RESUMEN
Clinical trials have identified ARID1A mutations as enriched among patients who respond favorably to immune checkpoint blockade (ICB) in several solid tumor types independent of microsatellite instability. We show that ARID1A loss in murine models is sufficient to induce anti-tumor immune phenotypes observed in ARID1A mutant human cancers, including increased CD8+ T cell infiltration and cytolytic activity. ARID1A-deficient cancers upregulated an interferon (IFN) gene expression signature, the ARID1A-IFN signature, associated with increased R-loops and cytosolic single-stranded DNA (ssDNA). Overexpression of the R-loop resolving enzyme, RNASEH2B, or cytosolic DNase, TREX1, in ARID1A-deficient cells prevented cytosolic ssDNA accumulation and ARID1A-IFN gene upregulation. Further, the ARID1A-IFN signature and anti-tumor immunity were driven by STING-dependent type I IFN signaling, which was required for improved responsiveness of ARID1A mutant tumors to ICB treatment. These findings define a molecular mechanism underlying anti-tumor immunity in ARID1A mutant cancers.
Asunto(s)
Linfocitos T CD8-positivos , Proteínas de Unión al ADN , Interferón Tipo I , Proteínas de la Membrana , Neoplasias , Transducción de Señal , Factores de Transcripción , Animales , Humanos , Ratones , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Línea Celular Tumoral , Proteínas de Unión al ADN/metabolismo , Exodesoxirribonucleasas/metabolismo , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Interferón Tipo I/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Ratones Endogámicos C57BL , Mutación , Neoplasias/inmunología , Neoplasias/genética , Proteínas Nucleares/metabolismo , Fosfoproteínas/metabolismo , Factores de Transcripción/metabolismo , Masculino , Quimiocinas/genética , Quimiocinas/metabolismoRESUMEN
Intrinsically disordered regions (IDRs) represent a large percentage of overall nuclear protein content. The prevailing dogma is that IDRs engage in non-specific interactions because they are poorly constrained by evolutionary selection. Here, we demonstrate that condensate formation and heterotypic interactions are distinct and separable features of an IDR within the ARID1A/B subunits of the mSWI/SNF chromatin remodeler, cBAF, and establish distinct "sequence grammars" underlying each contribution. Condensation is driven by uniformly distributed tyrosine residues, and partner interactions are mediated by non-random blocks rich in alanine, glycine, and glutamine residues. These features concentrate a specific cBAF protein-protein interaction network and are essential for chromatin localization and activity. Importantly, human disease-associated perturbations in ARID1B IDR sequence grammars disrupt cBAF function in cells. Together, these data identify IDR contributions to chromatin remodeling and explain how phase separation provides a mechanism through which both genomic localization and functional partner recruitment are achieved.
Asunto(s)
Ensamble y Desensamble de Cromatina , Complejos Multiproteicos , Proteínas Nucleares , Humanos , Cromatina , Proteínas de Unión al ADN/química , Proteínas Intrínsecamente Desordenadas/genética , Proteínas Nucleares/metabolismo , Factores de Transcripción/metabolismo , Complejos Multiproteicos/química , Complejos Multiproteicos/metabolismoRESUMEN
Macrophages elicit immune responses to pathogens through induction of inflammatory genes. Here, we examined the role of three variants of the SWI/SNF nucleosome remodeling complex-cBAF, ncBAF, and PBAF-in the macrophage response to bacterial endotoxin (lipid A). All three SWI/SNF variants were prebound in macrophages and retargeted to genomic sites undergoing changes in chromatin accessibility following stimulation. Cooperative binding of all three variants associated with de novo chromatin opening and latent enhancer activation. Isolated binding of ncBAF and PBAF, in contrast, associated with activation and repression of active enhancers, respectively. Chemical and genetic perturbations of variant-specific subunits revealed pathway-specific regulation in the activation of lipid A response genes, corresponding to requirement for cBAF and ncBAF in inflammatory and interferon-stimulated gene (ISG) activation, respectively, consistent with differential engagement of SWI/SNF variants by signal-responsive transcription factors. Thus, functional diversity among SWI/SNF variants enables increased regulatory control of innate immune transcriptional programs, with potential for specific therapeutic targeting.
