Marker For Renal Cell Carcinoma Research Articles

Niemann–Pick C1-like 1 as a Prognostic Marker in Renal Cell Carcinoma: A Retrospective Cohort Study

Niemann–Pick C1-like 1 as a Prognostic Marker in Renal Cell Carcinoma: A Retrospective Cohort Study

Identification of exosomal ceRNA networks as prognostic markers in clear cell renal cell carcinoma.

Aggressive clear cell renal cell carcinoma (ccRCC) has a bad prognosis. We seek new ccRCC biomarkers for diagnosis and treatment. We used exoRBase and The Cancer Genome Atlas Database to compare DEmRNAs, DEmiRNAs, DElncRNAs, and DEcircRNAs in ccRCC and normal renal tissues. CircRNAs and circRNAs targeting microRNAs (miRNAs) were anticipated and taken intersections, and several databases assessed the targeted link between common miRNAs and messenger RNAs (mRNAs). The Cancer Genome Atlas database was used to create a predictive mRNA signature that was validated in E-MTAB-1980. Finally, we examined competing endogenous RNA network miRNAs and long noncoding RNAs for ccRCC predictive biomarkers using overall survival analysis. We built the first competing endogenous RNA regulation network of circRNA-lncRNA-miRNA-mRNA and found that it substantially correlates with ccRCC prognosis. We unveiled ccRCC's posttranscriptional regulation mechanism in greater detail. Our findings identified novel biomarkers for ccRCC diagnosis, therapy, and prognosis.

A Frozen Tale of Two Tumors in the Pancreas: An Intraoperative Diagnostic Challenge of Clear Cell Pancreatic Neuroendocrine Tumor Mimicking Metastatic Clear Cell Renal Cell Carcinoma

Abstract Introduction/Objective Clear cell pancreatic neuroendocrine tumor (PanNET) is rare, with very few cases reported in the literature, and is often found in patients with von Hippel-Lindau (VHL) disease. The differential for this entity includes ectopic adrenal tissue and metastatic clear cell neoplasms. These challenges during intraoperative consultation add to the complexity of diagnosing this condition. Distinguishing it from other pancreatic lesions requires careful examination and further ancillary testing. Methods/Case Report We report a case of clear cell PanNET mimicking metastatic clear cell renal cell carcinoma (RCC) in a 56-year-old woman with recently diagnosed VHL. She presented with renal masses and a pancreatic lesion with previous biopsy showing conventional NET. Intraoperative consultation during her pancreaticoduodenectomy identified a 1.3 cm well-circumscribed, golden-yellow solid mass. Further characterization was deferred to permanent sections given the diagnostic challenge of distinguishing between a PanNET and metastatic clear cell RCC. Permanent sections showed nests of clear cells with prominent nucleoli. The neoplastic cells were immunohistochemically positive for neuroendocrine markers synaptophysin, chromogranin and insulinoma- associated protein 1(INSM1), as well as pankeratin and PAX8, with a Ki-67% proliferation index <1%, consistent with low-grade clear cell PanNET. Clear cell RCC marker, CA-IX, as well as adrenocortical marker SF1, were negative. The combination of immunohistochemical stains is key for making the diagnosis. The previously biopsied conventional PanNET was also identified, which was positive for neuroendocrine markers and had a Ki-67 proliferation index <1%. Results (if a Case Study enter NA) NA Conclusion Given the rarity of this entity and its strong association with VHL, clear cell PanNET should be considered in the intraoperative consultation to inform clinical management. Furthermore, literature review indicates that metastatic RCC in the pancreas is exceptionally rare in VHL patients and typically of low nuclear grade, suggesting low metastatic potential. Thus, this case emphasizes the diagnostic challenges and the necessity of deferring to permanent sections with immunohistochemical work-up during intraoperative consultation or when assessing small biopsies.

