RESUMEN
Relapse to anti-HER2 monoclonal antibody (mAb) therapies, such as trastuzumab in HER2+ breast cancer (BC), is associated with residual disease progression due to resistance to therapy. Here, we identify interferon-γ inducible protein 16 (IFI16)-dependent STING signaling as a significant determinant of trastuzumab responses in HER2+ BC. We show that down-regulation of immune-regulated genes (IRG) is specifically associated with poor survival of HER2+, but not other BC subtypes. Among IRG, IFI16 is identified as a direct target of EZH2, the underexpression of which leads to deficient STING activation and downstream CXCL10/11 expression in response to trastuzumab treatment. Dual inhibition of EZH2 and histone deacetylase (HDAC) significantly activates IFI16-dependent immune responses to trastuzumab. Notably, a combination of a novel histone methylation inhibitor with an HDAC inhibitor induces complete tumor eradication and long-term T cell memory in a HER2+ BC mouse model. Our findings demonstrate an epigenetic regulatory mechanism suppressing the expression of the IFI16-CXCL10/11 signaling pathway that provides a survival advantage to HER2+ BC to confer resistance to trastuzumab treatment.
Asunto(s)
Neoplasias de la Mama , Resistencia a Antineoplásicos , Proteínas de la Membrana , Proteínas Nucleares , Fosfoproteínas , Trastuzumab , Animales , Antineoplásicos Inmunológicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/inmunología , Línea Celular Tumoral , Quimiocina CXCL10 , Quimiocina CXCL11 , Resistencia a Antineoplásicos/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunidad , Proteínas de la Membrana/metabolismo , Ratones , Recurrencia Local de Neoplasia/genética , Proteínas Nucleares/metabolismo , Fosfoproteínas/metabolismo , Receptor ErbB-2/genética , Transducción de Señal , Trastuzumab/farmacologíaRESUMEN
Angiomatoid fibrous histiocytoma (AFH) is an uncommon soft tissue neoplasm that can exhibit diverse morphological features, including myxoid change. Rarely, the tumor occurs intracranially and poses considerable diagnostic challenges to neuropathologists. This is compounded by a recently coined entity, referred to as intracranial myxoid mesenchymal tumor (IMMT). These tumors show significant overlaps with intracranial myxoid AFH from clinicopathological and molecular genetic viewpoints. We described an unusual intracranial tumor in a 30-year-old man. The tumor exhibited "classic" histological features of myxoid AFH and EWSR1:CREM fusion, a relatively novel variant of EWSR1:CREB family fusion, first identified in IMMT. We also performed a comprehensive literature review comparing the clinicopathological features of intracranial AFHs and IMMTs. Peritumoral lymphoplasmacytic cuffing appears to be the only morphological finding that is consistently absent in reported cases of IMMT while being present in most intracranial AFHs. Otherwise, both tumors showed considerable overlaps in clinical, histological, and immunohistochemical features and have a common molecular genetic signature of EWSR1:CREB family fusion, including EWSR1:CREM fusion. Our case appeared to be the first described EWSR1:CREM-fused intracranial tumor to show prominent peritumoral lymphoplasmacytic cuffing and myxoid change in addition to most of the other "classic" morphologic features of AFH. As such, while the current literature appears to be lacking when it comes to defining intracranial myxoid AFH and IMMT as separate nosological entities, they likely represent a morphological spectrum of a common entity characterized by EWSR1 rearrangement, akin to solitary fibrous tumors and hemangiopericytomas with the signal transducer and activator of transcription 6 gene (STAT6) rearrangement.