Asunto(s)
Ensamble y Desensamble de Cromatina , Proteínas Cromosómicas no Histona , Elementos de Facilitación Genéticos , Inflamación , Macrófagos , Factores de Transcripción , Macrófagos/inmunología , Macrófagos/metabolismo , Animales , Ratones , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Proteínas Cromosómicas no Histona/metabolismo , Proteínas Cromosómicas no Histona/genética , Inflamación/inmunología , Inflamación/genética , Elementos de Facilitación Genéticos/genética , Cromatina/metabolismo , Regulación de la Expresión Génica , Ratones Endogámicos C57BL , Inmunidad Innata , HumanosRESUMEN
CD8+ T cells provide host protection against pathogens by differentiating into distinct effector and memory cell subsets, but how chromatin is site-specifically remodeled during their differentiation is unclear. Due to its critical role in regulating chromatin and enhancer accessibility through its nucleosome remodeling activities, we investigated the role of the canonical BAF (cBAF) chromatin remodeling complex in antiviral CD8+ T cells during infection. ARID1A, a subunit of cBAF, was recruited early after activation and established de novo open chromatin regions (OCRs) at enhancers. Arid1a deficiency impaired the opening of thousands of activation-induced enhancers, leading to loss of TF binding, dysregulated proliferation and gene expression, and failure to undergo terminal effector differentiation. Although Arid1a was dispensable for circulating memory cell formation, tissue-resident memory (Trm) formation was strongly impaired. Thus, cBAF governs the enhancer landscape of activated CD8+ T cells that orchestrates TF recruitment and activity and the acquisition of specific effector and memory differentiation states.
Asunto(s)
Linfocitos T CD8-positivos , Secuencias Reguladoras de Ácidos Nucleicos , Cromatina , Nucleosomas , AntiviralesRESUMEN
In a recent article, Maxwell et al. report that loss of tumor cell-specific AT-rich interaction domain 1A (ARID1A), a component of the chromatin remodeling SWI/SNF complex, triggers antitumor immunity via R-loop-mediated upregulation of the type-I interferon (IFN) pathway. These recent findings uncover a molecular mechanism underlying improved responses to immune checkpoint therapy (ICT) seen in patients harboring an ARID1A loss-of-function mutation.
Asunto(s)
Proteínas de Unión al ADN , Proteínas de la Membrana , Neoplasias , Factores de Transcripción , Humanos , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/genética , Neoplasias/inmunología , Neoplasias/genética , Animales , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Mutación , Transducción de Señal , Interferón Tipo I/metabolismo , Interferón Tipo I/inmunología , Ensamble y Desensamble de CromatinaRESUMEN
BACKGROUND: ARID1A, a subunit of the SWI/SNF chromatin remodeling complex, is thought to play a significant role both in tumor suppression and tumor initiation, which is highly dependent upon context. Previous studies have suggested that ARID1A deficiency may contribute to cancer development. The specific mechanisms of whether ARID1A loss affects tumorigenesis by RNA editing remain unclear. RESULTS: Our findings indicate that the deficiency of ARID1A leads to an increase in RNA editing levels and alterations in RNA editing categories mediated by adenosine deaminases acting on RNA 1 (ADAR1). ADAR1 edits the CDK13 gene at two previously unidentified sites, namely Q113R and K117R. Given the crucial role of CDK13 as a cyclin-dependent kinase, we further observed that ADAR1 deficiency results in changes in the cell cycle. Importantly, the sensitivity of ARID1A-deficient tumor cells to SR-4835, a CDK12/CDK13 inhibitor, suggests a promising therapeutic approach for individuals with ARID1A-mutant tumors. Knockdown of ADAR1 restored the sensitivity of ARID1A deficient cells to SR-4835 treatment. CONCLUSIONS: ARID1A deficiency promotes RNA editing of CDK13 by regulating ADAR1.