6477 Surprise Finding For A Thyroid Nodule: Metastatic Renal Cell Carcinoma

Abstract Disclosure: A. Xu: None. E. Hsu: None. Introduction: A patient with an incidental and asymptomatic thyroid nodule underwent fine needle aspiration biopsy (FNA) after the nodule increased in size. Without a definite pathology after three FNA attempts, thyroidectomy was performed, where pathology found metastatic renal cell carcinoma (RCC). Clinical Case: A 64 year old woman had a past medical history of obesity, type 2 diabetes, RCC (stage I: pT1bN0M0) treated with right radical nephrectomy five years prior and thought to be in remission, remote smoking history smoking, and coronary artery disease with coronary artery bypass graft (CABG) two months prior, on anticoagulation. The patient reported a distant history of right thyroid lobectomy over a decade prior for unclear reasons, but she was adamant that the pathology was benign. Two years prior to presentation, CT chest done for RCC surveillance had detected a left thyroid nodule. Ultrasound at the time revealed a 3.6 x 1.9 x 2.3 cm solid, isoechoic nodule in the upper left lobe, which was not taller than wide, and had smooth margins and no echogenic foci. A repeat ultrasound at the time of presentation showed interval growth of the nodule, now measuring 4.3 x 2.1 x 2.9 cm. FNA was unsatisfactory, yielding predominantly blood. Patient felt well and had no compressive neck symptoms. We opted to wait two months and repeat FNA, which resulted as atypia of undetermined significance - Bethesda category III (AUS). We recommended completion thyroidectomy, but patient preferred to avoid surgery. We decided to wait two months and repeat FNA with molecular testing. This third FNA resulted AUS again; however, due to non-medical reasons, molecular testing was not performed. Another ultrasound showed slight growth of the nodule, 5.1 x 2.9 x 2.0 cm, which appeared hypoechoic now, but was still not taller than wide, with smooth margins and no echogenic foci. Completion thyroidectomy was performed, with pathology showing metastatic clear cell renal cell carcinoma. Immunostains were positive for carbonic anhydrase and renal cell carcinoma marker and negative for TTF-1. Whole-body PET-CT showed no hypermetabolic foci, and a repeat PET-CT one year later still showed no evidence of metastatic disease. Other than a hospitalization for COVID-19, patient is doing well and asymptomatic now over a year after her thyroidectomy. Oncology will continue routine surveillance imaging for her metastatic renal cell carcinoma thought to be in remission. Clinical Lessons: This case of metastatic renal cell carcinoma to the thyroid adds to the small body of literature showing the thyroid as a possible site of RCC metastasis. The long time interval between initial RCC presentation and metastasis to the thyroid makes this diagnosis more difficult; however, clinicians should be aware of the possibility, making thyroidectomy a stronger option in cases where FNA cytology is indeterminate. Presentation: 6/2/2024

6477 Surprise Finding for a Thyroid Nodule: Metastatic Renal Cell Carcinoma

Abstract Disclosure: A. Xu: None. E. Hsu: None. Introduction: A patient with an incidental and asymptomatic thyroid nodule underwent fine needle aspiration biopsy (FNA) after the nodule increased in size. Without a definite pathology after three FNA attempts, thyroidectomy was performed, where pathology found metastatic renal cell carcinoma (RCC). Clinical Case: A 64 year old woman had a past medical history of obesity, type 2 diabetes, RCC (stage I: pT1bN0M0) treated with right radical nephrectomy five years prior and thought to be in remission, remote smoking history smoking, and coronary artery disease with coronary artery bypass graft (CABG) two months prior, on anticoagulation. The patient reported a distant history of right thyroid lobectomy over a decade prior for unclear reasons, but she was adamant that the pathology was benign. Two years prior to presentation, CT chest done for RCC surveillance had detected a left thyroid nodule. Ultrasound at the time revealed a 3.6 x 1.9 x 2.3 cm solid, isoechoic nodule in the upper left lobe, which was not taller than wide, and had smooth margins and no echogenic foci. A repeat ultrasound at the time of presentation showed interval growth of the nodule, now measuring 4.3 x 2.1 x 2.9 cm. FNA was unsatisfactory, yielding predominantly blood. Patient felt well and had no compressive neck symptoms. We opted to wait two months and repeat FNA, which resulted as atypia of undetermined significance - Bethesda category III (AUS). We recommended completion thyroidectomy, but patient preferred to avoid surgery. We decided to wait two months and repeat FNA with molecular testing. This third FNA resulted AUS again; however, due to non-medical reasons, molecular testing was not performed. Another ultrasound showed slight growth of the nodule, 5.1 x 2.9 x 2.0 cm, which appeared hypoechoic now, but was still not taller than wide, with smooth margins and no echogenic foci. Completion thyroidectomy was performed, with pathology showing metastatic clear cell renal cell carcinoma. Immunostains were positive for carbonic anhydrase and renal cell carcinoma marker and negative for TTF-1. Whole-body PET-CT showed no hypermetabolic foci, and a repeat PET-CT one year later still showed no evidence of metastatic disease. Other than a hospitalization for COVID-19, patient is doing well and asymptomatic now over a year after her thyroidectomy. Oncology will continue routine surveillance imaging for her metastatic renal cell carcinoma thought to be in remission. Clinical Lessons: This case of metastatic renal cell carcinoma to the thyroid adds to the small body of literature showing the thyroid as a possible site of RCC metastasis. The long time interval between initial RCC presentation and metastasis to the thyroid makes this diagnosis more difficult; however, clinicians should be aware of the possibility, making thyroidectomy a stronger option in cases where FNA cytology is indeterminate. Presentation: 6/2/2024

