RESUMO
Myxoid leiomyosarcoma (MLS) is a rare but well-documented tumor that often portends a poor prognosis compared to the conventional leiomyosarcoma. This rare sarcoma has been reported in the uterus, external female genitalia, soft tissue, and other locations. However, a definite rectal MLS has not been reported. Recently five cases of MLS were reported to harbor PLAG1 fusions (TRPS1::PLAG1, RAD51B::PLAG1, and TRIM13::PLAG1). In this report, we present a case of rectal MLS with a novel MIR143HG::PLAG1 fusion detected by RNA next-generation sequencing.
Assuntos
Proteínas de Ligação a DNA , Leiomiossarcoma , Neoplasias Retais , Humanos , Leiomiossarcoma/genética , Leiomiossarcoma/patologia , Neoplasias Retais/genética , Neoplasias Retais/patologia , Proteínas de Ligação a DNA/genética , Feminino , MicroRNAs/genética , Pessoa de Meia-Idade , Proteínas de Fusão Oncogênica/genéticaRESUMO
TFE3-rearranged renal cell carcinoma (rRCC) is a rare subtype of renal cell carcinomas belonging to the MiT family translocation RCC. To further elucidate the co-alterations that occur along with TFE3 fusions in rRCC, we characterized the genomic, transcriptional, and immune landscapes in comparison to clear cell (ccRCC) and papillary renal cell carcinoma (pRCC). Next-generation sequencing of RNA (whole transcriptome) and DNA (592-gene panel or whole exome) for rRCC (N = 20), pRCC (N = 20), and ccRCC samples (N = 392) was performed. Patients with rRCC were significantly younger and more frequently female (median 44.5 years, 75.0% female) as compared with patients with pRCC (68.5 years, 25.0% female; P < .05) and ccRCC (62.0 years, 27.8% female; P < .05). A total of 8 unique fusion partners were observed, including a novel fusion with SRRM2::TFE3 in 2 patients. ccRCC exhibited significantly higher mutation rates of VHL (0% rRCC, 0% pRCC, 78.7% ccRCC; P < .05) and PBMR1 (0% rRCC, 5.0% pRCC, 49.4% ccRCC; P < .05). The genomic landscapes of rRCC were sparse with no mutations occurring with a prevalence higher than 10% other than pTERT (18.2% rRCC, 0% pRCC, 9.2% ccRCC). rRCC were associated with significantly less M1 macrophages (0.8%) as compared with pRCC (1.4%) and ccRCC (2.7%) (P < .05), suggesting a cold tumor-immune microenvironment. However, rRCC were more commonly PD-L1+ (rRCC 50%, pRCC 19.0%, ccRCC 12.2%; P < .05). Gene set enrichment analysis showed that rRCC are enriched in genes related to oxidative phosphorylation when compared with both ccRCC and pRCC. Despite having a colder tumor-immune microenvironment than pRCC and ccRCC, increased PDL1+ rates in rRCC suggest a potential benefit from immune checkpoint inhibitor therapy.
Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Humanos , Feminino , Masculino , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Neoplasias Renais/genética , Neoplasias Renais/patologia , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Microambiente TumoralRESUMO
PURPOSE: We evaluated oncologic risks in a large cohort of patients with radiographic cystic renal masses who underwent active surveillance or intervention. MATERIALS AND METHODS: A single-institutional database of 4,340 kidney lesions managed with either active surveillance or intervention between 2000-2020 was queried for radiographically cystic renal masses. Association of radiographic tumor characteristics and high-grade pathology was evaluated. RESULTS: We identified 387 radiographically confirmed cystic lesions in 367 patients. Of these, 247 were resected (n=240) or ablated (n=7; n=247, 203 immediate vs 44 delayed intervention). Pathologically, 23% (n=56) demonstrated high-grade pathology. Cystic features were explicitly described by pathology in only 18% (n=33) of all lesions and in 7% (n=4) of high-grade lesions. Of the intervention cohort, African American race, male gender, and Bosniak score were associated with high-grade pathology (P < .05). On active surveillance (n=184), Bosniak IV lesions demonstrated faster growth rates than IIF and III lesions (2.7 vs 0.6 and 0.5 mm/y, P ≤ .001); however, growth rates were not associated with high-grade pathology (P = .5). No difference in cancer-specific survival was identified when comparing intervention vs active surveillance at 5 years (99% vs 100%, P = .2). No difference in recurrence was observed between immediate intervention vs delayed intervention (P > .9). CONCLUSIONS: A disconnect between "cystic" designation on imaging and pathology exists for renal lesions. Over 80% of radiographic Bosniak cystic lesions are not described as "cystic" on pathology reports. More than 1 in 5 resected cystic renal lesions demonstrated high-grade disease. Despite this finding, judiciously managed active surveillance ± delayed intervention is a safe and effective management option for most radiographic cystic renal masses.
