLUSION: This study illustrated the unique anti-tumor role of AZIN1 in KIRC and provided potential value for guiding immunotherapy and targeted therapy.
Subject(s)
Carcinoma, Renal Cell , Gene Expression Regulation, Neoplastic , Kidney Neoplasms , Humans , Carcinoma, Renal Cell/genetics , Carcinoma, Renal Cell/mortality , Carcinoma, Renal Cell/pathology , Carcinoma, Renal Cell/metabolism , Kidney Neoplasms/genetics , Kidney Neoplasms/pathology , Kidney Neoplasms/mortality , Kidney Neoplasms/metabolism , Prognosis , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Male , Carrier Proteins/genetics , Carrier Proteins/metabolism , FemaleABSTRACT
BACKGROUNDS: KLKs have been proved to be key regulators of the tumor microenvironment. In this study, we explored the potential of Kallikrein-related peptidases (KLKs) as clinical diagnostic and prognostic markers in patients with kidney renal clear cell carcinoma (KIRC) as well as their relationship with common immuno-inhibitor and immune cell infiltration in the tumor microenvironment to provide new targets and novel ideas for KIRC therapy. METHODS: Oncomine, Gene Expression Profiling Interactive Analysis (GEPIA), UCSC Xena, Genotype-Tissue Expression (GTEx), Kaplan-Meier plotter, cBioPortal, STRING, GeneMANIA, and TISIDB were used to analyze the differential expression, prognostic value, gene changes, molecular interaction, and immune infiltration of KLKs in patients with KIRC. RESULTS: From the gene expression level, it can be determined that KLK1, KLK6, and KLK7 are differentially expressed in KIRC and normal tissues. From the perspective of clinical prognosis, KLK1, KLK13, and KLK14 are highly correlated with the clinical prognosis of KIRC. The expression of KLKs is regulated by various immunosuppressive agents, with KDR, PVRL2, and VTCN1 being the most significant. The expression of KLKs is significantly correlated with the infiltration of various immune cells, of which Eosinophils and Neutrophils are the most significant. CONCLUSIONS: KLK1, KLK6, KLK7, KLK13, and KLK14 have potential as diagnostic and prognostic biomarkers, among which KLK1 is the most significant. This study may provide detailed immune information and promising targets for KIRC immunotherapy to assist in designing new immunotherapies.
Subject(s)
Carcinoma, Renal Cell , Computational Biology , Kallikreins , Kidney Neoplasms , Humans , Kallikreins/genetics , Kallikreins/metabolism , Carcinoma, Renal Cell/genetics , Carcinoma, Renal Cell/pathology , Kidney Neoplasms/genetics , Kidney Neoplasms/pathology , Kidney Neoplasms/immunology , Computational Biology/methods , Gene Expression Regulation, Neoplastic , Prognosis , Tumor Microenvironment/genetics , Tumor Microenvironment/immunology , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Gene Expression ProfilingABSTRACT
OBJECTIVES: Accurate survival predictions and early interventional therapy are crucial for people with clear cell renal cell carcinoma (ccRCC). METHODS: In this retrospective study, we identified differentially expressed immune-related (DE-IRGs) and oncogenic (DE-OGs) genes from The Cancer Genome Atlas (TCGA) dataset to construct a prognostic risk model using univariate Cox regression and least absolute shrinkage and selection operator (LASSO) analysis. We compared the immunogenomic characterization between the high- and low-risk patients in the TCGA and the PUCH cohort, including the immune cell infiltration level, immune score, immune checkpoint, and T-effector cell- and interferon (IFN)-γ-related gene expression. RESULTS: A prognostic risk model was constructed based on 9 DE-IRGs and 3 DE-OGs and validated in the training and testing TCGA datasets. The high-risk group exhibited significantly poor overall survival compared with the low-risk group in the training (P < 0.0001), testing (P = 0.016), and total (P < 0.0001) datasets. The prognostic risk model provided accurate predictive value for ccRCC prognosis in all datasets. Decision curve analysis revealed that the nomogram showed the best net benefit for the 1-, 3-, and 5-year risk predictions. Immunogenomic analyses of the TCGA and PUCH cohorts showed higher immune cell infiltration levels, immune scores, immune checkpoint, and T-effector cell- and IFN-γ-related cytotoxic gene expression in the high-risk group than in the low-risk group. CONCLUSION: The 12-gene prognostic risk model can reliably predict overall survival outcomes and is strongly associated with the tumor immune microenvironment of ccRCC.