Asunto(s)
Adenosina Desaminasa , Quinasas Ciclina-Dependientes , Proteínas de Unión al ADN , Edición de ARN , Proteínas de Unión al ARN , Factores de Transcripción , Adenosina Desaminasa/metabolismo , Adenosina Desaminasa/genética , Proteínas de Unión al ARN/metabolismo , Proteínas de Unión al ARN/genética , Humanos , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/genética , Quinasas Ciclina-Dependientes/metabolismo , Quinasas Ciclina-Dependientes/genética , Línea Celular Tumoral , Proteína Quinasa CDC2RESUMEN
Loss of AT-interacting domain-rich protein 1A (ARID1A) frequently occurs in human malignancies including lung cancer. The biological consequence of ARID1A mutation in lung cancer is not fully understood. This study was designed to determine the effect of ARID1A-depleted lung cancer cells on fibroblast activation. Conditioned media was collected from ARID1A-depleted lung cancer cells and employed to treat lung fibroblasts. The proliferation and migration of lung fibroblasts were investigated. The secretory genes were profiled in lung cancer cells upon ARID1A knockdown. Antibody-based neutralization was utilized to confirm their role in mediating the cross-talk between lung cancer cells and fibroblasts. NOD-SCID-IL2RgammaC-null (NSG) mice received tumor tissues from patients with ARID1A-mutated lung cancer to establish patient-derived xenograft (PDX) models. Notably, ARID1A-depleted lung cancer cells promoted the proliferation and migration of lung fibroblasts. Mechanistically, ARID1A depletion augmented the expression and secretion of prolyl 4-hydroxylase beta (P4HB) in lung cancer cells, which induced the activation of lung fibroblasts through the ß-catenin signaling pathway. P4HB-activated lung fibroblasts promoted the proliferation, invasion, and chemoresistance in lung cancer cells. Neutralizing P4HB hampered the tumor growth and increased cisplatin cytotoxic efficacy in two PDX models. Serum P4HB levels were higher in ARID1A-mutated lung cancer patients than in healthy controls. Moreover, increased serum levels of P4HB were significantly associated with lung cancer metastasis. Together, our work indicates a pivotal role for P4HB in orchestrating the cross-talk between ARID1A-mutated cancer cells and cancer-associated fibroblasts during lung cancer progression. P4HB may represent a promising target for improving lung cancer treatment.
Asunto(s)
Neoplasias Pulmonares , Prolil Hidroxilasas , Proteína Disulfuro Isomerasas , Humanos , Animales , Ratones , Prolil Hidroxilasas/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Resistencia a Antineoplásicos/genética , Línea Celular Tumoral , Proliferación Celular , Ratones Endogámicos NOD , Ratones SCID , Transformación Celular Neoplásica , Pulmón/patología , Fibroblastos/metabolismo , Proteínas de Unión al ADN/genética , Factores de Transcripción/genética , Procolágeno-Prolina Dioxigenasa/metabolismo , Procolágeno-Prolina Dioxigenasa/farmacologíaRESUMEN
Chromatin remodelers are commonly altered in human cancer. The mutation of AT-rich interactive domain 1A (ARID1A) in gastric cancer (GC), a component of the SWI/SNF chromatin remodeling complex, was proven associated with treatment response in our previous study. However, ARID1A loss of function was caused not only by mutations but also copy number deletions. The clinicopathologic, genomic, and immunophenotypic correlates of ARID1A loss is largely uncharacterized in GC. Here, 819 patients with clinicopathological information and sequencing data or formalin-fixed paraffin-embedded tissues from four cohorts, Zhongshan Hospital (ZSHS) cohort (n = 375), The Cancer Genome Atlas (TCGA) cohort (n = 371), Samsung Medical Center (SMC) cohort (n = 53), and ZSHS immunotherapy cohort (n = 20), were enrolled. ARID1A loss was defined by genome sequencing or deficient ARID1A expression by immunohistochemistry. We found that ARID1A mutation and copy number deletion were enriched in GC with microsatellite instability (MSI) and chromosomal-instability (CIN), respectively. In the TCGA and ZSHS cohorts, only CIN GC with ARID1A loss could benefit from fluorouracil-based adjuvant chemotherapy. In the SMC and ZSHS immunotherapy cohorts, ARID1A loss exhibited a tendency of superior responsiveness and indicated favorable overall survival after anti-PD-1 immunotherapy. ARID1A-loss tumors demonstrated elevated mutation burden, neoantigen load, and interferon gamma pathway activation. Moreover, in CIN GC, ARID1A loss was correlated with higher homologous recombination deficiency. ARID1A loss defines a distinct subtype of GC characterized by high levels of genome instability, neoantigen formation, and immune activation. These tumors show sensitivity to both chemotherapy and anti-PD-1 immunotherapy. This study provides valuable insights for precision treatment strategies in GC.