Assuntos
Carcinoma de Células Renais , Doenças Renais Císticas , Neoplasias Renais , Humanos , Masculino , Neoplasias Renais/diagnóstico por imagem , Neoplasias Renais/cirurgia , Neoplasias Renais/patologia , Doenças Renais Císticas/diagnóstico por imagem , Doenças Renais Císticas/cirurgia , Tomografia Computadorizada por Raios X/métodos , Rim/patologia , Carcinoma de Células Renais/patologia , Estudos RetrospectivosRESUMO
OBJECTIVE: Targeted therapy is an important part of the treatment of lung adenocarcinoma. Tests for EGFR mutation, ALK, ROS1, RET and NTRK gene fusions are needed to make a treatment decision. These gene fusions are traditionally detected by fluorescence in situ hybridisation (FISH) or immunohistochemistry. In this study, we investigated whether gene fusions in pulmonary adenocarcinoma could be accurately detected by RNA next-generation sequencing (RNA-NGS) and whether cytology cell blocks could be used effectively for this test. METHODS: Archived cytological specimens of lung adenocarcinoma submitted for RNA sequencing between 2019 and 2022 at Fox Chase Cancer Center were retrospectively retrieved. Hybrid capture-based targeted RNA next generation sequencing was used, which covers 507 fusion genes, including ALK, ROS1, RET and NTRKs, irrespective of their partner genes. DNA NGS, FISH and chromosomal microarray analysis were used to confirm the results of the RNA-NGS. RESULTS: A total of 129 lung adenocarcinoma cytology specimens were submitted for molecular testing. Eight of 129 (6.2%) cases were excluded from RNA sequencing as their cell blocks contained inadequate numbers of tumour cells. One case (0.8%) failed to yield adequate RNA. The overall success rate was 93% (120/129). Ten of 120 (8.3%) cytology cases were positive for gene fusions, including 7 ALK, 2 ROS1 fusion genes, and 1 RET fusion gene. Twenty-two cell block cases were also tested for ALK fusion genes using FISH. However, 11 of 22 (50%) failed the testing due to inadequate material. CONCLUSIONS: Cytology cell blocks can be used as the main source of material for molecular testing for lung cancer. Detection of gene fusions by RNA-based NGS on cell blocks is convenient and reliable in daily practice.
Assuntos
Adenocarcinoma de Pulmão , Adenocarcinoma , Neoplasias Pulmonares , Humanos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Quinase do Linfoma Anaplásico/genética , Proteínas Tirosina Quinases/genética , Receptores Proteína Tirosina Quinases/genética , RNA , Estudos Retrospectivos , Adenocarcinoma/diagnóstico , Adenocarcinoma/genética , Adenocarcinoma/patologia , Proteínas Proto-Oncogênicas/genética , Adenocarcinoma de Pulmão/diagnóstico , Adenocarcinoma de Pulmão/genética , Fusão Gênica , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Proteínas de Fusão Oncogênica/genéticaRESUMO
Extraskeletal myxoid chondrosarcoma (EMC) is a rare sarcoma of uncertain differentiation, characterized by recurrent chromosomal translocation involving NR4A3 (9q22.33) in more than 90% of cases. Five fusion partners for NR4A3 have been described including: EWSR1 (22q12.2), TAF15 (17q12), FUS (16p11.2), TCF12 (15q21), and TFG (3q12.2). This report describes a patient with an EMC at the dorsum of the right foot. The tumor showed a cord-like and reticular pattern in a background of myxoid matrix. The tumor cells demonstrated an epithelioid morphology with prominent nucleoli. The tumor cells were positive for synaptophysin, GFAP, with focal positivity for CD117, S100, Cam5.2, and NSE, and negative for AE1/3, desmin, and SMA. An RNA next-generation sequencing test showed a SMARCA2-NR4A3 gene fusion which has not been previously reported. The exon 3 of SMARCA2 was fused to exon 3 of NR4A3. This fusion was confirmed by NR4A3 break-apart FISH, although both SMARCA2 (9p24.3) and NR4A3 (9q22.33) are located on chromosome 9. The tumor cells showed retained expression of INI1 and SMARCA2 by immunohistochemistry.