Asunto(s)
Neoplasias Encefálicas , Histiocitoma Fibroso Benigno , Histiocitoma Fibroso Maligno , Neoplasias de los Tejidos Blandos , Adulto , Neoplasias Encefálicas/genética , Modulador del Elemento de Respuesta al AMP Cíclico/genética , Fusión Génica , Humanos , Masculino , Proteína EWS de Unión a ARN/genéticaRESUMEN
Defective mitophagy linked to dysfunction in the proteins Parkin and PTEN-induced putative kinase 1 (PINK1) is implicated in the pathogenesis of Parkinson's disease. Although the mechanism by which Parkin mediates mitophagy in a PINK1-dependent manner is becoming clearer, the triggers for this mitophagy pathway remain elusive. Reactive oxygen species (ROS) have been suggested as such triggers, but this proposal remains controversial because ROS scavengers fail to retard mitophagy. Here we demonstrate that the role of ROS in mitophagy has been underappreciated as a result of the inefficiency of ROS scavengers to control ROS bursts after high-dose treatment with carbonyl cyanide m-chlorophenylhydrazone. Supporting this, combinatorial treatment with N-acetyl-l-cysteine and catalase substantially inhibited the ROS upsurge and PINK1-dependent Parkin translocation to mitochondria in response to carbonyl cyanide m-chlorophenylhydrazone treatment. In addition to the chemical mitophagy inducer, overexpression of voltage-dependent anion channel 1 (VDAC1) induced Parkin translocation to mitochondria, presumably by stimulating ROS generation. Similarly, combined N-acetyl-l-cysteine and catalase treatment also suppressed VDAC1-induced redistribution of Parkin. Alongside these observations, we also found that the elevated protein level of PINK1 was not necessary for Parkin translocation to mitochondria. Thus, our data suggest that ROS may act as a trigger for the induction of Parkin/PINK1-dependent mitophagy. In addition, our study casts doubt on the importance of protein quantity of PINK1 in the recruitment of Parkin to mitochondria.
Asunto(s)
Mitocondrias/metabolismo , Mitofagia/fisiología , Proteínas Quinasas/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Acetilcisteína/farmacología , Depuradores de Radicales Libres/farmacología , Células HeLa , Humanos , Mitocondrias/genética , Mitofagia/efectos de los fármacos , Proteínas Quinasas/genética , Transporte de Proteínas/efectos de los fármacos , Transporte de Proteínas/genética , Ubiquitina-Proteína Ligasas/genéticaRESUMEN
BACKGROUND: Angiosarcoma is a sarcoma that occurs in a range of tissue types, and only rarely in the salivary glands, showing a predilection for the parotid glands of older patients. Preoperative diagnosis may be challenging, especially on cytology, with significant morphological overlap with high-grade primary salivary gland carcinomas. The molecular alterations of this rare salivary gland neoplasm are also not well-characterized. METHODS AND RESULTS: We present a case of right submandibular gland swelling in a 73-year-old male. On fine needle aspiration, including immunohistochemical stains on cell block, the tumor was initially diagnosed as poorly differentiated carcinoma. Resection of the submandibular gland revealed epithelioid angiosarcoma. We performed molecular work-up of the tumor, utilizing targeted next-generation sequencing, DNA methylation profiling and fluorescence in-situ hybridization. Histopathologic assessment revealed an infiltrative tumor comprising solid sheets of epithelioid cells. The tumor cells formed haphazardly anastomosing vascular channels with intracytoplasmic lumina containing red blood cells. On immunohistochemistry, the tumor cells were positive for CD31, CD34 and ERG. Approximately 40% of the tumor cells showed nuclear expression of GATA3. A pathogenic TP53 R267W mutation was detected on next-generation sequencing. DNA methylation analysis did not cluster the tumor with any known sarcoma type. Copy number analysis showed possible MYC amplification and CDKN2A losses, although only the latter was confirmed on fluorescence in-situ hybridization. CONCLUSION: Epithelioid angiosarcoma is an important differential diagnosis to high-grade salivary gland carcinoma. In particular, GATA3 expression may be encountered in both angiosarcoma and high-grade salivary gland carcinomas and cause diagnostic confusion. Identification of TP53 mutations and CDKN2A losses suggest shared oncogenic pathways with soft tissue angiosarcomas, and should be further investigated.
