Advances in treatment strategies for non–clear cell renal cell carcinoma

Renal cell carcinoma is the sixth most commonly diagnosed cancer in men and the tenth in women,with clear cell renal cell carcinoma accounting for nearly 75%of cases.The remaining 25%consists of non–clear cell renal cell carcinoma,a diverse and less prevalent group.Although current treatments for clear cell types are well-defined,progress in treating non–clear cell renal cell carcinoma has been limited owing to its heterogeneity and rarity,relying primarily on findings from small-scale phase Ⅱ clinical trials.This review examined recent advancements in the treatment of non–clear cell renal cell carcinoma,particularly in the areas of immunotherapy and targeted therapy.

Network pharmacology and molecular docking analysis reveal insights into the molecular mechanism of Gualou Qumai Wan in clear cell renal cell carcinoma

Background:To initially clarify the potential therapeutic targets and pharmacological mechanism regarding Gualou Qumai Wan(GQW),a kind of traditional Chinese medicine(TCM),in clear cell renal cell carcinoma(ccRCC)by virtue of the network pharmacology analysis and molecular docking analysis.Methods:The screening of bioactive components and targets of GQW was based on the Traditional Chinese Medicine System Pharmacology(TCMSP)and the UniProt platform served for standardizing their targets.Online Mendelian Inheritance in Man(OMIM),PharmGkb,TTD,DrugBank and GeneCards databases were searched to collect the disease targets of ccRCC.Cytoscape assisted in constructing herb-compound-target(H-C-T)networks.The STRING database was searched for constructing the target protein-protein interaction(PPI)networks,while the R programming language served for analyzing GO functional terms and the KEGG pathways related to potential targets.Analyses of core genes related to survival and tumor microenvironment(TME)were conducted respectively based on the GEPIA2 database and TIMER 2.0 database.Human Protein Atlas(HPA)and The Cancer Genome Atlas(TCGA)helped to obtain core genes’protein expression as well as transcriptome expression level.Autodock Vina software validated the molecular docking regarding GQW components and pivotal targets.Results:The constructed H-C-T networks mainly had 33 compounds and 65 targets.A topological analysis of the PPI network identified that ESR1,AKT1,HIF1A,PTGS2,TP53 and VEGFA serve as core targets in the way GQW affects ccRCC.According to the GO and KEGG pathway enrichment analyses,the effects of GQW are mediated by genes related to hypoxia and oxidative stress as well as the Chemical carcinogenesis-receptor activation and PI3K-Akt signaling pathways.AKT1 shows a close relation to the recruitment of various immune cells and can remarkably affect disease prognosis according to reports.Molecular docking and molecular dynamics simulations showed that diosgenin has higher affinity with core targets.Conclusion:The study makes a comprehensive explanation of the biological activity,potential targets,as well as molecular mechanism regarding GQW against ccRCC,which promisingly assists in revealing the action mechanism of TCM formulae in disease treatment and the respective and scientific basis.

Aryl hydrocarbon receptor nuclear translocator 2 as a prognostic biomarker and immunotherapeutic indicator for clear cell renal cell carcinoma

Background:In many cancer types,aryl hydrocarbon receptor nuclear translocator 2(ARNT2)has been found to be associated with tumor cell proliferation and prognosis.However,the role of ARNT2 in clear cell renal cell carcinoma(ccRCC)has not been completely elucidated.In this study,the potential role of ARNT2 in ccRCC development was characterized.Methods:A pan-cancer dataset(TCGA-TARGET-GTEx)was accessed from UCSC Xena Data Browser.ARNT2 expression in normal and tumor samples was compared.Univariate Cox regression was performed to evaluate the prognostic value of ARNT2.Single sample gene set enrichment analysis(ssGSEA)was used to estimate the enrichment of functional pathways and gene signatures.CIBERSORT and ESTIMATE methods evaluated the immune infiltration.The ARNT2 expression was determined in ccRCC tissue and cell lines using RT-qPCR and Western blot.Results:ARNT2 expression was significantly dysregulated in 23 out of 30 cancer types.Pan-cancer data revealed a strong correlation between ARNT2 expression and immune modulators,immune cell infiltration,and genomic alternations.In ccRCC patients,the low-ARNT2 expression group had higher immune infiltration,CD8 T cells,and programmed cell death ligand 1 expression,as well as higher enrichment score of immunotherapeutic predictors than those in the high-ARNT2 expression group.Low-ARNT2 expression group was more responsive to immunotherapy.Moreover,low ARNT2 expression was observed in ccRCC tissue and cell lines.Conclusions:Dysregulated ARNT2 expression is involved in cancer development and the modulation of the immune microenvironment.ARNT2 can be potentially used as a prognostic indicator and an immunotherapeutic indicator for ccRCC.