Integrated Analysis of Clinical Outcome of Mesenchymal Stem Cell-related Genes in Pan-cancer.

Although the application of mesenchymal stem cells (MSCs) in engineered medicine, such as tissue regeneration, is well known, new evidence is emerging that shows that MSCs can also promote cancer progression, metastasis, and drug resistance. However, no large-scale cohort analysis of MSCs has been conducted to reveal their impact on the prognosis of cancer patients. We propose the MSC score as a novel surrogate for poor prognosis in pan-cancer. We used single sample gene set enrichment analysis to quantify MSC-related genes into a signature score and identify the signature score as a potential independent prognostic marker for cancer using multivariate Cox regression analysis. TIDE algorithm and neural network were utilized to assess the predictive accuracy of MSC-related genes for immunotherapy. MSC-related gene expression significantly differed between normal and tumor samples across the 33 cancer types. Cox regression analysis suggested the MSC score as an independent prognostic marker for kidney renal papillary cell carcinoma, mesothelioma, glioma, and stomach adenocarcinoma. The abundance of fibroblasts was also more representative of the MSC score than the stromal score. Our findings supported the combined use of the TIDE algorithm and neural network to predict the accuracy of MSC-related genes for immunotherapy. We comprehensively characterized the transcriptome, genome, and epigenetics of MSCs in pan-cancer and revealed the crosstalk of MSCs in the tumor microenvironment, especially with cancer-related fibroblasts. It is suggested that this may be one of the key sources of resistance to cancer immunotherapy.

The role of immunohistochemistry (PAX2 and PAX8) as prognostic markers in renal cell carcinoma

The role of immunohistochemistry (PAX2 and PAX8) as prognostic markers in renal cell carcinoma

21 Decoding Kidney Tumours: A Comparative Study of Immunohistochemical Markers in Renal Oncocytoma and Chromophobe Renal Cell Carcinoma

21 Decoding Kidney Tumours: A Comparative Study of Immunohistochemical Markers in Renal Oncocytoma and Chromophobe Renal Cell Carcinoma

Acetylation- and ubiquitination-regulated SFMBT2 acts as a tumor suppressor in clear cell renal cell carcinoma