Assuntos
Condrossarcoma/patologia , Proteínas de Ligação a DNA/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Neoplasias de Tecido Conjuntivo e de Tecidos Moles/patologia , Proteínas de Fusão Oncogênica/genética , Receptores de Esteroides/genética , Receptores dos Hormônios Tireóideos/genética , Fatores de Transcrição/genética , Condrossarcoma/genética , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias de Tecido Conjuntivo e de Tecidos Moles/genética , PrognósticoRESUMO
PURPOSE: Concern for discordance between clinical staging and final pathology drives current management of patients deemed appropriate candidates for radical cystectomy. Therefore, we set out to prospectively investigate reliability and shortcomings of cystoscopic evaluation in radical cystectomy candidates. MATERIALS AND METHODS: Patients undergoing radical cystectomy for urothelial carcinoma were enrolled in a prospective single-arm study to evaluate reliability of Systematic Endoscopic Evaluation in predicting pT0 urothelial carcinoma (NCT02968732). Systematic Endoscopic Evaluation consisted of cystoscopy and tissue sampling at the time of radical cystectomy. Systematic Endoscopic Evaluation results were compared to radical cystectomy pathology. The primary end point was the negative predictive value of Systematic Endoscopic Evaluation findings in predicting radical cystectomy pathology. RESULTS: A total of 61 patients underwent Systematic Endoscopic Evaluation and radical cystectomy. Indications included muscle invasive bladder cancer in 42 (68.9%) and high risk nonmuscle invasive bladder cancer in 19 (31.1%). In all, 38 (62.3%, 90.5% of patients with muscle invasive bladder cancer) received neoadjuvant chemotherapy. On Systematic Endoscopic Evaluation, 31 (50.8%) patients demonstrated no visual nor biopsy-based evidence of disease (seeT0), yet 16/31 (51.6%) harbored residual disease (>pT0), including 8 (8/31, 25.8%) with residual ≥pT2 disease upon radical cystectomy. The negative predictive value of Systematic Endoscopic Evaluation predicting a pT0 bladder was 48.4% (CI 30.2-66.9), which was below our prespecified hypothesis. Therefore, the trial was stopped for futility. CONCLUSIONS: Approximately 1 of 4 patients with seeT0 at the time of radical cystectomy harbored residual muscle invasive bladder cancer. These prospective data definitively confirm major limitations of endoscopic assessment for pT0 bladder cancer. Future work should focus on novel imaging and biomarker strategies to optimize evaluations before radical cystectomy for improved decision making regarding bladder preservation.
Assuntos
Cistoscopia , Neoplasias da Bexiga Urinária/patologia , Idoso , Cistectomia , Feminino , Humanos , Masculino , Estadiamento de Neoplasias , Valor Preditivo dos Testes , Estudos Prospectivos , Reprodutibilidade dos Testes , Manejo de Espécimes , Neoplasias da Bexiga Urinária/cirurgiaRESUMO
PURPOSE OF REVIEW: Artificial intelligence holds tremendous potential for disrupting clinical medicine. Here we review the current role of artificial intelligence in the kidney cancer space. RECENT FINDINGS: Machine learning and deep learning algorithms have been developed using information extracted from radiomic, histopathologic, and genomic datasets of patients with renal masses. SUMMARY: Although artificial intelligence applications in medicine are still in their infancy, they already hold immediate promise to improve accuracy of renal mass characterization, grade, and prognostication. As algorithms become more robust and generalizable, artificial intelligence is poised to significantly disrupt kidney cancer care.