Iris metastasis from clear cell renal cell carcinoma: A case report

BACKGROUND Clear cell renal cell carcinoma(ccRCC)is a common type of tumor that can metastasize to any organs and sites.However,it is extremely rare for ccRCC to metastasize to the iris.Here,we describe a rare case of iris metastasis from ccRCC with a history of left nephrectomy in 2010.CASE SUMMARY A 62-year-old male was admitted to the hospital due to blurred vision and red eyes,and a mass was found on the iris in the right eye.B-scan ultrasonography revealed a well-bounded high-density lesion at the corner of the anterior chamber at the 3-4 o’clock position.Phacoemulsification with simultaneous intraocular lens implantation and iridocyclectomy was performed in the right eye.The lesion was confirmed to be metastatic ccRCC by histological and immunohistochemical analyses.The patient was still alive at 9 mo after surgical treatment.Ocular metastasis can be an initial sign with a poor prognosis.Timely detection and treatment may improve survival.Clinicians should pay attention to similar metastatic diseases to prevent misdiagnosis leading to missed treatment oppor-tunities.CONCLUSION This report of the characteristics and successful management of a rare case of iris metastasis from ccRCC highlights the importance of a comprehensive medical history,histopathology,immunohistochemistry,and clinical manifestation for successful disease diagnosis.

Correlation between Hypovitaminosis D Status and Hyperactivation of IL-6/STAT3 Signaling in Clear Cell Renal Cell Carcinoma

Objective:To analyze serum vitamin D levels in patients with clear cell renal cell carcinoma(ccRCC)by flow cytometry and to investigate the relationship between hypovitaminosis D status and hyperactivation of IL-6/STAT3 signaling in ccRCC.Methods:Eighty patients diagnosed with ccRCC by our oncology department from January 2019 to December 2021 were selected as study subjects,and the control subjects were selected from patients who were receiving health check-up from our hospital(matched according to case group:control group,1:2),with 160 healthy patients.All serum samples collected from the case-control subjects were allowed to stand for 1–2 hours,centrifuged at 3000 rpm for 10 minutes,and stored in a-80°C refrigerator,from which they were removed and thawed to measure 25-hydroxyvitamin D(25(OH)D)and interleukin 6(IL-6)levels.Results:The blood calcium level of patients in the cancer group was significantly lower than that of patients in the non-cancer group,and the difference was statistically significant(P<0.05).The IL-6 level of the cancer group was significantly higher than that of the non-cancer group.In high vitamin D state,the IL-6 level of the non-cancer group was higher than that of the cancer group,and the average concentration of IL-6 in both the cancer group and the non-cancer group was significantly higher in low vitamin D state compared with high vitamin D state(P<0.05);the correlation between hypovitaminosis D status and renal Ki-67 was found to be positive.Conclusion:The results showed that serum IL-6 levels were elevated in the cancer group and circulating serum 25(OH)D levels were negatively correlated with IL-6 levels.In addition,signal transducer and activator of transcription 3(STAT3)signaling in RCC tissues was activated in ccRCC patients and in those with low vitamin D status among the cancer group and was higher than that in those with high vitamin D status.These results suggest that hypovitaminosis D status in ccRCC patients is associated with activated IL-6/STAT3 signaling and the activation of tumor proliferation markers proliferating cell nuclear antigen(PCNA),cyclin D1,and Ki-67.