BackgroundClear cell renal cell carcinoma (RCC) is the most common kidney tumor. The analysis from medical database showed that Scm-like with four MBT domains protein 2 (SFMBT2) was decreased in advanced clear cell RCC cases, and its downregulation was associated with the poor prognosis. This study aims to investigate the role of SFMBT2 in clear cell RCC.MethodsThe expression of SFMBT2 in clear cell RCC specimens were determined by immunohistochemistry staining and western blot. The overexpression and knockdown of SFMBT2 was realized by infection of lentivirus loaded with SFMBT2 coding sequence or silencing fragment in 786-O and 769-P cells, and its effects on proliferation and metastasis were assessed by MTT, colony formation, flow cytometry, wound healing, transwell assay, xenograft and metastasis experiments in nude mice. The interaction of SFMBT2 with histone deacetylase 3 (HDAC3) and seven in absentia homolog 1 (SIAH1) was confirmed by co-immunoprecipitation.ResultsIn our study, SFMBT2 exhibited lower expression in clear cell RCC specimens with advanced stages than those with early stages. Overexpression of SFMBT2 inhibited the growth and metastasis of clear cell RCC cells, 786-O and 769-P, in vitro and in vivo, and its silencing displayed opposites effects. HDAC3 led to deacetylation of SFMBT2, and the HDAC3 inhibitor-induced acetylation prevented SFMBT2 from SIAH1-mediated ubiquitination modification and proteasome degradation. K687 in SFMBT2 protein molecule may be the key site for acetylation and ubiquitination.ConclusionsSFMBT2 exerted an anti-tumor role in clear cell RCC cells, and HDAC3-mediated deacetylation promoted SIAH1-controlled ubiquitination of SFMBT2. SFMBT2 may be considered as a novel clinical diagnostic marker and/or therapeutic target of clear cell RCC, and crosstalk between its post-translational modifications may provide novel insights for agent development.

Exploring G-quadruplex structure in PRCC-TFE3 fusion oncogene: Plausible use as anti cancer therapy for translocation Renal cell carcinoma (tRCC)

The TFE3 fusion gene, byproduct of Xp11.2 translocation, is the diagnostic marker for translocation renal cell carcinoma (tRCC). Absence of any clinically recognized therapy for tRCC, pressing a need to create novel and efficient therapeutic approaches. Previous studies shown that stabilization of the G-quadruplex structure in oncogenes suppresses their expression machinery. To combat the oncogenesis caused by fusion genes, our objective is to locate and stabilize the G-quadruplex structure within the PRCC-TFE3 fusion gene. Using the Quadruplex-forming G Rich Sequences (QGRS) mapper and the Non-B DNA motif search tool (nBMST) online server, we found putative G-quadruplex forming sequences (PQS) in the PRCC-TFE3 fusion gene. Circular dichroism demonstrating a parallel G-quadruplex in the targeted sequence. Fluorescence and UV–vis spectroscopy results suggest that pyridostatin binds to this newly discovered G-quadruplex. The PCR stop assay, as well as transcriptional or translational inhibition using real time PCR and Dual luciferase assay, revealed that stable G-quadruplex formation affects biological processes. Confocal microscopy of HEK293T cells transfected with the fusion transcript confirmed G-quadruplexes formation in cell. This investigation may shed light on G-quadruplex’s functions in fusion genes and may help in the development of therapies specifically targeted against fusion oncogenes, which would enhance the capability of current tRCC therapy approach.

Influence of Dietary Polyunsaturated Fatty Acid Intake on Potential Lipid Metabolite Diagnostic Markers in Renal Cell Carcinoma: A Case-Control Study.

Non-invasive diagnostics are crucial for the timely detection of renal cell carcinoma (RCC), significantly improving survival rates. Despite advancements, specific lipid markers for RCC remain unidentified. We aimed to discover and validate potent plasma markers and their association with dietary fats. Using lipid metabolite quantification, machine-learning algorithms, and marker validation, we identified RCC diagnostic markers in studies involving 60 RCC and 167 healthy controls (HC), as well as 27 RCC and 74 HC, by analyzing their correlation with dietary fats. RCC was associated with altered metabolism in amino acids, glycerophospholipids, and glutathione. We validated seven markers (l-tryptophan, various lysophosphatidylcholines [LysoPCs], decanoylcarnitine, and l-glutamic acid), achieving a 96.9% AUC, effectively distinguishing RCC from HC. Decreased decanoylcarnitine, due to reduced carnitine palmitoyltransferase 1 (CPT1) activity, was identified as affecting RCC risk. High intake of polyunsaturated fatty acids (PUFAs) was negatively correlated with LysoPC (18:1) and LysoPC (18:2), influencing RCC risk. We validated seven potential markers for RCC diagnosis, highlighting the influence of high PUFA intake on LysoPC levels and its impact on RCC occurrence via CPT1 downregulation. These insights support the efficient and accurate diagnosis of RCC, thereby facilitating risk mitigation and improving patient outcomes.

A three miRNAs panel in paraffin tissue serves as tool for predicting prognosis of renal cell carcinoma.