Subject(s)
Carcinoma, Renal Cell , Kidney Neoplasms , Nomograms , Tumor Microenvironment , Humans , Carcinoma, Renal Cell/genetics , Carcinoma, Renal Cell/immunology , Carcinoma, Renal Cell/pathology , Carcinoma, Renal Cell/mortality , Tumor Microenvironment/immunology , Tumor Microenvironment/genetics , Kidney Neoplasms/genetics , Kidney Neoplasms/immunology , Kidney Neoplasms/pathology , Kidney Neoplasms/mortality , Prognosis , Retrospective Studies , Female , Male , Middle Aged , Risk Assessment/methods , Biomarkers, Tumor/genetics , Aged , Gene Expression Regulation, NeoplasticABSTRACT
BUD31, a splicing factor, is linked to various cancers. This study examines BUD31's expression, prognostic value, mutation profile, genomic instability, tumor immune environment, and role in clear cell renal cell carcinoma (ccRCC), focusing on cell cycle regulation via alternative splicing. BUD31 expression was analyzed using TCGA and GTEx databases across 33 cancers. Techniques included IHC staining, survival analysis, Cox regression, and nomogram construction. Mutation landscape, genomic instability, and tumor immune microenvironment were evaluated. Functional assays on ccRCC cell lines involved BUD31 knockdown, RNA sequencing, and alternative splicing analysis. BUD31 was upregulated in multiple tumors, including ccRCC. High BUD31 expression correlated with worse survival outcomes and was identified as an independent predictor of poor prognosis in ccRCC. High BUD31 expression also correlated with increased genomic instability and a less active immune microenvironment. BUD31 knockdown inhibited cell proliferation, migration, and invasion in vitro and reduced tumor growth in vivo. RNA sequencing identified 390 alternative splicing events regulated by BUD31, including 17 cell cycle-related genes. KEGG analysis highlighted pathways involved in cell cycle regulation, indicating BUD31's role in promoting cell cycle progression through alternative splicing. BUD31 is upregulated in various tumors and is associated with poor outcomes, increased genomic instability, and a suppressed immune microenvironment in ccRCC. BUD31 promotes cell cycle progression via alternative splicing, suggesting it as a prognostic biomarker and potential therapeutic target in ccRCC.
Subject(s)
Alternative Splicing , Carcinoma, Renal Cell , Kidney Neoplasms , Tumor Microenvironment , Carcinoma, Renal Cell/genetics , Carcinoma, Renal Cell/immunology , Carcinoma, Renal Cell/pathology , Carcinoma, Renal Cell/mortality , Humans , Tumor Microenvironment/immunology , Tumor Microenvironment/genetics , Prognosis , Kidney Neoplasms/genetics , Kidney Neoplasms/pathology , Kidney Neoplasms/immunology , Kidney Neoplasms/mortality , Cell Line, Tumor , Gene Expression Regulation, Neoplastic , Animals , Cell Proliferation , Female , Biomarkers, Tumor/genetics , Male , Survival Analysis , Mice , Genomic InstabilityABSTRACT
BACKGROUND: Our study aims to investigate the mechanisms through which Fc receptor-like A (FCRLA) promotes renal cell carcinoma (RCC) and to examine its significance in relation to tumor immune infiltration. MATERIALS AND METHODS: The correlation between FCRLA and data clinically related to RCC was explored using The Cancer Genome Atlas (TCGA), then validated using Gene Expression Omnibus (GEO) gene chip data. Enrichment and protein-protein interaction (PPI) network analyses were performed for FCRLA and its co-expressed genes. FCRLA was knocked down in RCC cell lines to evaluate its impact on biological behavior. Then the potential downstream regulators of FCRLA were determined by western blotting, and rescue experiments were performed for verification. The relevance between FCRLA and various immune cells was analyzed through GSEA, TIMER, and GEPIA tools. TIDE and ESTIMATE algorithms were used to predict the effect of FCRLA in immunotherapy. RESULTS: Fc receptor-like A was associated with clinical and T stages and could predict the M stage (AUC = 0.692) and 1-3- and 5-year survival rates (AUC = 0.823, 0.834, and 0.862) of RCC patients. Higher expression of FCLRA predicted an unfavorable overall survival (OS) in TCGA-RCC and GSE167573 datasets (p = 0.03, p = 0.04). FCRLA promoted the malignant biological behavior of RCC cells through the pERK1/2/-MMP2 pathway and was associated with tumor immune microenvironment in RCC. CONCLUSION: Fc receptor-like A is positively correlated with poor outcomes in RCC patients and plays an oncogenic role in RCC through the pERK1/2-MMP2 pathway. Patients with RCC might benefit from immunotherapy targeting FCRLA.