Epigenomics of clear cell renal cell carcinoma： mechanisms and potential use in molecular pathology

Clear cell renal cell carcinoma （ccRCC） is one frequent form of urologic malignancy with numerous genetic and epigenetic alterations. This review summarizes the recent major findings of epigenetic alterations including DNA methylation, histone modifications, microRNAs and recently identified long noncoding RNAs in the development and progression of ccRCC. These epigenetic profilings can provide a promising means of prognostication and early diagnosis for patients with ccRCCs. With the developed high- throughput technologies nowadays, the epigenetic analyses will have possible clinical applications in the molecular pathology of ccRCC.

Aberrant DNA methyltransferase 1 expression in clear cell renal cell carcinoma development and progression

Objective： To better understand the contribution of dysregulated DNA methyltransferase 1 （DNMT1） expression to the progression and biology of clear cell renal cell carcinoma （ccRCC）. Methods： We examined the differences in the expression of DNMT1 in 89 ecRCC and 22 normal tissue samples by immunohistochemistry. In addition, changes in cell viability, apoptosis, colony formation and invading ability of ccRCC cell lines （786-0 and Caki-1） were assessed after transfection with DNMT1 siRNA. Results： We found DNMT1 protein was significantly higher expressed in ccRCC than that of in no-tumor tissues （56.2% and 27.3%, respectively, P=0.018）. The expression of DNMT1 was strongly associated with ccRCC tumor size, tumor pathology stage, histological grading, lymph node metastasis, vascular invasion, recurrence and prognosis. Moreover, knockdown of DNMT1 expression significantly inhibited ccRCC cell viability, induced apoptosis, decreased colony formation and invading ability. Conclusions： Expression of DNMTI protein is increased in ccRCC tissues, and DNMT1 expression is associated with poor prognosis of patients. Experiments in vitro further showed DNMT1 played an essential role in proliferation and invasion of renal cancer cells. Moreover, targeting this enzyme could be a promising strategy for treating ccRCC, as evidenced by inhibited cell viability, increased apoptosis, decreased colony formation and invading ability.

RNF43 is a novel tumor-suppressor and prognostic indicator in clear cell renal cell carcinoma

Identifying prognostic indicators of clear cell renal cell carcinoma(ccRCC)and elucidating the mechanisms underlying ccRCC progression are crucial for improving ccRCC patient prognosis.This study investigated the clinical significance and biological role of Ring finger protein 43(RNF43)in ccRCC.Two independent cohorts of patients with ccRCC were employed to determine the prognostic significance of RNF43 by immunohistochemistry and statistical analyses.In vitro and in vivo experiments,RNA-seq,and other techniques were used to determine the biological role of RNF43 in ccRCC and related molecular mechanisms.RNF43 expression was commonly decreased in ccRCC specimens,and low expression of RNF43 indicated a higher TNM stage,SSIGN score,and WHO/ISUP grade and short survival in patients with ccRCC.Additionally,RNF43 overexpression suppressed the proliferation,migration,and targeted drug resistance of ccRCC cells,while the knockdown of RNF43 enhanced these characteristics of ccRCC.RNF43 knockdown activated YAP signaling by decreasing YAP phosphorylation by p-LATS1/2 and increasing the transcription and nuclear distribution of YAP.By contrast,RNF43 overexpression showed the opposite effects.Decreasing YAP abolished the effect of RNF43 knockdown in promoting the malignant features of ccRCC.Additionally,restoring RNF43 expression suppressed the resistance of the targeted drug pazopanib in in vivo orthotopic ccRCC.Furthermore,combining the expression of RNF43 and YAP with TNM stage or the SSIGN score exhibited greater accuracy than any of these indicators alone in assessing the postoperative prognosis of ccRCC patients.In summary,our study identified a novel tumor suppressor,RNF43,which is also a prognostic indicator and potential target for ccRCC.

Expression of caveolin-1 in clear cell renal cell carcinoma and its correlation with microvessel density

Objective:The aim of the study was to investigate the clinicopathologic significance of caveolin-1 expression in clear cell renal cell carcinoma (CCRCC) and its correlation with microvessel density (MVD).Methods:The expression of caveolin-1 was detected by the immunohistochemistry method,while the microvessel density was detected by the immunohistochemistry expression of CD34.Results:In the CCRCCs,the positive rate of caveolin-1 was 67.4%,the over expression of caveolin-1 was not related with sex and age,but related with clinicopathologic parameter,such as tumor sizes,clinical TMN stage,nuclear stage and survival time (P < 0.05).The MVD of positive caveolin-1 cases was significantly higher than that without caveolin-1 expression (P < 0.05).Conclusion:The expression of caveolin-1 is helpful in the prognostic evaluation of CCRCCs and it may be involved in the tumor angiogenesis.