Renal cell carcinoma (RCC) stands as the most prevalent form of urogenital cancer. However, there is currently no universally accepted method for predicting the prognosis of RCC. MiRNA holds great potential as a prognostic biomarker for RCC. A total of 100 cases with complete paraffin specimens and over 5-year follow-up data meeting the requirements were collected. Utilizing the clinical information and follow-up data of the specimens, an information model was developed. The expression levels of eight microRNAs were identified using RT-qPCR. Finally, determine and analyze the clinical application value of these microRNAs as prognostic markers for RCC. Significant differences were observed in the expression of two types of miRNAs (miR-378a-5p, miR-23a-5p) in RCC tissue, and three types of miRNAs (miR-378a-5p, miR-642a-5p, miR-23a-5p) were found to be linked to the prognosis of RCC. Establish biomarker combinations of miR-378a-5p, miR-642a-5p, and miR-23a-5p to evaluate RCC prognosis. The combination of three microRNA groups (miR-378a-5p, miR-642a-5p, and miR-23a-5p) identified in paraffin section specimens of RCC in this study holds significant potential as biomarkers for assessing RCC prognosis.

Increased level of serum leucine-rich-alpha-2-glycoprotein 1 in patients with clear cell renal cell carcinoma

BackgroundCurrently, no useful serum markers exist for clear cell renal cell carcinoma (ccRCC), making early detection challenging as diagnosis relies solely on imaging tests. Radiation exposure is also a concern due to multiple required CT examinations during treatment. Renal cell carcinoma (RCC) histological types include ccRCC and non-clear cell RCC (non-ccRCC); however, treatment response to medications varies which necessitates accurate differentiation between the two. Therefore, we aimed to identify a novel serum marker of RCC. Increased LRG1 expression in the serum has been demonstrated in multiple cancer types. However, the expression of LRG1 expression in the serum and cancer tissues of patients with RCC has not been reported. Since ccRCC is a hypervascular tumor and LRG1 is capable of accelerating angiogenesis, we hypothesized that the LRG1 levels may be related to ccRCC. Therefore, we examined LRG1 expression in sera from patients with RCC.MethodsUsing an enzyme-linked immunosorbent assay, serum levels of leucine-rich-alpha-2-glycoprotein 1 (LRG1) were measured in 64 patients with ccRCC and 22 patients non-ccRCC who underwent radical or partial nephrectomy, as well as in 63 patients without cancer.ResultsMedian values of serum LRG1 and their inter-quartile ranges were 63.2 (42.8–94.2) µg/mL in ccRCC, 23.4 (17.7–29.6) µg/mL in non-ccRCC, and 36.0 (23.7–56.7) µg/mL in patients without cancer, respectively (ccRCC vs. non-ccRCC or patients without cancer: P < 0.001). C-reactive protein (CRP) levels (P = 0.002), anemia (P = 0.037), hypercalcemia (P = 0.023), and grade (P = 0.031) were independent predictors of serum LRG1 levels in ccRCC. To assess diagnostic performance, the area under the receiver operating characteristic curve of serum LRG1 was utilized to differentiate ccRCC from non-cancer and non-ccRCC, with values of 0.73 (95% CI, 0.64–0.82) and 0.91 (95% CI, 0.82–0.96), respectively.ConclusionsLRG1 served as a serum marker associated with inflammation, indicated by CRP, anemia, hypercalcemia, and malignant potential in ccRCC. Clinically, serum LRG1 levels may assist in differentiating ccRCC from non-ccRCC with excellent diagnostic accuracy.

A Systematic Review on Prognostic DNA Methylation Markers for Renal Cell Carcinoma: Are We Moving Forward?