Asunto(s)
Proteínas de Unión al ADN , Neoplasias Gástricas , Humanos , Proteínas de Unión al ADN/genética , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/genética , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , MutaciónRESUMEN
Stem cells self-renew or give rise to transit-amplifying cells (TACs) that differentiate into specific functional cell types. The fate determination of stem cells to TACs and their transition to fully differentiated progeny is precisely regulated to maintain tissue homeostasis. Arid1a, a core component of the switch/sucrose nonfermentable complex, performs epigenetic regulation of stage- and tissue-specific genes that is indispensable for stem cell homeostasis and differentiation. However, the functional mechanism of Arid1a in the fate commitment of mesenchymal stem cells (MSCs) and their progeny is not clear. Using the continuously growing adult mouse incisor model, we show that Arid1a maintains tissue homeostasis through limiting proliferation, promoting cell cycle exit and differentiation of TACs by inhibiting the Aurka-Cdk1 axis. Loss of Arid1a overactivates the Aurka-Cdk1 axis, leading to expansion of the mitotic TAC population but compromising their differentiation ability. Furthermore, the defective homeostasis after loss of Arid1a ultimately leads to reduction of the MSC population. These findings reveal the functional significance of Arid1a in regulating the fate of TACs and their interaction with MSCs to maintain tissue homeostasis.
Asunto(s)
Aurora Quinasa A/metabolismo , Proteína Quinasa CDC2/metabolismo , Proteínas de Unión al ADN/metabolismo , Incisivo/embriología , Células Madre Mesenquimatosas/metabolismo , Mitosis , Transducción de Señal , Factores de Transcripción/metabolismo , Animales , Aurora Quinasa A/genética , Proteína Quinasa CDC2/genética , Proteínas de Unión al ADN/genética , Ratones , Ratones Transgénicos , Factores de Transcripción/genéticaRESUMEN
BACKGROUND: The poor chemo-response and high DNA methylation of ovarian clear cell carcinoma (OCCC) have attracted extensive attentions. Recently, we revealed the mutational landscape of the human kinome and additional cancer-related genes and found deleterious mutations in ARID1A, a component of the SWI/SNF chromatin-remodeling complex, in 46% of OCCC patients. The present study aims to comprehensively investigate whether ARID1A loss and genome-wide DNA methylation are co-regulated in OCCC and identify putative therapeutic targets epigenetically regulated by ARID1A. METHODS: DNA methylation of ARID1Amt/ko and ARID1Awt OCCC tumors and cell lines were analyzed by Infinium MethylationEPIC BeadChip. The clustering of OCCC tumors in relation to clinical and mutational status of tumors were analyzed by hierarchical clustering analysis of genome-wide methylation. GEO expression profiles were used to identify differentially methylated (DM) genes and their expression level in ARID1Amt/ko vs ARID1Awt OCCCs. Combining three pre-ranked GSEAs, pathways and leading-edge genes epigenetically regulated by ARID1A were revealed. The leading-edge genes that passed the in-silico validation and showed consistent ARID1A-related methylation change in tumors and cell lines were regarded as candidate genes and finally verified by bisulfite sequencing and RT-qPCR. RESULTS: Hierarchical clustering analysis of genome-wide methylation showed two clusters of OCCC tumors. Tumor stage, ARID1A/PIK3CA mutations and TP53 mutations were significantly different between the two clusters. ARID1A mutations in OCCC did not cause global DNA methylation changes but were related to DM promoter or gene-body CpG islands of 2004 genes. Three pre-ranked GSEAs collectively revealed the significant enrichment of EZH2- and H3K27me3-related gene-sets by the ARID1A-related DM genes. 13 Leading-edge DM genes extracted from the enriched gene-sets passed the expression-based in-silico validation and showed consistent ARID1A-related methylation change in tumors and cell lines. Bisulfite sequencing and RT-qPCR analysis showed promoter hypermethylation and lower expression of IRX1, TMEM101 and TRIP6 in ARID1Amt compared to ARID1Awt OCCC cells, which was reversed by 5-aza-2'-deoxycytidine treatment. CONCLUSIONS: Our study shows that ARID1A loss is related to the differential methylation of a number of genes in OCCC. ARID1A-dependent DM genes have been identified as key genes of many cancer-related pathways that may provide new candidates for OCCC targeted treatment.