Subject(s)
Carcinoma, Renal Cell , Kidney Neoplasms , Humans , Carcinoma, Renal Cell/genetics , Carcinoma, Renal Cell/immunology , Carcinoma, Renal Cell/pathology , Carcinoma, Renal Cell/metabolism , Kidney Neoplasms/genetics , Kidney Neoplasms/immunology , Kidney Neoplasms/pathology , Kidney Neoplasms/metabolism , Cell Line, Tumor , Gene Expression Regulation, Neoplastic , Receptors, Fc/genetics , Receptors, Fc/metabolism , Prognosis , Tumor Microenvironment/immunology , Male , Cell Proliferation , Female , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Protein Interaction Maps , Lymphocytes, Tumor-Infiltrating/immunology , Lymphocytes, Tumor-Infiltrating/metabolism , Matrix Metalloproteinase 2/genetics , Matrix Metalloproteinase 2/metabolismABSTRACT
Repurposing of FDA-approved drugs is a quick and cost-effective alternative to de novo drug development. Here, we identify genes involved in bortezomib sensitivity, predict cancer types that may benefit from treatment with bortezomib, and evaluate the mechanism-of-action of bortezomib in breast cancer (BT-474 and ZR-75-30), melanoma (A-375), and glioblastoma (A-172) cells in vitro. Cancer cell lines derived from cancers of the blood, kidney, nervous system, and skin were found to be significantly more sensitive to bortezomib than other organ systems. The in vitro studies confirmed that although bortezomib effectively inhibited the ß5 catalytic site in all four cell lines, cell cycle arrest was only induced in G2/M phase and apoptosis in A-375 and A-172 after 24h. The genomic and transcriptomic analyses identified 33 genes (e.g. ALDH18A1, ATAD2) associated with bortezomib resistance. Taken together, we identified biomarkers predictive of bortezomib sensitivity and cancer types that might benefit from treatment with bortezomib.
Subject(s)
Antineoplastic Agents , Bortezomib , Drug Repositioning , Hematologic Neoplasms , Humans , Bortezomib/pharmacology , Bortezomib/therapeutic use , Drug Repositioning/methods , Cell Line, Tumor , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/pharmacology , Hematologic Neoplasms/drug therapy , Hematologic Neoplasms/genetics , Kidney Neoplasms/drug therapy , Kidney Neoplasms/genetics , Drug Resistance, Neoplasm/genetics , Apoptosis/drug effects , Gene Expression Profiling , Gene Expression Regulation, Neoplastic/drug effects , Female , MultiomicsABSTRACT
BACKGROUND: Renal cell carcinoma (RCC) is a type of cancer that can develop at any point in adulthood, spanning the range of age-related changes that occur in the body. However, the specific molecular mechanisms underlying the connections between age and genetic mutations in RCC have not been extensively investigated. METHODS: Clinical and genetic data from patients diagnosed with RCC were collected from two prominent medical centers in China as well as the TCGA dataset. The patients were categorized into two groups based on their prognosticated age: young adults (YAs) and older adults (OAs). Univariate and multivariate analysis were employed to evaluate the relationships between age and genetic mutations. Furthermore, a mediation analysis was conducted to assess the association between age and overall survival, with genetic disparities serving as a mediator. RESULTS: Our analysis revealed significant differences in clinical presentation between YAs and OAs with RCC, including histopathological types, histopathological tumor stage, and sarcomatoid differentiation. YAs were found to have lower mutation burden and significantly mutated genes (SMGs) of RCC. However, we did not observe any significant differences between the two groups in terms of 10 canonical oncogenic signaling pathways-related genes mutation, telomerase-related genes (TRGs) mutation, copy number changes, and genetic mutations associated with clinically actionable targeted drugs. Importantly, we demonstrate superior survival outcomes in YAs, and we confirmed the mediating effect of genetic disparities on these survival outcome differences between YAs and OAs. CONCLUSION: Our findings reveal previously unrecognized associations between age and the molecular underpinnings of RCC. These associations may serve as valuable insights to guide precision diagnostics and treatments for RCC.