Asunto(s)
Hemangiosarcoma , Neoplasias de la Glándula Submandibular , Humanos , Masculino , Anciano , Hemangiosarcoma/genética , Hemangiosarcoma/patología , Hemangiosarcoma/diagnóstico , Neoplasias de la Glándula Submandibular/patología , Neoplasias de la Glándula Submandibular/genética , Neoplasias de la Glándula Submandibular/diagnóstico , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/genética , CitologíaRESUMEN
Sarcomas are a diverse group of tumors, with >70 subtypes in the current World Health Organization classification, each with distinct biological behavior requiring specific clinical management. A significant portion of sarcomas are molecularly defined by expression of a driver fusion gene; identification of such fusions is the basis of molecular diagnostics in sarcomas, which is of increasing complexity due to the ongoing discovery of new gene fusions. Recently, a multiplex NanoString platform-based assay was developed and clinically implemented, with fusion junction-spanning probes that detect the majority of sarcoma fusion types, with high sensitivity and specificity, and with lower cost and shorter turnaround time than those of targeted next-generation sequencing-based alternatives. Despite the effectiveness of this assay, there are several entities for which fusion-junction probes are not suitable due to multiple possible gene partners or excessive variability at the exon junctions. Here, the development and evaluation of a companion assay are described that uses NanoString-based gene expression analysis to detect aberrant 3'/5' exon expression imbalance and/or total gene overexpression as a surrogate marker for fusion gene rearrangement. This assay evaluates exon imbalance in 23 genes involved in over 25 mesenchymal tumor types and five genes specific to sarcomas with CIC rearrangements. Based on evaluation of 115 retrospectively and 91 prospectively collected cases, an assay sensitivity of 92.8% and specificity of 93.5% are demonstrated.
Asunto(s)
Sarcoma , Neoplasias de los Tejidos Blandos , Humanos , Estudios Retrospectivos , Sarcoma/diagnóstico , Sarcoma/genética , Sarcoma/patología , Fusión Génica , Exones/genética , Neoplasias de los Tejidos Blandos/genética , Biomarcadores de Tumor/genética , Expresión Génica , Proteínas de Fusión Oncogénica/genéticaRESUMEN
The survival rate of patients with osteosarcoma (OS) has not improved over the last 30 years. Mutations in the genes TP53, RB1 and c-Myc frequently occur in OS and enhance RNA Polymerase I (Pol I) activity, thus supporting uncontrolled cancer cell proliferation. We therefore hypothesised that Pol I inhibition may be an effective therapeutic strategy for this aggressive cancer. The Pol I inhibitor CX-5461 has demonstrated therapeutic efficacy in different cancers in pre-clinical and phase I clinical trials; thus, the effects were determined on ten human OS cell lines. Following characterisation using genome profiling and Western blotting, RNA Pol I activity, cell proliferation and cell cycle progression were evaluated in vitro, and the growth of TP53 wild-type and mutant tumours was measured in a murine allograft model and in two human xenograft OS models. CX-5461 treatment resulted in reduced ribosomal DNA (rDNA) transcription and Growth 2 (G2)-phase cell cycle arrest in all OS cell lines. Additionally, tumour growth in all allograft and xenograft OS models was effectively suppressed without apparent toxicity. Our study demonstrates the efficacy of Pol I inhibition against OS with varying genetic alterations. This study provides pre-clinical evidence to support this novel therapeutic approach in OS.
RESUMEN
PBRM1 encodes an accessory subunit of the PBAF SWI/SNF chromatin remodeller, and the inactivation of PBRM1 is a frequent event in kidney cancer. However, the impact of PBRM1 loss on chromatin remodelling is not well examined. Here we show that, in VHL-deficient renal tumours, PBRM1 deficiency results in ectopic PBAF complexes that localize to de novo genomic loci, activating the pro-tumourigenic NF-κB pathway. PBRM1-deficient PBAF complexes retain the association between SMARCA4 and ARID2, but have loosely tethered BRD7. The PBAF complexes redistribute from promoter proximal regions to distal enhancers containing NF-κB motifs, heightening NF-κB activity in PBRM1-deficient models and clinical samples. The ATPase function of SMARCA4 maintains chromatin occupancy of pre-existing and newly acquired RELA specific to PBRM1 loss, activating downstream target gene expression. Proteasome inhibitor bortezomib abrogates RELA occupancy, suppresses NF-κB activation and delays growth of PBRM1-deficient tumours. In conclusion, PBRM1 safeguards the chromatin by repressing aberrant liberation of pro-tumourigenic NF-κB target genes by residual PBRM1-deficient PBAF complexes.