Asunto(s)
Adenocarcinoma de Células Claras , Metilación de ADN , Proteínas de Unión al ADN , Regulación Neoplásica de la Expresión Génica , Proteínas Nucleares , Neoplasias Ováricas , Factores de Transcripción , Humanos , Metilación de ADN/genética , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Femenino , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Línea Celular Tumoral , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Adenocarcinoma de Células Claras/genética , Adenocarcinoma de Células Claras/patología , Genoma Humano , Mutación/genética , Epigénesis Genética , Análisis por ConglomeradosRESUMEN
AIM: Gastrointestinal medullary carcinoma is a rare histologic subtype of adenocarcinoma. As nonampullary small bowel medullary carcinomas (SB-MCs) are poorly characterized, we aimed to analyse their clinicopathologic and immunohistochemical features and to compare them with nonmedullary small bowel adenocarcinomas (NM-SBAs). METHODS AND RESULTS: Surgically resected SBAs collected through the Small Bowel Cancer Italian Consortium were classified as SB-MCs (carcinomas with ≥50% of tumour fulfilling the typical histologic criteria of MC) or NM-SBAs. Immunohistochemistry for cytokeratin (CK)7, CK20, CDX2, programmed death-ligand 1 (PD-L1) and mismatch repair proteins was performed in both SB-MCs and NM-SBAs. SB-MCs were also tested for CK8/18, synaptophysin, SMARCB1, SMARCA2, SMARCA4, and ARID1A and for Epstein-Barr virus (EBV)-encoded RNAs by in-situ hybridization. MLH1 promoter methylation status was evaluated in MLH1-deficient cases. Eleven SB-MCs and 149 NM-SBAs were identified. One (9%) SB-MC was EBV-positive, while 10 (91%) harboured mismatch repair deficiency (dMMR). MLH1 promoter hypermethylation was found in all eight dMMR SB-MCs tested. Switch/sucrose nonfermentable deficiency was seen in two (18%) SB-MCs, both with isolated loss of ARID1A. Compared with NM-SBAs, SB-MCs exhibited an association with coeliac disease (P < 0.001), higher rates of dMMR (P < 0.001), and PD-L1 positivity by both tumour proportion score and combined positive score (P < 0.001 for both), and a lower rate of CK20 expression (P = 0.024). Survival analysis revealed a better prognosis of SB-MC patients compared to NM-SBA cases (P = 0.02). CONCLUSION: SB-MCs represent a distinct histologic subtype, with peculiar features compared to NM-SBAs, including association with coeliac disease, dMMR, PD-L1 expression, and better prognosis.
RESUMEN
BACKGROUND: Exploring predictive biomarkers and therapeutic strategies of ICBs has become an urgent need in clinical practice. Increasing evidence has shown that ARID1A deficiency might play a critical role in sculpting tumor environments in various tumors and might be used as pan-cancer biomarkers for immunotherapy outcomes. The current study aims to explored the immune-modulating role of ARID1A deficiency in Hepatitis B virus (HBV) related hepatocellular carcinoma (HBV-HCC) and its potential immunotherapeutic implications. METHODS: In the current study, we performed a comprehensive analysis using bioinformatics approaches and pre-clinical experiments to evaluate the ARID1A regulatory role on the biological behavior, and immune landscape of Hepatitis B virus (HBV) related hepatocellular carcinoma (HBV-HCC). A total of 425 HBV-related hepatocellular carcinoma patients from TCGA-LIHC, AMC and CHCC-HBV cohort were enrolled in bioinformatics analysis. Immunohistochemical staining of HBV-HCC specimens and ARID1A deficiency cellular models were used to validate the results of the analysis. RESULTS: Our results have shown that ARID1A deficiency promoted tumor proliferation and metastasis. More importantly, ARID1A deficiency in HBV-HCC was associated with the higher TMB, elevated immune activity, and up-regulated expression of immune checkpoint proteins, especially TIM-3 in HBV-HCC. Further, the expression of Galectin-9, which is the ligand of TIM-3, was elevated in the ARID1A knockout HBV positive cell line. CONCLUSION: To conclude, we have shown that the ARID1A deficiency was correlated with more active immune signatures and higher expression of immune checkpoints in HBV-HCC. Additionally, the present study provides insights to explore the possibility of the predictive role of ARID1A in HBV-HCC patients responsive to immunotherapy.