Subject(s)
Carcinoma, Renal Cell , Kidney Neoplasms , Mutation , Humans , Carcinoma, Renal Cell/genetics , Carcinoma, Renal Cell/pathology , Carcinoma, Renal Cell/mortality , Male , Female , Kidney Neoplasms/genetics , Kidney Neoplasms/mortality , Kidney Neoplasms/pathology , Adult , Middle Aged , Aged , Age Factors , Prognosis , China/epidemiology , Young Adult , Genomics/methods , Aged, 80 and overABSTRACT
The efficacy of immunotherapy for clear cell renal cell carcinoma (ccRCC), especially advanced ccRCC, is limited, presenting a clinical challenge. This limitation is closely tied to the immune regulation network. Understanding the heterogeneity of the tumour microenvironment (TME) is crucial for developing advanced ccRCC therapies. Using publicly available ccRCC data (scRNA-seq, bulk RNA-seq, and somatic mutation data), a multiomics study was performed to explore TME heterogeneity. Three distinct ccRCC immune subtypes were identified through combined scRNA-seq and bulk RNA-seq analysis. A prognostic model based on unique cell signalling molecules in immunosuppressive tumour subtype was validated in the TCGA and CheckMate cohorts. MDK emerged as a critical regulatory gene in the immunosuppressive subtype, predicting a poor ccRCC prognosis and a poor immunotherapy response. MDK promotes M2 macrophage polarization via the MDK-LRP1 interaction, and the inhibition of MDK suppressed M2 polarization. This study revealed the heterogeneity of the ccRCC TME and a reliable prognostic model, shedding light on the vital role of MDK in the immunosuppressive TME and paving the way for optimized ccRCC immunotherapy.
Subject(s)
Carcinoma, Renal Cell , Kidney Neoplasms , Macrophages , Tumor Microenvironment , Carcinoma, Renal Cell/pathology , Carcinoma, Renal Cell/immunology , Carcinoma, Renal Cell/genetics , Carcinoma, Renal Cell/metabolism , Tumor Microenvironment/immunology , Humans , Kidney Neoplasms/pathology , Kidney Neoplasms/immunology , Kidney Neoplasms/genetics , Kidney Neoplasms/metabolism , Macrophages/metabolism , Macrophages/immunology , Prognosis , Gene Expression Regulation, Neoplastic , Immunotherapy/methods , Macrophage Activation/immunology , Cell Line, TumorABSTRACT
BACKGROUND: Large-scale sequencing plays important roles in revealing the genomic map of ccRCC and predicting prognosis and therapeutic response to targeted drugs. However, the relevant clinical data is still sparse in Chinese population. METHODS: Fresh tumor specimens were collected from 66 Chinese ccRCC patients, then the genomic RNAs were subjected to whole transcriptome sequencing (WTS). We comprehensively analyzed the frequently mutated genes from our hospital's cohort as well as TCGA-KIRC cohort. RESULTS: VHL gene is the most frequently mutated gene in ccRCC. In our cohort, BAP1 and PTEN are significantly associated with a higher tumor grade and DNM2 is significantly associated with a lower tumor grade. The mutant type (MT) groups of BAP1 or PTEN, BAP1 or SETD2, BAP1 or TP53, BAP1 or MTOR, BAP1 or FAT1 and BAP1 or AR had a significantly correlation with higher tumor grade in our cohort. Moreover, we identified HMCN1 was a hub mutant gene which was closely related to worse prognosis and may enhance anti-tumor immune responses. CONCLUSIONS: In this preliminary research, we comprehensively analyzed the frequently mutated genes in the Chinese population and TCGA database, which may bring new insights to the diagnosis and medical treatment of ccRCC.