Pomegranate extract inhibits EMT in clear cell renal cell carcinoma in a NF-κB and JNK dependent manner

Objective:Clear cell renal cell carcinoma(ccRCC)is the most common subtype of renal cell carcinoma(RCC)and is characterized by biallelic inactivation of the von Hippel-Lindau(VHL)tumor suppressor gene.One effect of VHL inactivation is hypoxia inducible factor alpha(HIFa)-independent constitutive activation of nuclear factor kappa B(NF-κB)and c-jun N-terminal kinase(JNK).Both NF-κB and JNK drive ccRCC growth and epithelial to mesenchymal transition(EMT).The purpose of this study was to determine the biochemical effects of pomegranate juice extracts(PE)on RCC cell lines.Methods:The pre-clinical effects of PE on NF-κB,JNK,and the EMT phenotype were assayed,including its effect on proliferation,anchorage-independent growth,and invasion of pVHLdeficient RCCs.Results:PE inhibits the NF-κB and JNK pathways and consequently inhibits the EMT phenotype of pVHL-deficient ccRCCs.The effects of PE are concentration-dependent and affect not only biochemical markers of EMT(i.e.,cadherin expression)but also functional manifestations of EMT,such as invasion.These effects are manifested within days of exposure to PE when diluted 2000-fold.Highly dilute concentrations of PE(106 dilution),which do not impact these pathways in the short term,were found to have NF-κB and JNK inhibitory effects and ability to reverse the EMT phenotype following prolonged exposure.Conclusion:These findings suggest that PE may mediate inhibition growth of pVHL-deficient ccRCCs and raises the possibility of its use as a dietary adjunct to managing patients with active surveillance for small,localized,incidentally identified renal tumors so as to avoid more invasive procedures such as nephrectomy.

Link between dysregulated hypoxia signaling and aberrant methylation in clear cell renal cell carcinoma？

Dysregulated pseudo-hypoxia （through its effects on cell survival, angiogenesis, metabolism, invasion） and epigenetic dysregulation [through widespread suppression of tumor suppressor genes involved in cell cycle, apoptosis, adhesion, immune evasion, etc. （1）] are considered to be the two central driving pathogenic features in the progression of clear cell Renal Cell Carcinoma （ccRCC） （2,3）.

A potential impact of A Disintegrin and Metalloproteinase Domain-Like Protein Decysin-1(ADAMDEC1)on clear cell renal cell carcinoma propagation

Clear cell renal cell carcinoma(KIRC)is the most common and aggressivemalignancy subtype of renal neoplasm that arises from proximal convoluted tubules.It is characterized by poor clinical outcomes and high mortality of patients due to the lack of specific biomarkers for varying stages of the disease and no effective treatment.Proteases are associated with the development of several malignant tumors in humans by their ability to degrade extracellular matrices,facilitating metastasis.Herein,differentially expressed genes in KIRC cases compared to healthy kidneys were screened out from the Gene Expression Profiling Interactive Analysis(GEPIA)database.This data was applied to determine the most elevated protease in KIRC and as a result,A Disintegrin and Metalloproteinase Domain-Like Protein Decysin-1(ADAMDEC1)was selected.This expression pattern was exclusive for KIRC and not observed for papillary and chromophobe renal cell carcinomas,in which ADAMDEC1 was at the same level in tumors and non-cancer specimens.Furthermore,the ADAMDEC1 significant increase was detected in the fourteen other human malignancies compared to healthy samples,which suggested its strong involvement in cancer development.Next,GEPIA and Pathology Atlas correlated ADAMDEC1 high expression with more advanced tumor grade and shorter survival of KIRC patients.Xena Functional Genomics Explorer presented that ADAMDEC1 could be hypermethylated in some tumor cases and one somatic mutation in the gene sequence was detected.Finally,a Search Tool for the Retrieval of Interacting Genes/Proteins;STRING base was utilized to predict the interactions of ADAMDEC1 with other molecules and construct the signaling network.In summary,ADAMDEC1 showed the tremendous potential to be the predictive marker for the KIRC and its development.Therefore,this review with data analysis can be a good base for further in vitro and in vivo research that experimentally can confirm the ADAMDEC1 as prognostic biomarkers and therapeutic target of KIRC.

