Renal medullary carcinomas (RMC) habor a distinct methylation phenotype
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PROVIDER: PRJNA873031 | ENA |
REPOSITORIES: ENA
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Project description:Renal medullary carcinomas (RMC) are rare aggressive tumors of the kidneys, characterized by a -mostly- biallelic loss of SMARCB1. Characteristically, these tumors arise in patients with sickle cell trait or other hemoglobinopathies. Recent molecular and landscaping characterization efforts have unraveled oncogenic pathways that drive tumorigenesis. Among these, gene sets that characterize replicative stress and the innate immune response are upregulated in RMCs. Despite comprehensive genetic and transcriptomic characterizations, commonalities or differences to other SMARCB1 deficient entities so far have not been investigated. We analyzed the methylome of four novel primary RMC and compared it to other, SMARCB1 deficient entities such as rhabdoid tumors (RT) and epithelioid sarcomas using 850K methylation arrays. In accordance with previous gene expression data, we find that RMCs separate from other SMARCB1 deficient entities such as extra-and intracranial rhabdoid tumors, pointing to a potentially different cell of origin and a role of additional mutations or genetic aberrations that may drive tumorigenesis and thus alter the methylome when compared to rhabdoid tumors. In a focused analysis of genes that are important for nephrogenesis, we detected particularly genes that govern early nephrogenesis such as FOXI to be hypomethylated and expressed at high levels in RMC. Overall, our analyses underscore the fact that RMCs represent a separate entity with limited similarities to rhabdoid tumors warranting specific treatment, tailored to the aggressiveness of the disease.
2022-11-02 | GSE211942 | GEO
Project description:<p>We derived faithful cancer cell lines from patients with a diagnosis of renal medullary carcinomas (RMC). These models have been sequenced with whole genome, exome and transcriptome technologies along with the patient's primary germline and tumor samples. We took these faithful models and performed loss-of-function genetic perturbation screens (e.g. RNAi and CRISPR-Cas9) along with an orthogonal small molecule screen. We identified the ubiquitin-proteasome system as an important target in RMC as well as other SMARCB1 deficient cancers.</p>
| phs001800 | dbGaP
Project description:Genomics of pediatric renal medullary carcinomas
| PRJNA528529 | ENA
Project description:Genomics of pediatric renal medullary carcinomas
| PRJNA528528 | ENA
Project description:Renal medullary carcinoma (RMC) predominantly afflicts young individuals of African descent harboring sickle hemoglobinopathies such as sickle cell disease (SCD) or sickle cell anemia (SCA). RMC is refractory to targeted and immune therapy strategies used for other renal cell carcinomas. We have demonstrated that RMC is resistant to immune checkpoint inhibition despite harboring an inflamed tumor immune microenvironment. Hence, novel therapeutic strategies are urgently needed to reverse this resistance. We discovered that CD8+ T cells under SCD condition exhibit altered genomic architecture and ferroptosis, which significantly impairs the anti-tumor immunity of effector T cells. These observations may underscore a fundamental mechanism behind the distinct resistance of RMC resistance to immune checkpoint therapies. By leveraging the use of both mouse SCD model and humanized mice phenotypically representing SCD/SCA, as well as primary CD8+ T cells isolated from patients with SCA, we identified that the SLC7A11 gene is transcriptionally downregulated in the CD8+ T cells of SCA donors via genomic architecture alteration. The reduced expression of SLC7A11 partially accounts for the ferroptosis observed in the CD8+ T cells of SCD disease, via impairing the cystine transportation and synthesis of Glutathione (GSH). Our findings also demonstrated that treatment using a hydrogen sulfide slow-releasing donor restored the expression of SLC7A11, antagonized the ferroptosis of CD8+ T cells under SCD/SDA condition and restored anti-tumor immunity in vivo. Hence, our research findings provide novel mechanistic insights into SCD and RMC and pave the way to develop innovative therapeutic strategies to sensitize RMC to immune therapies.