Purpose: In this study, we update 2 previously published systematic reviews on prognostic DNA methylation markers for renal cell carcinoma and provide a comprehensive overview of the latest markers and methylation signatures that merit further validation. Materials and Methods: We performed a systematic literature search of PubMed, EMBASE, and Web of Science including all studies published after our previous systematic review (ie, between March 2017 and December 2021). Data extraction and evaluation using the Reporting Recommendations for Tumor Marker Prognostic Studies criteria and the level of evidence was performed for all 58 included studies. DNA methylation markers were considered promising when findings were validated in more than one study or within multiple cohorts. Results: We identified 11 promising single DNA methylation markers (ie, RUNX3, EVI2A, HHLA2, TACSTD2, KEAP1, LAG3, NSD1, ZNF492, GPR149, LEP, and LEPR), three multimarker panels (ie, (1) RAC2, PLCB2, VAV1 and PARVG; (2) NCKAP1L, EVI2A, and BATF; and (3) GREM1, GATA5, LAD1, NEFH, and NEURL) and 5 DNA methylation signatures. Remarkably, since our previous systematic review, only part of the markers recommended for validation were evaluated in subsequent validation efforts, emphasizing the lack of validation in this field. Conclusion: Validation studies for prognostic DNA methylation markers have been scarce despite previously published recommendations. Nevertheless, since then, other novel DNA methylation markers or signatures have been proposed as promising biomarkers emphasizing the current focus on expanding evidence instead of further building the evidence on specific markers with the aim of clinical translation.

FZD1: As a Novel Prognostic Marker for Renal Clear Cell Carcinoma, is Associated with Tumor Immunoinfiltration

FZD1: As a Novel Prognostic Marker for Renal Clear Cell Carcinoma, is Associated with Tumor Immunoinfiltration

Alpha-methyl CoA racemase (AMACR) reactivity across the spectrum of clear cell renal cell neoplasms

a-Methylacyl coenzyme A racemase (AMACR) is traditionally considered to be a marker of papillary renal cell carcinoma. However, AMACR expression can be seen in other renal tumors. The aim of this study was to investigate AMACR immunoreactivity within the spectrum of clear cell renal cell neoplasms.Fifty-three clear cell renal epithelial tumors were used in assembling the following four cohorts: low grade (LG) clear cell renal cell carcinoma (CCRCC), high grade (HG) CCRCC, CCRCC with cystic changes, and multilocular cystic renal neoplasm of low malignant potential (MCRNLMP). Representative blocks were stained for AMACR, using two different clones (SP52 and OV-TL12/30).There were at least some AMACR immunoreactivity in 77.8 % and 68.9 % of CCRCCs (using SP52 and OV-TL12/30 clone, respectively). Moderate to strong positivity, or positivity in more than one third of the tumor (even weak in intensity) was detected in 46.7 % of CCRCCs using SP52 and in 48.9 % of CCRCC using OV-TL12/30 clone. The highest AMACR reactivity was observed in HG CCRCC (60 % by SP52 and 66.7 % by OV-TL12/30). Strong and diffuse AMACR positivity was detected in 8.9 % of all CCRCCs. AMACR immunoreactivity in MCRNLMP was 37.5 % (SP52 clone) and 25 % (OV-TL12/30 clone).We demonstrated relatively high expression rate of AMACR in CCRCC, while very variable in intensity and distribution. This finding may have diagnostic implications especially in limited samples (i.e., core biopsies), as AMACR positivity does not exclude the diagnosis of CCRCC.

Abstract 4555: c-Met/AXL crosstalk in mediating therapeutic resistance in renal cell carcinoma