Co-expression Network Analysis Identifies Fourteen Hub Genes Associated with Prognosis in Clear Cell Renal Cell Carcinoma

Summary:Renal cancer is a common genitourinary malignance,of which clear cell renal cell carcinoma(ccRCC)has high aggressiveness and leads to most cancer-related deaths.Identification of sensitive and reliable biomarkers for predicting tumorigenesis and progression has great significance in guiding the diagnosis and treatment of ccRCC.Here,we identified 2397 common difTerentially expressed genes(DEGs)using paired normal and tumor ccRCC tissues from GSE53757 and The Cancer Genome Atlas(TCGA).Then,we performed weighted gene co-expression network analysis and protein-protein interaction network analysis,17 candidate hub genes were identified.These candidate hub genes were further validated in GSE36895 and Oncomine database and 14 real hub genes were identified.All the hub genes were up-regulated and significantly positively correlated with pathological stage and histologic grade of ccRCC.Survival analysis showed that the higher expression level of each hub gene tended to predict a worse clinical outcome.ROC analysis showed that all the hub genes can accurately distinguish between tumor and normal samples,and between early stage and advanced stage ccRCC.Moreover,all the hub genes were positively associated with distant metastasis,lymph node infiltration,tumor recurrence and the expression of MKi67,suggesting these genes might promote tumor proliferation,invasion and metastasis.Furthermore,the functional annotation demonstrated that most genes were enriched in cell-cycle related biological function.In summary,our study identified 14 potential biomarkers for predicting tumorigenesis and progression,which might contribute to early diagnosis,prognosis prediction and therapeutic intervention.

Tumor-to-tumor metastasis of clear cell renal cell carcinoma to contralateral synchronous pheochromocytoma:A case report

BACKGROUND Tumor-to-tumor metastasis(TTM)is an uncommon condition.Only a few cases of renal cell carcinoma(RCC)as donor tumor of TTM have been reported in literature,and none of these studies have described RCC metastasizing to synchronous pheochromocytoma(PCC).CASE SUMMARY The patient was a 54-year-old woman who presented with recurrent dull abdominal pain for six months,which was further aggravated for one more month.Enhanced computed tomography revealed a tumor mass in the right kidney and another mass in the left retroperitoneum/adrenal gland.Histopathology and immunochemistry of resected specimens confirmed the diagnosis of clear cell renal cell carcinoma(CCRCC)of the right kidney,and the left retroperitoneum revealed a typical PCC with CCRCC metastasis.Whole exome sequencing revealed the presence of a c.529A>T somatic mutation of the Von Hippel Lindau(VHL)gene in the metastasized CCRCC,which was also present in the primary right kidney CCRCC,as confirmed by Sanger sequencing.No VHL mutation was detected in the PCC or in normal right kidney tissue.Fluorescence in situ hybridization revealed loss of chromosome 3p in both the primary right kidney CCRCC and CCRCC metastasized to PCC in the left kidney.CONCLUSION This is the first case showing metastasis of CCRCC to PCC,thus leading to tumorto-tumor metastasis.

Decreased cross-sectional muscle area in male patients with clear cell renal cell carcinoma and peritumoral collateral vessels

BACKGROUND Sarcopenia is the loss of skeletal muscle mass(SMM)and is a sign of cancer cachexia.Patients with advanced renal cell carcinoma(RCC)may show cachexia.AIM To evaluate the amount of SMM in male clear cell RCC(ccRCC)patients with and without collateral vessels.METHODS In this study,we included a total of 124 male Caucasian patients divided into two groups:ccRCCa group without collateral vessels(n=54)and ccRCCp group with collateral vessels(n=70).Total abdominal muscle area(TAMA)was measured in both groups using a computed tomography imaging-based approach.TAMA measures were also corrected for age in order to rule out age-related effects.RESULTS There was a statistically significant difference between the two groups in terms of TAMA(P<0.05)driven by a reduction in patients with peritumoral collateral vessels.The result was confirmed by repeating the analysis with values corrected for age(P<0.05),indicating no age effect on our findings.CONCLUSION This study showed a decreased TAMA in ccRCC patients with peritumoral collateral vessels.The presence of peritumoral collateral vessels adjacent to ccRCC might be a fine diagnostic clue to sarcopenia.