2025-07-02 | GSE240827 | GEO
Project description:Renal medullary carcinoma (RMC) predominantly afflicts young individuals of African descent harboring sickle hemoglobinopathies such as sickle cell disease (SCD) or sickle cell anemia (SCA). RMC is refractory to targeted and immune therapy strategies used for other renal cell carcinomas. We have demonstrated that RMC is resistant to immune checkpoint inhibition despite harboring an inflamed tumor immune microenvironment. Hence, novel therapeutic strategies are urgently needed to reverse this resistance. We discovered that CD8+ T cells under SCD condition exhibit altered genomic architecture and ferroptosis, which significantly impairs the anti-tumor immunity of effector T cells. These observations may underscore a fundamental mechanism behind the distinct resistance of RMC resistance to immune checkpoint therapies. By leveraging the use of both mouse SCD model and humanized mice phenotypically representing SCD/SCA, as well as primary CD8+ T cells isolated from patients with SCA, we identified that the SLC7A11 gene is transcriptionally downregulated in the CD8+ T cells of SCA donors via genomic architecture alteration. The reduced expression of SLC7A11 partially accounts for the ferroptosis observed in the CD8+ T cells of SCD disease, via impairing the cystine transportation and synthesis of Glutathione (GSH). Our findings also demonstrated that treatment using a hydrogen sulfide slow-releasing donor restored the expression of SLC7A11, antagonized the ferroptosis of CD8+ T cells under SCD/SDA condition and restored anti-tumor immunity in vivo. Hence, our research findings provide novel mechanistic insights into SCD and RMC and pave the way to develop innovative therapeutic strategies to sensitize RMC to immune therapies.
2025-07-02 | GSE231386 | GEO
Project description:Purpose: Renal medullary carcinoma (RMC) is a highly aggressive malignancy defined by the loss of the SMARCB1 tumor suppressor. It mainly affects young individuals of African descent with sickle cell trait, and it is resistant to conventional therapies used for other renal cell carcinomas. This study aimed to identify potential biomarkers for early detection and disease monitoring of RMC. Experimental Design: Integrated profiling of primary untreated RMC tumor tissues and paired adjacent kidney controls was performed using RNA-sequencing (RNA-seq) and histone Chromatin Immunoprecipitation Sequencing (ChIP-seq). The expression of serum cancer antigen 125 (CA-125), was prospectively evaluated in 47 patients with RMC. Functional studies were conducted in RMC cell lines to assess the effects of SMARCB1 re-expression and MUC16 knockdown. Results: MUC16, encoding for CA-125, was identified as one of the top upregulated genes in RMC tissues, with concomitant enrichment of active histone marks H3K4me3 and H3K27ac at its promoter. Elevated serum CA-125 levels were found in 31 of 47 (66%) RMC patients and correlated significantly with metastatic tumor burden (p = 0.03). SMARCB1 re-expression significantly reduced MUC16 expression in RMC cell lines. Functional studies in RMC cell lines demonstrated that SMARCB1 re-expression significantly reduced MUC16 expression, and that MUC16 knockdown induced apoptosis and reduced cell proliferation. Conclusions: The correlation between serum CA-125 levels and metastatic burden suggests that CA-125 is a clinically relevant biomarker for RMC. These findings support further exploration of CA-125 for disease monitoring and targeted therapeutics in RMC.