Abstract Receptor Tyrosine Kinase (RTK), c-Met, is overexpressed in renal cancer and correlates with a decreased survival rate. Upon binding with its specific ligand, Hepatocyte Growth Factor (HGF), c-Met activates pro-tumorigenic signaling. c-Met/RTK inhibitors are used for the treatment of advanced renal cell carcinoma (RCC). However, acquired therapeutic resistance is a major clinical problem and the underlying mechanisms are largely unknown. Hence, novel therapeutic targets are needed to overcome the clinical hurdles; and the RTK, AXL, can be a potential target. AXL is overexpressed and a poor prognostic marker in RCC. AXL overexpression drives wide-ranging processes, including epithelial-to-mesenchymal transition (EMT), tumor angiogenesis, and resistance to chemotherapeutics. Cabozantinib (XL184/Cabo), is approved for advanced-stage RCC and can inhibit c-Met and VEGFR2 activation (including AXL and a few other RTKs); however, it is not a specific/potent inhibitor of AXL. Hence, inhibiting c-Met alone may not be sufficient when AXL remains active. Therefore, the pro-tumorigenic role of AXL and its cross-talk with c-Met in renal cancer need to be thoroughly investigated. We compared the expression of c-Met and AXL in TCGA and found significantly high expression of both c-Met and AXL in primary renal tumor tissues compared to normal tissues. Our data showed that AXL forms a complex with c-Met and may have a significant cross-talk which can be involved in therapeutic resistance. We have also found that prolonged treatment of c-Met inhibitor Cabo, (including Crizotinib and PF-4217903) induced c-Met and AXL overexpression in RCC cells. Interestingly, c-Met inhibitor(s)-induced overexpressed c-Met can also be increasingly phosphorylated (at low concentrations) in the presence of HGF, which may cause enhanced downstream tumor-promoting signaling. To understand the role of AXL in tumor-promoting pathways and therapeutic resistance, we have generated CRISPR/Cas9-mediated AXL knock-out cells (AXL-KO) and found that silencing AXL can prevent c-Met-inhibitor(s)-mediated c-Met overexpression. Furthermore, to identify the effect of AXL-KO on pro-tumorigenic signaling, transcriptional profiles of control clones and AXL-KO cells were compared. The gene set enrichment analysis (GSEA) showed that genes involved in ‘EMT’, ‘Hypoxia’, and ‘K-Ras’ signaling pathways were significantly downregulated. We have also utilized an AXL-specific small molecule inhibitor, TP-0903, in combination with Cabo and validated our data. We have also generated a Cabo-resistant cell line (Caki-1) and found high expression of c-Met and AXL in these cells. Furthermore, either silencing of AXL (using siRNA) or inhibiting AXL (using TP0903) induced significant apoptosis in these Cabo-resistant cells. Together, our data suggest that inhibition of AXL along with c-Met can be beneficial in preventing acquired therapeutic resistance in RCC. Citation Format: Akash Sabarwal, Laxminarayan Rawat, Johannes Wedel, Murugabaskar Balan, Gwo-Shu Mary Lee, Toni K. Choueiri, Soumitro Pal. c-Met/AXL crosstalk in mediating therapeutic resistance in renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4555.

Sirtuin 1, as a potential prognosis marker in clear cell renal cell carcinoma, regulates lipid metabolism and immune infiltration.

Clear cell renal cell carcinoma (ccRCC) is a malignancy with a dismal prognosis, caused by the buildup of fat and glycogen. Sirtuin 1 (Sirt1) is a deacetylase that regulates lipid metabolism. In this study, we collected tumor and paracancer tissues from 386 ccRCC patients and followed their prognosis over an extended time period. The expression of Sirt1 in these tissues was assessed using immunohistochemistry, and LinkedOmics database analysis identified differentially expressed genes associated with Sirt1. The survival curve was generated using the Kaplan-Meier method, and immune infiltration was analyzed using the Tumor Immune Estimation Resource (TIMER) web tool. Our findings revealed that Sirt1 was expressed in tumor tissues, but not in normal tissues, and its high expression was associated with a worse prognosis. Furthermore, we observed a positive correlation between high Sirt1 expression and perirenal fat invasion and necrosis, leading to poorer survival outcomes. We established a nomogram to predict prognosis, and a correlation was observed with immune infiltration. In conclusion, our results suggest that high Sirt1 expression is associated with lipid metabolism disorder and immune infiltration, ultimately contributing to a dismal prognosis in ccRCC.

Survival pattern of metastatic renal cell carcinoma patients according to WHO/ISUP grade: a long-term multi-institutional study