Prognostic significance of carbonic anhydrase IX expression in clear cell renal cell carcinoma

Objective To evaluate the prognostic significance of carbonic anhydrase IX ( CA IX) expression in patients with clear cell renal cell carcinoma ( ccRCC) . Methods CA IX excression in a cohort of 120 patients with ccRCC was evaluated by P-V immunohistochemistry

Characteristics of clear cell renal cell carcinoma metastases to the thyroid gland: A systematic review

BACKGROUND Thyroid gland is an uncommon site for metastases from clear cell renal cell carcinoma(CCRCC)and literature is scarce.Due to the variable and often long lag time before development of metastases in patients with CCRCC,thyroid nodules may be misdiagnosed initially as benign.This systematic review aims at a better understanding of the nature of these metastases.METHODS A bibliographic search was performed using PubMed(1990-2019),key words being“renal cell carcinoma,thyroid,kidney cancer,clear cell.”147 cases were analyzed.The patient’s characteristics assessed were:age,sex,stage,size of metastases,lag time,diagnostic modality,initial symptoms,treatment and outcome in last documented follow up.Binary logistic regression,Spearman’s rho and ANOVA were used to identify differences between the existing variables.RESULTS The mean age(±SD)was 64±(10)years in males and 64(±11)in females.The mean lag time to diagnosis of thyroid metastases was 8.7(±6.3)years.Gender distribution of the patients was 46.3%male,52.4%female.There was a weak correlation between lag time and size of metastases,not statistically significant.Size of metastases was significantly higher in symptomatic patients(6.06±3.51 cm)compared to those with painless mass(4.6±0.29 cm)and asymptomatic ones(3.93±1.99 cm)(P=0.03).Fine Needle Aspiration was diagnostic in 29.4%of cases,47.1%were non diagnostic.Most patients(80.3%)underwent thyroid surgery.At 1 year follow up,55.6%of patients operated were alive versus 35.3%who did not have surgery,though this was not statistically significant(P=0.1).CONCLUSION A larger size of thyroid metastasis was more likely to present with symptomatology.A high index of suspicion is warranted when evaluating thyroid nodules in CCRCC patients.There was no significant difference in outcome between patients who underwent surgery and those who did not.With the wider use of immune check-point inhibitors and tyrosine kinase inhibitors in metastatic CCRCC,surgery may eventually be reserved only for palliative purposes.

Metastatic clear cell renal cell carcinoma in isolated retroperitoneal lymph node without evidence of primary tumor in kidneys: A case report

BACKGROUND Retroperitoneal lymph node dissection(RPLND)plays a diagnostic,therapeutic,and prognostic role in myriad urologic malignancies,including testicular carcinoma,renal cell carcinoma(RCC),and upper urinary tract urothelial carcinoma.RCC represents 2%of all cancers with approximately 25%of patients presenting with advanced disease.Clear cell RCC(CCRCC)is the most common RCC,accounting for 75%-80%of all RCC.CASE SUMMARY A 71-year-old man presented with a history of benign prostatic hypertrophy.He was asymptomatic without any hematuria,pain,or other urinary symptoms.A computed tomography(CT)scan of the abdomen and pelvis showed a 1.8 cm left retroperitoneal lymph node.There was no evidence of renal pathology.A core biopsy was performed of the left para-aortic lymph node.Although the primary tumor site was unknown,the morphological and immunohistochemical features were most consistent with CCRCC.A RPLND was performed which revealed a single mass 5.5 cm in greatest dimension with extensive necrosis.The retroperitoneal lymph node was most compatible with CCRCC.A nephrectomy was not conducted as a renal mass had not been detected on any prior imaging studies.The patient did not receive any type of adjuvant therapy.The patient underwent surveillance with serial CT scans with contrast of the chest,abdomen,and pelvis for the next 5 years,all of which demonstrated no recurrent or metastatic disease and no evidence of retroperitoneal adenopathy.CONCLUSION Our unique case emphasizes the therapeutic role of metastasectomy in metastatic CCRCC even in the absence of primary tumor in the kidneys.