2025-01-07 | GSE284318 | GEO
Project description:Purpose: Renal medullary carcinoma (RMC) is a highly aggressive malignancy defined by the loss of the SMARCB1 tumor suppressor. It mainly affects young individuals of African descent with sickle cell trait, and it is resistant to conventional therapies used for other renal cell carcinomas. This study aimed to identify potential biomarkers for early detection and disease monitoring of RMC. Experimental Design: Integrated profiling of primary untreated RMC tumor tissues and paired adjacent kidney controls was performed using RNA-sequencing (RNA-seq) and histone Chromatin Immunoprecipitation Sequencing (ChIP-seq). The expression of serum cancer antigen 125 (CA-125), was prospectively evaluated in 47 patients with RMC. Functional studies were conducted in RMC cell lines to assess the effects of SMARCB1 re-expression and MUC16 knockdown. Results: MUC16, encoding for CA-125, was identified as one of the top upregulated genes in RMC tissues, with concomitant enrichment of active histone marks H3K4me3 and H3K27ac at its promoter. Elevated serum CA-125 levels were found in 31 of 47 (66%) RMC patients and correlated significantly with metastatic tumor burden (p = 0.03). SMARCB1 re-expression significantly reduced MUC16 expression in RMC cell lines. Functional studies in RMC cell lines demonstrated that SMARCB1 re-expression significantly reduced MUC16 expression, and that MUC16 knockdown induced apoptosis and reduced cell proliferation. Conclusions: The correlation between serum CA-125 levels and metastatic burden suggests that CA-125 is a clinically relevant biomarker for RMC. These findings support further exploration of CA-125 for disease monitoring and targeted therapeutics in RMC.
2025-01-07 | GSE284394 | GEO
Project description:Purpose: Renal medullary carcinoma (RMC) is a highly aggressive malignancy defined by the loss of the SMARCB1 tumor suppressor. It mainly affects young individuals of African descent with sickle cell trait, and it is resistant to conventional therapies used for other renal cell carcinomas. This study aimed to identify potential biomarkers for early detection and disease monitoring of RMC. Experimental Design: Integrated profiling of primary untreated RMC tumor tissues and paired adjacent kidney controls was performed using RNA-sequencing (RNA-seq) and histone Chromatin Immunoprecipitation Sequencing (ChIP-seq). The expression of serum cancer antigen 125 (CA-125), was prospectively evaluated in 47 patients with RMC. Functional studies were conducted in RMC cell lines to assess the effects of SMARCB1 re-expression and MUC16 knockdown. Results: MUC16, encoding for CA-125, was identified as one of the top upregulated genes in RMC tissues, with concomitant enrichment of active histone marks H3K4me3 and H3K27ac at its promoter. Elevated serum CA-125 levels were found in 31 of 47 (66%) RMC patients and correlated significantly with metastatic tumor burden (p = 0.03). SMARCB1 re-expression significantly reduced MUC16 expression in RMC cell lines. Functional studies in RMC cell lines demonstrated that SMARCB1 re-expression significantly reduced MUC16 expression, and that MUC16 knockdown induced apoptosis and reduced cell proliferation. Conclusions: The correlation between serum CA-125 levels and metastatic burden suggests that CA-125 is a clinically relevant biomarker for RMC. These findings support further exploration of CA-125 for disease monitoring and targeted therapeutics in RMC.
2025-01-07 | GSE284319 | GEO
Project description:Renal medullary carcinoma (RMC) is an aggressive tumour driven by bi-allelic loss of SMARCB1 and tightly associated with sickle cell trait. However, the cell-of-origin and oncogenic mechanism remain poorly understood. Using single-cell sequencing of human RMC, we defined transformation of thick ascending limb (TAL) cells into an epithelial-mesenchymal gradient of RMC cells associated with loss of renal epithelial transcription factors TFCP2L1, HOXB9 and MITF and gain of MYC and NFE2L2-associated oncogenic and ferroptosis resistance programs. We describe the molecular basis for this transcriptional switch that is reversed by SMARCB1 re-expression repressing the oncogenic and ferroptosis resistance programs leading to ferroptotic cell death. Ferroptosis resistance links TAL cell survival with the high extracellular medullar iron concentrations associated with sickle cell trait, an environment propitious to the mutagenic events associated with RMC development. This unique environment may explain why RMC is the only SMARCB1-deficient tumour arising from epithelial cells, differentiating RMC from rhabdoid tumours arising from neural crest cells.
2023-03-06 | GSE181000 | GEO