Asunto(s)
Carcinoma Hepatocelular , Hepatitis B , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/patología , Virus de la Hepatitis B/genética , Neoplasias Hepáticas/patología , Receptor 2 Celular del Virus de la Hepatitis A , Biomarcadores de Tumor , Hepatitis B/complicaciones , Proteínas de Unión al ADN , Factores de TranscripciónRESUMEN
BACKGROUND: The purpose of the study was to conduct a comprehensive genomic characterization of gene alterations, microsatellite instability (MSI), and tumor mutational burden (TMB) in submucosal-penetrating (Pen) early gastric cancers (EGCs) with varying prognoses. METHODS: Samples from EGC patients undergoing surgery and with 10-year follow-up data available were collected. Tissue genomic alterations were characterized using Trusight Oncology panel (TSO500). Pathway instability (PI) scores for a selection of 218 GC-related pathways were calculated both for the present case series and EGCs from the TCGA cohort. RESULTS: Higher age and tumor location in the upper-middle tract are significantly associated with an increased hazard of relapse or death from any cause (p = 0.006 and p = 0.032). Even if not reaching a statistical significance, Pen A tumors more frequently present higher TMB values, higher frequency of MSI-subtypes and an overall increase in PI scores, along with an enrichment in immune pathways. ARID1A gene was observed to be significantly more frequently mutated in Pen A tumors (p = 0.006), as well as in patients with high TMB (p = 0.027). Tumors harboring LRP1B alterations seem to have a higher hazard of relapse or death from any cause (p = 0.089), being mutated mainly in relapsed patients (p = 0.093). CONCLUSIONS: We found that the most aggressive subtype Pen A is characterized by a higher frequency of ARID1A mutations and a higher genetic instability, while LRP1B alterations seem to be related to a lower disease-free survival. Further investigations are needed to provide a rationale for the use of these markers to stratify prognosis in EGC patients.
RESUMEN
INTRODUCTION: Genetic mutations and amplifications found in hepatocellular carcinoma (HCC) have a potentially prognostic impact. The aim of this study was to investigate the prognostic value of mutations and amplifications in HCC from patients that were liver resected. METHODS: Patients liver resected for HCC at Copenhagen University Hospital Rigshospitalet between May 2014 and January 2018 were included. DNA from freshly frozen tumour tissue was investigated with TruSight Oncology 500. Mutations and amplifications were correlated with disease-free survival and overall survival using multivariate Cox regression to assess the effect on prognosis. RESULTS: Of the 51 patients included, 88% were male and the median age was 69 years. Most patients had a single tumour (84%) with no vascular invasion (67%) in a non-cirrhotic liver (76% with fibrosis, 24% with cirrhosis). The median follow-up was 37 months. Patients with a MYC amplification (8%) were significantly younger than the remaining patients. Furthermore, they had a significantly shorter overall survival (15 months (95% CI: 0.0-31.6) vs. 59 months (95% CI: 34.4-83.6), p = < 0.001) and disease-free survival (8 months (95% CI: 4.6-11.4) vs. 19 months (95% CI: 12.3-25.7), p = 0.03). However, only overall survival remained statistically significant in the adjusted analysis. Furthermore, all patients with an ARID1A mutation (6%) had microvascular invasion and significantly larger tumours than the patients without ARID1A mutation. CONCLUSION: MYC amplifications had a prognostic influence on survival, whereas ARID1A gene mutations were correlated with microvascular invasion. These may serve as prognostic biomarkers and should be validated in large, independent cohort.
Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Masculino , Anciano , Femenino , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/cirugía , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/cirugía , Pronóstico , Cirrosis Hepática/patología , Hepatectomía , Genómica , Estudios RetrospectivosRESUMEN
BACKGROUND: Neuropathic pain, a complex condition originating from nervous system damage, remains a significant clinical challenge due to limited understanding of its underlying mechanisms. Recent research highlights the SOX11 transcription factor, known for its role in nervous system development, as a crucial player in neuropathic pain development and maintenance. This study investigates the role of the SOX11-ARID1A-SOCS3 pathway in neuropathic pain modulation within the spinal cord. METHODS AND RESULTS: Using a spinal nerve ligation (SNL) model in mice, we observed a significant upregulation of Sox11 in the spinal cord dorsal horn post-injury. Intrathecal administration of Sox11 shRNA mitigated SNL-induced neuropathic pain behaviors, including mechanical allodynia and heat hyperalgesia. Further, we demonstrated that Sox11 regulates neuropathic pain via transcriptional control of ARID1A, with subsequent modulation of SOCS3 expression. Knockdown of ARID1A and SOCS3 via shRNA resulted in alleviation of Sox11-induced pain sensitization. Additionally, Sox11 overexpression led to an increase in ARID1A binding to the SOCS3 promoter, enhancing chromatin accessibility and indicating a direct regulatory relationship. These findings were further supported by in vitro luciferase reporter assays and chromatin accessibility analysis. CONCLUSIONS: The SOX11-ARID1A-SOCS3 pathway plays a pivotal role in the development and maintenance of neuropathic pain. Sox11 acts as a master regulator, modulating ARID1A, which in turn influences SOCS3 expression, thereby contributing to the modulation of neuropathic pain. These findings provide a deeper understanding of the molecular mechanisms underlying neuropathic pain and highlight potential therapeutic targets for its treatment. The differential regulation of this pathway in the spinal cord and dorsal root ganglia (DRG) underscores its complexity and the need for targeted therapeutic strategies.