Clinical significance,molecular characterization,and immune microenvironment analysis of coagulation-related genes in clear cell renal cell carcinoma

Background:Numerous studies have revealed a tight connection between tumor development and the coagulation system.However,the effects of coagulation on the prognosis and tumor microenvironment(TME)of clear cell renal cell carcinoma(ccRCC)remain poorly understood.Methods:We employed the consensus clustering method to characterize distinct molecular subtypes associated with coagulation patterns.Subsequently,we examined variations in the overall survival(OS),genomic profiles,and TME characteristics between these subtypes.To develop a prognostic coagulation-related risk score(CRRS)model,we utilized the least absolute shrinkage and selection operator Cox regression and stepwise multivariate Cox regression analyses.We also created a nomogram to aid in the clinical application of the risk score,evaluating the relationships between the CRRS and the immune microenvironment,responsiveness to immunotherapy,and targeted treatment.The clinical significance of PLAUR and its biological function in ccRCC were also further analyzed.Results:There were significant differences in clinical features,prognostic stratification,genomic variation,and TME characteristics between the two coagulation-related subtypes.We established and validated a CRRS using six coagulation-related genes that can be employed as an effective indicator of risk stratification and prognosis estimation for ccRCC patients.Significant variations in survival outcomes were observed between the high-and low-risk groups.The nomogram was proficient in predicting the 1-,3-,and 5-year OS.Additionally,the CRRS emerged as a novel tool for evaluating the clinical effectiveness of immunotherapy and targeted treatments in ccRCC.Moreover,we confirmed upregulated PLAUR expression in ccRCC samples that was significantly correlated with poor patient prognosis.PLAUR knockdown notably inhibited ccRCC cell proliferation and migration.Conclusion:Our data suggested that CRRS may be employed as a reliable predictive biomarker that can provide therapeutic benefits for immunotherapy and targeted therapy in ccRCC.

The unique genomic landscape and prognostic mutational signature of Chinese clear cell renal cell carcinoma

Background:The genomic background affects the occurrence and metastasis of cancers,including clear cell renal cell carcinoma(ccRCC).However,reports focusing on the prognostic mutational signature of Chinese ccRCC are lacking.Methods:Overall,929 patients,including a training cohort with Chinese patients(n=201),a testing cohort with Caucasian patients(n=274),and a validation cohort(n=454)were analyzed for the genomic landscape of ccRCC.Then,machine-learning algorithms were used to identify and evaluate the genomic mutational signature(GMS)in ccRCC.Analyses for prognosis,immune microenvironment,association with independent clinicopathological features,and predictive responses for immune checkpoint therapies(ICTs)were performed.Results:The DNA variation data of 929 patients with ccRCC suggested markedly differential genomic mutational frequency of the most frequent genes,such as VHL,PBRM1,BAP1,SETD2,and KDM5C between the Chinese and Caucasian populations.PBRM1 showed significant co-occurrence with VHL and SETD2.We then successfully iden-tified a seven-gene mutational signature(GMS^(Mut))that included mutations in FBN1,SHPRH,CELSR1,COL6A6,DST,ABCA13,and BAP1.The GMS^(Mut)significantly predicted progressive progression(P<0.0001,HR=2.81)and poor prognosis(P<0.0001,HR=3.89)in the Chinese training cohort.Moreover,ccRCC patients with the GMS^(Mut)had poor survival rates in the testing cohort(P=0.020)and poor outcomes were predicted for those treated with ICTs in the validation cohort(P=0.036).Interestingly,a favorable clinical response to ICTs,ele-vated expression of immune checkpoints,and increased abundance of tumor-infiltrated lymphocytes,specifically CD8^(+)T cells,Tregs,and macrophages,were observed in the GMS^(Mut)cluster.Conclusions:This study described the pro-tumorigenic GMS^(Mut)cluster that improved the prognostic accuracy in Chinese patients with ccRCC.Our discovery of the novel independent prognostic signature highlights the relationship between tumor phenotype and genomic mutational characteristics of ccRCC.