The World Health Organization/International Society of Urological Pathology (WHO/ISUP) grading of renal cell carcinoma (RCC) is classified from grade 1–4, regardless of subtype. The National Comprehensive Cancer Network (NCCN) guidelines (2022) state that if there is an adverse pathological feature, such as grade 3 or higher RCC in stage 1 patients, more rigorous follow-up imaging is recommended. However, the RCC guidelines do not provide specific treatment or follow-up policies by tumor grade. Therefore, this study attempted to find out whether tumor grade affects survival rates in patients with metastatic RCC. The Korean Renal Cancer Study Group (KRoCS) database includes 3108 patients diagnosed with metastatic RCC between September 1992 and February 2017, with treatment methods, progression, and survival data collected from 11 tertiary hospitals. To obtain information on survival rates or causes of death, we utilized the Korea National Statistical Office database and institutional medical records. Data were accessed for research purpose on June, 2023. We then reviewed these sources to gather comprehensive and reliable data on the outcomes of our study cohort. This database was retrospectively analyzed, and out of 3108 metastatic RCC patients, 911 had been identified as WHO/ISUP grade. Grades were classified into either a low-grade (WHO/ISUP grade 1–2) or a high-grade group (WHO/ISUP grade 3–4). The patients were then analyzed related to progression and overall survival (OS). In metastatic clear cell RCC patients, the 1-year OS rate was 69.4% and the median OS was 17.0 months (15.5–18.5) followed up to 203.6 months. When comparing the patient groups, 119 low-grade and 873 high-grade cases were identified. No baseline difference was observed between the two groups, except that the high-grade group had a higher ECOG 1 ratio of 50.4% compared with 34.5% for the low-grade group (p = 0.009). There was a significant difference in OS between high-grade and low-grade groups. OS was 16.0 months (14.6–17.4) in the high-grade group and 28.0 months (21.1–34.9) in the low-grade group (p < 0.001). However, there was no difference in progression-free survival (PFS) rates with 9.0 months (8.0–10.0) for the high-grade group and 10.0 months (6.8–13.2) for the low-grade group (p = 0.377) in first-line treatment. In multivariable analysis, WHO/ISUP grade was a risk factor (HR = 1.511[1.135–2.013], p = 0.005) that influenced the OS. In conclusion, WHO/ISUP grade is a major data source that can be used as a ubiquitous marker of metastatic RCC in pre-IO era. Depending on whether the RCC is high or low grade, the follow-up schedule will need to be tailored according to grade, with higher-grade patients needing more active treatment as it can not only affect the OS in the previously known localized/locoregional recurrence but also the metastatic RCC patient.

GSDMB: A novel, independent prognostic marker and potential new therapeutic target in clear cell renal cell carcinoma.

Gasdermin (GSDM) family members are involved in numerous biological processes, including pyroptosis, as well as in the initiation and progression of various types of cancer. However, the specific role of GSDM genes in clear cell renal cell carcinoma (ccRCC) has yet to be fully clarified. The present study investigated the differential expression and genetic alterations GSDM genes, their effects on prognosis and immune modulation, and their functional enrichment in ccRCC. Several bioinformatics databases were used, including UALCAN, The Cancer Genome Atlas, Gene Expression Profiling Interactive Analysis, Metascape, Tumor Immune Estimation Resource, GSCALite and cBioPortal. The results revealed that the expression levels of GSDMA, GSDMB, GSDMC and GSDMD were significantly upregulated in cancer tissues compared with those in paracancerous tissues in patients with ccRCC, whereas the expression of DFNB59 exhibited the opposite trend. The results were experimentally validated in patients with ccRCC, and it was confirmed that the expression levels of GSDMA, GSDMB, GSDMC, GSDMD and GSDME (DFNA5) were significantly enhanced, whereas (PJVK, DFNB59) expression was reduced. In addition, elevated GSDMB, GSDMD and DFNA5 expression levels were clearly associated with worse pathological characteristics of ccRCC, including a high pathological stage and high tumor grade. Furthermore, the high expression levels of GSDMB, GSDMC, GSDMD, DFNA5 and PJVK were shown to be associated with worse overall survival (OS) and progression-free interval in patients with ccRCC. Both univariate and multivariate analyses indicated that the expression of GSDMB was independently associated with the OS of patients with ccRCC. Additionally, a high mutation rate of GSDM genes (33%) was observed in patients with ccRCC, and GSDM gene mutations were also significantly associated with a poor OS in patients with ccRCC. Significant associations between GSDM genes and ccRCC immunoprofiling and drug sensitivity were also determined. In conclusion, the findings of the present study indicated that GSDMB, GSDMD and DFNA5 may be considered promising therapeutic agents and potential biomarkers for patients with ccRCC. Furthermore, GSDMB could act as an independent predictor for the OS of patients with ccRCC.