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Inteligência Artificial , Neoplasias Renais , Algoritmos , Humanos , Rim , Neoplasias Renais/terapia , Aprendizado de MáquinaRESUMO
Primary tracheobronchial adenoid cystic carcinoma is rare, accounting for less than 1% of all lung tumors. Many adenoid cystic carcinomas have been reported to have a specific chromosome translocation t(6;9)/MYB-NFIB. More recently, t(8;9)/MYBL1-NFIB gene fusion was reported in salivary gland adenoid cystic carcinomas which lacked a t(6;9)/MYB-NFIB. Two prior studies showed t(6;9)/MYB-NFIB in tracheobronchial adenoid cystic carcinoma; however, only rare cases of MYBL1 rearrangement have been reported in this carcinoma. In this study, we used targeted RNA sequencing to investigate fusion genes in tracheobronchial adenoid cystic carcinoma at our institution. Fusions of either MYB or MYBL1 genes were detected in 7 of 7 carcinomas. Three cases had MYB-NFIB, and 3 had MYBL1-NFIB. The remaining case showed a rare MYBL1-RAD51B fusion. These findings suggest that rearrangement involving MYB or MYBL1 is a hallmark of tracheobronchial adenoid cystic carcinoma.
Assuntos
Neoplasias Brônquicas/genética , Carcinoma Adenoide Cístico/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Proteínas Proto-Oncogênicas c-myb/genética , Proteínas Proto-Oncogênicas/genética , Neoplasias da Traqueia/genética , Transativadores/genética , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Fusão Oncogênica/análise , Proteínas de Fusão Oncogênica/genéticaRESUMO
Microphthalmia-associated transcription factor (MiT) family translocation renal cell carcinoma harbors variable gene fusions involving either TFE3 or TFEB genes. Multiple 5' fusion partners for TFE3 have been reported, including ASPSCR1, CLTC, DVL2, LUC7L3, KHSRP, PRCC, PARP14, NONO, SFPQ1, MED15, and RBM10. Each of these fusion genes activates TFE3 transcription which can be detected by immunostaining. Using targeted RNA-sequencing, TFE3 fusion gene partners were identified in 5 cases of TFE3 immunohistochemistry positive translocation renal cell carcinoma. Three cases demonstrated known fusions: ASPSCR1-TFE3, MED15-TFE3 and RBM10-TFE3. However, two cases showed unreported NEAT1-TFE3 and KAT6A-TFE3 fusion transcripts. The NEAT1-TFE3 RCC arose in a 59-year-old male; which demonstrated overlapping morphological features seen in NEAT2(MALAT1)-TFEB t(6;11) renal cell carcinoma, including biphasic alveolar/nested tumor cells with eosinophilic cytoplasm. The KAT6A-TFE3 renal cell carcinoma demonstrated typical morphological features of TFE3/Xp11 renal cell carcinoma including papillae, eosinophilic cytoplasm with focal clearing and abundant psammoma bodies. KAT6A gene fusion was reported in some cases of acute myeloid leukemia, which has not been previously reported in solid tumors. This report highlights the genetic complexity of TFE3 translocation renal cell carcinoma; and RNA-sequencing is a powerful approach for elucidating the underlying genetic alterations.