Asunto(s)
Proteínas de Unión al ADN , Neuralgia , Factores de Transcripción SOXC , Proteína 3 Supresora de la Señalización de Citocinas , Animales , Ratones , Cromatina , Hiperalgesia , ARN Interferente Pequeño , Factores de Transcripción SOXC/genética , Médula Espinal , Proteína 3 Supresora de la Señalización de Citocinas/genética , Proteínas de Unión al ADN/genéticaRESUMEN
Coffin-Siris syndrome is an autosomal dominant disorder with neurological, cardiovascular, and gastrointestinal symptoms. Patients with Coffin-Siris syndrome typically have variable degree of developmental delay or intellectual disability, muscular hypotonia, dysmorphic facial features, sparse scalp hair, but otherwise hirsutism and fifth digit nail or distal phalanx hypoplasia or aplasia. Coffin-Siris syndrome is caused by pathogenic variants in 12 different genes including SMARCB1 and ARID1A. Pathogenic SMARCB1 gene variants cause Coffin-Siris syndrome 3 whereas pathogenic ARID1A gene variants cause Coffin-Siris syndrome 2. Here, we present two prenatal Coffin-Siris syndrome cases with autosomal dominant pathogenic variants: SMARCB1 gene c.1066_1067del, p.(Leu356AspfsTer4) variant, and a novel ARID1A gene c.1920+3_1920+6del variant. The prenatal phenotype in Coffin-Siris syndrome has been rarely described. This article widens the phenotypic spectrum of prenatal Coffin-Siris syndrome with severely hypoplastic right ventricle with VSD and truncus arteriosus type III, persisting left superior and inferior caval vein, bilateral olfactory nerve aplasia, and hypoplastic thymus. A detailed clinical description of the patients with ultrasound, MRI, and post mortem pictures of the affected fetuses showing the wide phenotypic spectrum of the disease is presented.
Asunto(s)
Anomalías Múltiples , Cara/anomalías , Deformidades Congénitas de la Mano , Discapacidad Intelectual , Micrognatismo , Cuello/anomalías , Humanos , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/genética , Discapacidad Intelectual/patología , Anomalías Múltiples/diagnóstico , Anomalías Múltiples/genética , Anomalías Múltiples/patología , Cara/patología , FenotipoRESUMEN
Endometriosis is a hormone-dependent, chronic inflammatory condition that affects 5-10% of reproductive-aged women. It is a complex disorder characterized by the growth of endometrial-like tissue outside the uterus, which can cause chronic pelvic pain and infertility. Despite its prevalence, the underlying molecular mechanisms of this disease remain poorly understood. Current treatment options are limited and focus mainly on suppressing lesion activity rather than eliminating it entirely. Although endometriosis is generally considered a benign condition, substantial evidence suggests that it increases the risk of developing specific subtypes of ovarian cancer. The discovery of cancer driver mutations in endometriotic lesions indicates that endometriosis may share molecular pathways with cancer. Moreover, the application of single-cell and spatial genomics, along with the development of organoid models, has started to illuminate the molecular mechanisms underlying disease etiology. This review aims to summarize the key genetic mutations and alterations that drive the development and progression of endometriosis to malignancy. We also review the significant recent advances in the understanding of the molecular basis of the disorder, as well as novel approaches and in vitro models that offer new avenues for improving our understanding of disease pathology and for developing new targeted therapies.
Asunto(s)
Endometriosis , Endometriosis/patología , Endometriosis/genética , Endometriosis/etiología , Endometriosis/metabolismo , Humanos , Femenino , Neoplasias Ováricas/patología , Neoplasias Ováricas/etiología , Neoplasias Ováricas/genética , Neoplasias Ováricas/metabolismo , Mutación , AnimalesRESUMEN
The application of immune checkpoint inhibitor (ICI) using monoclonal antibodies has brought about a profound transformation in the clinical outcomes for patients grappling with advanced gastric cancer (GC). Nonetheless, despite these achievements, the quest for effective functional biomarkers for ICI therapy remains constrained. Recent research endeavours have shed light on the critical involvement of modified epigenetic regulators in the pathogenesis of gastric tumorigenesis, thus providing a glimpse into potential biomarkers. Among these regulatory factors, AT-rich interaction domain 1A (ARID1A), a pivotal constituent of the switch/sucrose non-fermentable (SWI/SNF) complex, has emerged as a promising candidate. Investigations have unveiled the pivotal role of ARID1A in bridging the gap between genome instability and the reconfiguration of the tumour immune microenvironment, culminating in an enhanced response to ICI within the landscape of gastric cancer treatment. This all-encompassing review aims to dissect the potential of ARID1A as a valuable biomarker for immunotherapeutic approaches in gastric cancer, drawing from insights garnered from both preclinical experimentation and clinical observations.