Subject(s)
Carcinoma, Renal Cell , Kidney Neoplasms , Mutation , Humans , Carcinoma, Renal Cell/genetics , Carcinoma, Renal Cell/pathology , Kidney Neoplasms/genetics , Kidney Neoplasms/pathology , Male , Female , Middle Aged , China/epidemiology , Aged , Asian People/genetics , Databases, Genetic , Adult , East Asian PeopleABSTRACT
BACKGROUND: Zinc Finger Protein 337 (ZNF337) is a novel Zinc Finger (ZNF) protein family member. However, the roles of ZNF337 in human cancers have not yet been investigated. METHODS: In this study, with the aid of TCGA databases, GTEx databases, and online websites, we determined the expression levels of ZNF337 in pan-cancer and its potential value as a diagnostic and prognostic marker for pan-cancer and analyzed the relationship between ZNF337 expression and immune cell infiltration and immune checkpoint genes. We then focused our research on the potential of ZNF337 as a biomarker for diagnostic and prognostic in KIRC (kidney renal clear cell carcinoma) and validated in the E-MTAB-1980 database. Moreover, the expression of ZNF337 was detected through qRT-PCR and Western blotting (WB). CCK-8 experiment, colony formation experiment, and EDU experiment were performed to evaluate cell proliferation ability. Wound healing assay and transwell assay were used to analyze its migration ability. The qRT-PCR and WB were used to detect the expression of ZNF337 in tumor tissues and paracancerous tissues of KIRC patients. RESULTS: The pan-cancer analysis revealed that abnormal ZNF337 expression was found in multiple human cancer types. ZNF337 had a high diagnostic value in pan-cancer and a significant association with the prognosis of certain cancers, indicating that ZNF337 may be a valuable prognostic biomarker for multiple cancers. Further analysis demonstrated that the expression level of ZNF337 displayed significant correlations with cancer-associated fibroblasts, immune cell infiltration, and immune checkpoint genes in many tumors. Additionally, ZNF337 was observed to have a high expression in KIRC. Its expression was significantly associated with poor prognosis [overall survival (OS), disease-specific survival (DSS)], age, TNM stage, histologic grade, and pathologic stage. The high ZNF337 expression was associated with poor prognosis in the E-MTAB-1980 validation cohort. The in vitro experiments suggested that the expression of ZNF337 in KIRC tumor tissues was higher than in adjacent tissues, and ZNF337 knockdown inhibited the proliferation and migration of KIRC cells, whereas overexpression of ZNF337 had the opposite effects. CONCLUSIONS: ZNF337 might be an important prognostic and immunotherapeutic biomarker for pan-cancer, especially in KIRC.
Subject(s)
Biomarkers, Tumor , Humans , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Prognosis , Cell Proliferation/genetics , Neoplasms/genetics , Neoplasms/immunology , Neoplasms/diagnosis , Neoplasms/mortality , Neoplasms/pathology , Cell Line, Tumor , Carcinoma, Renal Cell/genetics , Carcinoma, Renal Cell/pathology , Carcinoma, Renal Cell/immunology , Carcinoma, Renal Cell/mortality , Carcinoma, Renal Cell/diagnosis , Female , Gene Expression Regulation, Neoplastic , Male , Kidney Neoplasms/genetics , Kidney Neoplasms/immunology , Kidney Neoplasms/pathology , Kidney Neoplasms/mortality , Kidney Neoplasms/diagnosis , Cell Movement/geneticsABSTRACT
Pyrroline-5-carboxylate reductase (PYCR) is pivotal in converting pyrroline-5-carboxylate (P5C) to proline, the final step in proline synthesis. Three isoforms, PYCR1, PYCR2, and PYCR3, existed and played significant regulatory roles in tumor initiation and progression. In this study, we first assessed the molecular and immune characteristics of PYCRs by a pan-cancer analysis, especially focusing on their prognostic relevance. Then, a kidney renal clear cell carcinoma (KIRC)-specific prognostic model was established, incorporating pathomics features to enhance predictive capabilities. The biological functions and regulatory mechanisms of PYCR1 and PYCR2 were investigated by in vitro experiments in renal cancer cells. The PYCRs' expressions were elevated in diverse tumors, correlating with unfavorable clinical outcomes. PYCRs were enriched in cancer signaling pathways, significantly correlating with immune cell infiltration, tumor mutation burden (TMB), and microsatellite instability (MSI). In KIRC, a prognostic model based on PYCR1 and PYCR2 was independently validated statistically. Leveraging features from H&E-stained images, a pathomics feature model reliably predicted patient prognosis. In vitro experiments demonstrated that PYCR1 and PYCR2 enhanced the proliferation and migration of renal carcinoma cells by activating the mTOR pathway, at least in part. This study underscores PYCRs' pivotal role in various tumors, positioning them as potential prognostic biomarkers and therapeutic targets, particularly in malignancies like KIRC. The findings emphasize the need for a broader exploration of PYCRs' implications in pan-cancer contexts.