Assuntos
Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Biomarcadores Tumorais/genética , Carcinoma de Células Renais/genética , Fusão Gênica , Histona Acetiltransferases/genética , Neoplasias Renais/genética , RNA Longo não Codificante/genética , Idoso , Carcinoma de Células Renais/patologia , Feminino , Predisposição Genética para Doença , Humanos , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Adulto JovemRESUMO
OBJECTIVE: MicroRNAs (miRs) are short noncoding RNA molecules that posttranscriptionally modulate protein expression. There are distinct miR alterations characterizing urothelial cell carcinoma (UCC) of the urinary bladder. STUDY DESIGN: In this study, we investigate the possibility of using miR as a noninvasive marker in the screening of UCC. The total RNA was extracted from 75 cytology specimens including bladder or renal washings and voided urines. Cases comprise UCC (21 high grade and 6 low grade), 25 normal controls and 23 cases with a history of UCC but negative at the time of testing (negative with a positive history). The expressions of miR-96, miR-182, miR-183, miR-200c, miR-21, miR-141 and miR-30b were determined using quantitative TaqMan real-time PCR. RESULTS AND CONCLUSION: This study shows that the level of miR-182 is higher in cytology specimens from high-grade UCC patients as compared to normal controls. Measuring miR-182 may provide a potential alternative or adjunct approach for screening high-grade UCC.
Assuntos
Biomarcadores Tumorais/genética , MicroRNAs/genética , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia , Urotélio/metabolismo , Urotélio/patologia , Biomarcadores Tumorais/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , MicroRNAs/metabolismo , Gradação de Tumores , Curva ROCRESUMO
BRCA1 exerts transcriptional repression through interaction with CtIP in the C-terminal BRCT domain and ZBRK1 in the central domain. A dozen genes, including angiopoietin-1 (ANG1), a secreted angiogenic factor, are corepressed by BRCA1 and CtIP based on microarray analysis of mammary epithelial cells in 3D culture. BRCA1, CtIP, and ZBRK1 form a complex that coordinately represses ANG1 expression via a ZBRK1 recognition site in the ANG1 promoter. Impairment of this complex upregulates ANG1, which stabilizes endothelial cells that form a capillary-like network structure. Consistently, Brca1-deficient mouse mammary tumors exhibit accelerated growth, pronounced vascularization, and overexpressed ANG1. These results suggest that, besides its role in maintaining genomic stability, BRCA1 directly regulates the expression of angiogenic factors to modulate the tumor microenvironment.
Assuntos
Angiopoietina-1/genética , Proteína BRCA1/metabolismo , Proteínas de Transporte/metabolismo , Proteínas de Ligação a DNA/metabolismo , Neoplasias Mamárias Experimentais/patologia , Proteínas Nucleares/metabolismo , Regiões Promotoras Genéticas/genética , Proteínas Repressoras/metabolismo , Animais , Proteína BRCA1/genética , Linhagem Celular , Sobrevivência Celular/genética , Sobrevivência Celular/fisiologia , Endodesoxirribonucleases , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Feminino , Regulação da Expressão Gênica/genética , Humanos , Neoplasias Mamárias Experimentais/genética , Neoplasias Mamárias Experimentais/metabolismo , Camundongos , Camundongos Knockout , Modelos Biológicos , Mutação/genética , Neovascularização Patológica/patologia , Ligação Proteica , Interferência de RNA , Elementos de Resposta/genéticaRESUMO
Small-cell carcinomas (SCCs) of the genitourinary (GU) tract are rare malignancies with high metastatic potential. The most common primary sites are the bladder and prostate, but case reports of primary SCC of the kidney, ureter, and urethra also exist. The majority of patients present with gross hematuria, irritative or obstructive urinary symptoms, and symptoms of locoregionally advanced or metastatic disease at initial presentation. SCC of the bladder presents with nodal or metastatic involvement in the majority of cases and requires the use of platinum-based chemotherapy in combination with surgery and/or radiation. SCC of the prostate is most commonly seen in the metastatic castrate-resistant setting, and aggressive variant disease presents with a greater propensity for visceral metastases, osteolytic lesions, and relatively low serum prostate-specific antigen for volume of disease burden. Multiple retrospective and prospective randomized studies support the use of a multimodal approach combining platinum-based systemic therapy regimens with radiation and/or surgery for localized disease. This evidence-based strategy is reflected in multiple consensus guidelines. Emerging data suggest that small-cell bladder and prostate cancers transdifferentiate from a common progenitor of conventional urothelial bladder carcinoma and prostatic acinar adenocarcinoma, respectively. Areas of active basic research include efforts to identify the key genetic and epigenetic drivers involved in the emergence of small cell cancers to exploit them for novel therapies. Here, we review these efforts, discuss diagnosis and currently supported management strategies, and summarize ongoing clinical trials evaluating novel therapies to treat this rare, aggressive GU cancer.