RESUMEN
Epigenetic regulation of gene expression plays a central role in bladder urothelium development and maintenance. ATPase-dependent chromatin remodeling is a major epigenetic regulatory mechanism, but its role in the bladder has not been explored. Here, we show the functions of Arid1a, the largest subunit of the SWI/SNF or BAF chromatin remodeling ATPase complex, in embryonic and adult bladder urothelium. Knockout of Arid1a in urothelial progenitor cells significantly increases cell proliferation during bladder development. Deletion of Arid1a causes ectopic cell proliferation in the terminally differentiated superficial cells in adult mice. Consistently, gene-set enrichment analysis of differentially expressed genes demonstrates that the cell cycle-related pathways are significantly enriched in Arid1a knockouts. Gene-set of the polycomb repression complex 2 (PRC2) pathway is also enriched, suggesting that Arid1a antagonizes the PRC2-dependent epigenetic gene silencing program in the bladder. During acute cyclophosphamide-induced bladder injury, Arid1a knockouts develop hyperproliferative and hyperinflammatory phenotypes and exhibit a severe loss of urothelial cells. A Hallmark gene-set of the oxidative phosphorylation pathway is significantly reduced in Aria1a mutants before injury and is unexpectedly enriched during injury response. Together, this study uncovers functions of Arid1a in both bladder progenitor cells and the mature urothelium, suggesting its critical roles in urothelial development and regeneration.
Asunto(s)
Vejiga Urinaria , Urotelio , Adenosina Trifosfatasas/genética , Animales , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Epigénesis Genética , Ratones , Ratones Noqueados , Complejo Represivo Polycomb 2/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Vejiga Urinaria/metabolismo , Urotelio/metabolismoRESUMEN
Mullerian clear cell carcinoma (CCC) is often aggressive and chemoresistant. The prognostic significance of molecular subclassification of endometrioid carcinomas is well established. However, less is known about the molecular landscape of CCC. The aim of this study was to better characterize the genetic landscape of a large cohort of CCC and correlate these findings with clinicopathologic features. CCC of the ovary (n = 72), endometrium (n = 24), and peritoneum/abdominal wall (n = 5) were retrospectively identified. Tumors had undergone tumor-only targeted sequencing using a hybrid capture next-generation sequencing panel. Median tumor mutational burden was 6.8 mutations/megabase (range, 1.3-185, 21% were ≥10 mutations/Mb). The most frequently mutated genes were ARID1A (48%), PIK3CA (45%), TP53 (23%), and PTEN (10%). ERBB2 amplification occurred in 4%. When classified according to the Cancer Genome Atlas/the Proactive Molecular Risk Classifier for Endometrial Cancer endometrial carcinoma molecular subgroups, 3 (3%) were POLE ultramutated, 5 (5%) were microsatellite instability-high (MSI-H), 20 (20%) were TP53-mutant subgroup, and 73 (72%) were no specific molecular profile (NSMP). Immunohistochemical expression of estrogen receptor, progesterone receptor, and programmed death-ligand 1 were not associated with the molecular subgroup. POLE and MSI-H tumors were characterized by an excellent prognosis, and the TP53-mutant subgroup had a worse disease-free survival than NSMP. NSMP tumors could be further substratified as high-risk NSMP if they lacked PIK3CA, PIK3R1, and ARID1A mutations, and/or harbored a TERT-promoter mutation. The Cancer Genome Atlas and NSMP-specific stratifications were prognostic for both the entire cohort and the subset of stage I ovarian tumors. On multivariable analysis, stage, lymphovascular invasion, and tumor mutational burden were prognostic for disease-free survival, whereas advanced stage and TP53-mutant subgroup - but not a TP53 mutation in isolation - were negative prognostic factors for overall survival. These data suggest that routine molecular profiling of Mullerian CCC may be warranted for both prognosis and identification of potential targeted treatments, such as immunotherapy and anti-HER2 agents.