Subject(s)
Carcinoma, Renal Cell , Kidney Neoplasms , Pyrroline Carboxylate Reductases , Humans , Pyrroline Carboxylate Reductases/metabolism , Pyrroline Carboxylate Reductases/genetics , Carcinoma, Renal Cell/immunology , Carcinoma, Renal Cell/pathology , Carcinoma, Renal Cell/genetics , Carcinoma, Renal Cell/metabolism , Prognosis , Kidney Neoplasms/immunology , Kidney Neoplasms/pathology , Kidney Neoplasms/genetics , Kidney Neoplasms/metabolism , Biomarkers, Tumor/metabolism , Biomarkers, Tumor/genetics , Cell Line, Tumor , Gene Expression Regulation, Neoplastic , delta-1-Pyrroline-5-Carboxylate Reductase , Cell Proliferation , Lymphocytes, Tumor-Infiltrating/immunology , Lymphocytes, Tumor-Infiltrating/metabolism , Signal TransductionABSTRACT
BACKGROUND: Renal cell carcinoma (RCC), one of the most fatal urologic tumors, accounts for approximately 3% of all adult cancers and exhibits a high metastatic index at diagnosis and a high rate of relapse. Radical or partial nephrectomy is a curative option for nonmetastatic RCCs. Targeted therapy has been shown to improve the survival of patients with metastatic RCCs. However, the underlying cellular and molecular events associated with RCC pathogenesis are not well known. METHODS: To investigate the clinical role of the transcription factor activator protein (AP)-2α in RCC, methylated CpG island recovery assays and microarray analysis were employed. COBRA and RTâqPCR assays were performed to assess AP-2α expression in RCC. RESULTS: A negative correlation was noted between AP-2α mRNA expression levels and methylation status. Multivariate analyses showed that AP-2α mRNA was a major risk factor not only for overall and disease-free survival in RCC but also for disease-free survival in clear cell RCC. CONCLUSIONS: Our results indicated that AP-2α expression was deregulated in RCC and associated with overall patient survival and disease-free survival. Such findings suggest that AP-2α might play an important role in the pathogenesis of RCC.
Subject(s)
Carcinoma, Renal Cell , DNA Methylation , Gene Expression Regulation, Neoplastic , Kidney Neoplasms , Transcription Factor AP-2 , Humans , Carcinoma, Renal Cell/genetics , Carcinoma, Renal Cell/mortality , Carcinoma, Renal Cell/pathology , Transcription Factor AP-2/genetics , Transcription Factor AP-2/metabolism , Male , Female , Kidney Neoplasms/genetics , Kidney Neoplasms/mortality , Kidney Neoplasms/pathology , Middle Aged , Aged , CpG Islands/genetics , Adult , Prognosis , Disease-Free Survival , RNA, Messenger/genetics , RNA, Messenger/metabolismABSTRACT
PURPOSE: The aim of this study was to detect candidate oncogenes of rhabdoid tumor of the kidney (RTK) and evaluate their roles in RTK in vitro. METHODS: An integrated analysis of messenger RNA (mRNA) and microRNA (miRNA) sequencing was performed to determine the expression profile of exosome-derived miRNAs and mRNAs in human RTK-derived cell lines and a human embryonic renal cell line. A Gene Ontology enrichment analysis was performed to analyze the functional characteristics of differentially expressed mRNAs in RTK cells. Matrigel invasion and wound-healing assays were performed to evaluate the cell invasion and migration abilities. RESULTS: Forty mRNAs were highly expressed in RTK cells targeted by exosomal miRNAs, the expression of which was lower in RTK cells than in the controls. These mRNAs were primarily related to cell adhesion. Of these mRNAs, we selected neuropilin 1 (NRP1) as a candidate oncogene because its upregulated expression is associated with a poor prognosis of several types of tumors. RTK cells in which NRP1 had been knocked down exhibited decreased invasive and migratory abilities. CONCLUSION: Our study indicates that NRP1 acts as an oncogene by promoting the invasion and migration of RTK cells and that it could serve as a therapeutic target.