Assuntos
Carcinoma , Neoplasias Pulmonares , Neoplasias da Próstata , Carcinoma de Pequenas Células do Pulmão , Neoplasias da Bexiga Urinária , Masculino , Humanos , Estudos Retrospectivos , Estudos Prospectivos , Neoplasias da Bexiga Urinária/terapia , Neoplasias da Próstata/terapiaRESUMO
Metachronous oligometastatic clear cell renal cell carcinoma may take many years before becoming clinically apparent. Herein we report regional lymph node recurrence of clear cell renal cell carcinoma more than two decades following radical nephrectomy. Chromosomal microarray analysis demonstrated multiple chromosomal alterations, including 3pq deletion shared by the original and recurrent tumors, and 17p deletion containing the TP53 gene present only in the latter. Sequencing of 1550 genes revealed mutations of VHL in both the primary and metastasis and BAP1 only in the metastatic lesion. These findings genetically link the original and recurrent tumors and suggest that VHL, TP53, and BAP1 alterations played an evolutionary role in recurrence decades after initial resection.
Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Humanos , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/cirurgia , Genômica , Nefrectomia , Neoplasias Renais/genética , Neoplasias Renais/cirurgia , Evolução MolecularRESUMO
Hypothyroidism is commonly detected in patients with medulloblastoma (MB). A possible link between thyroid hormone (TH) signaling and MB pathogenicity has not been reported. Here, we find that TH plays a critical role in promoting tumor cell differentiation. Reduction in TH levels frees the TH receptor, TRα1, to bind to EZH2 and repress expression of NeuroD1, a transcription factor that drives tumor cell differentiation. Increased TH reverses EZH2-mediated repression of NeuroD1 by abrogating the binding of EZH2 and TRα1, thereby stimulating tumor cell differentiation and reducing MB growth. Importantly, TH-induced differentiation of tumor cells is not restricted by the molecular subgroup of MB. These findings establish an unprecedented association between TH signaling and MB pathogenicity, providing solid evidence for TH as a promising modality for MB treatment.
RESUMO
Molecular profiling of clear cell renal cell carcinoma (ccRCC) tumors of patients in a clinical trial has identified distinct transcriptomic signatures with predictive value, yet data in non-clear cell variants (nccRCC) are lacking. We examined the transcriptional profiles of RCC tumors representing key molecular pathways, from a multi-institutional, real-world patient cohort, including ccRCC and centrally reviewed nccRCC samples. ccRCC had increased angiogenesis signature scores compared with the heterogeneous group of nccRCC tumors, while cell cycle, fatty acid oxidation/AMPK signaling, and fatty acid synthesis/pentose phosphate signature scores were increased in one or more nccRCC subtypes. Among both ccRCC and nccRCC tumors, T effector scores statistically correlated with increased immune cell infiltration and were more commonly associated with immunotherapy-related markers (PD-L1+/TMBhi/MSIhi). In conclusion, this study provides evidence of differential gene transcriptional profiles among ccRCC versus nccRCC tumors, providing insights for optimizing personalized and histology-specific therapeutic strategies for patients with advanced RCC.
Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Transcriptoma , Humanos , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/metabolismo , Neoplasias Renais/genética , Neoplasias Renais/patologia , Neoplasias Renais/metabolismo , Feminino , Masculino , Regulação Neoplásica da Expressão Gênica , Pessoa de Meia-Idade , Idoso , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Perfilação da Expressão GênicaRESUMO
Hypothyroidism is commonly detected in patients with medulloblastoma (MB). However, whether thyroid hormone (TH) contributes to MB pathogenicity remains undetermined. Here, we find that TH plays a critical role in promoting tumor cell differentiation. Reduction in TH levels frees the TH receptor, TRα1, to bind to EZH2 and repress expression of NeuroD1, a transcription factor that drives tumor cell differentiation. Increased TH reverses EZH2-mediated repression of NeuroD1 by abrogating the binding of EZH2 and TRα1, thereby stimulating tumor cell differentiation and reducing MB growth. Importantly, TH-induced differentiation of tumor cells is not restricted by the molecular subgroup of MB, suggesting that TH can be used to broadly treat MB subgroups. These findings establish an unprecedented association between TH signaling and MB pathogenicity, providing solid evidence for TH as a promising modality for MB treatment.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos , Diferenciação Celular , Proteína Potenciadora do Homólogo 2 de Zeste , Meduloblastoma , Hormônios Tireóideos , Meduloblastoma/patologia , Meduloblastoma/metabolismo , Meduloblastoma/genética , Humanos , Diferenciação Celular/efeitos dos fármacos , Animais , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Camundongos , Hormônios Tireóideos/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Neoplasias Cerebelares/patologia , Neoplasias Cerebelares/metabolismo , Neoplasias Cerebelares/genética , Neoplasias Cerebelares/tratamento farmacológico , Linhagem Celular Tumoral , Progressão da Doença , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Receptores alfa dos Hormônios Tireóideos/metabolismo , Receptores alfa dos Hormônios Tireóideos/genética , Transdução de Sinais/efeitos dos fármacosRESUMO
PURPOSE: Given the emergence of PSMA-targeted diagnostic agents and therapeutics, we sought to investigate patterns of FOLH1 expression in RCC and their impacts on RCC outcomes. METHODS: We conducted a pooled multi-institutional analysis of patients with RCC having undergone DNA and RNA next-generation sequencing. FOLH1-high/low expression was defined as the ≥75th/<25th percentile of RNA transcripts per million (TPM). Angiogenic, T-effector, and myeloid expression signatures were calculated using previously defined gene sets. Kaplan-Meier estimates were calculated from the time of tissue collection or therapy start. RESULTS: We included 1,724 patients in the analysis. FOLH1 expression was significantly higher in clear cell (71%) compared to non-clear cell RCC tumors (19.0 versus 3.3 TPM, p < 0.001) and varied by specimen site (45% primary kidney/55% metastasis, 13.6 versus 9.9 TPM, p < 0.001). FOLH1 expression was correlated with angiogenic gene expression (Spearman = 0.76, p < 0.001) and endothelial cell abundance (Spearman = 0.76, p < 0.001). While OS was similar in patients with FOLH1-high versus -low ccRCC, patients with FOLH1-high clear cell tumors experienced a longer time on cabozantinib treatment (9.7 versus 4.6 months, respectively, HR 0.57, 95% CI 0.35-0.93, p < 0.05). CONCLUSIONS: We observed differential patterns of FOLH1 expression based on histology and tumor site in RCC. FOLH1 was correlated with angiogenic gene expression, increased OS, and a longer duration of cabozantinib treatment.
RESUMO
BACKGROUNDMetastases are the hallmark of lethal cancer, though underlying mechanisms that drive metastatic spread to specific organs remain poorly understood. Renal cell carcinoma (RCC) is known to have distinct sites of metastases, with lung, bone, liver, and lymph nodes being more common than brain, gastrointestinal tract, and endocrine glands. Previous studies have shown varying clinical behavior and prognosis associated with the site of metastatic spread; however, little is known about the molecular underpinnings that contribute to the differential outcomes observed by the site of metastasis.METHODSWe analyzed primary renal tumors and tumors derived from metastatic sites to comprehensively characterize genomic and transcriptomic features of tumor cells as well as to evaluate the tumor microenvironment at both sites.RESULTSWe included a total of 657 tumor samples (340 from the primary site [kidney] and 317 from various sites of metastasis). We show distinct genomic alterations, transcriptomic signatures, and immune and stromal tumor microenvironments across metastatic sites in a large cohort of patients with RCC.CONCLUSIONWe demonstrate significant heterogeneity among primary tumors and metastatic sites and elucidate the complex interplay between tumor cells and the extrinsic tumor microenvironment that is vital for developing effective anticancer therapies.