Asunto(s)
Carcinoma de Células Renales , Neoplasias Renales , Humanos , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/metabolismo , Cromatina/genética , Proteínas Cromosómicas no Histona/genética , ADN Helicasas/genética , Proteínas de Unión al ADN/genética , Genómica , Neoplasias Renales/metabolismo , FN-kappa B/genética , Proteínas Nucleares/genética , Factores de Transcripción/genéticaRESUMEN
The purpose of this study is to characterize the clinicopathological features of mass-forming immunoglobulin G4-related disease (IgG4-RD). A retrospective search for cases of mass-forming IgG4-RD diagnosed at Singapore General Hospital between 2008 and 2019 was performed. A total of 15 cases of mass-forming IgG4-RD were identified. The male-to-female ratio was 2.5:1, and the median age was 61 years old. The majority of cases showed a solitary lesion (12/15) with a mean size of 35 mm. IgG4-RD was considered as a clinical differential diagnosis only in one case (1/15) prior to the surgical resection. Diagnostic histopathological features, such as dense lymphoplasmacytic infiltrate positive for IgG4 plasma cells (15/15), storiform fibrosis (15/15), and obliterative phlebitis (9/15), were observed in most cases. These findings were distributed heterogeneously within the lesions. Cases with single organ involvement showed a low relapse rate (2/10) and normal serum IgG4 level after surgical resection. Mass-forming IgG4-RD has a male predilection and involves various organ systems. It may be initially misdiagnosed as malignancy and undergo surgical resection. The diagnostic histological features of IgG4-RD are readily identified in different organs. However, they may be distributed heterogeneously within a single lesion. Cases of single organ involvement show an indolent clinical course and normal serum IgG4 level after surgical resection.
Asunto(s)
Enfermedad Relacionada con Inmunoglobulina G4 , Femenino , Fibrosis , Humanos , Inmunoglobulina G , Enfermedad Relacionada con Inmunoglobulina G4/diagnóstico , Enfermedad Relacionada con Inmunoglobulina G4/patología , Masculino , Persona de Mediana Edad , Células Plasmáticas/patología , Estudios RetrospectivosRESUMEN
Clear cell sarcoma of the kidney (CCSK) and primitive myxoid mesenchymal tumour of infancy (PMMTI) are paediatric sarcomas that most commonly harbour internal tandem duplications (ITDs) of exon 15 of the BCOR gene, in the range of 87-114 base pairs (bp). Some cases, instead, have BCOR-CCNB3 or YWHAE-NUTM2 gene fusions. About 10% of cases lack any of these genetic alterations when tested by standard methods. Two cases of CCSK and one PMMTI lacking the aforementioned mutations were analysed using Archer FusionPlex technology. Two related BCOR exon 15 RNA transcripts with ITDs of lengths 388 and 96 bp were detected in each case; only the 388 bp transcript was identified when genomic DNA was sequenced. In silico analysis of this transcript revealed acceptor and donor splice sites indicating that, at the RNA level, the 388-bp transcript was likely spliced to form the 96-bp transcript. The results were confirmed by Sanger sequencing using primers targeting the ITD breakpoint. This novel and unusually long ITD segment is difficult to identify by DNA sequencing using typical primer design strategies flanking entire duplicated segments because it exceeds the typical read lengths of most sequencing platforms as well as the usual fragment lengths obtained from formalin-fixed paraffin-embedded material. As diagnosis of CCSK and PMMTI may be challenging by morphology and immunohistochemistry alone, it is important to identify mutations in these cases. Knowledge of this novel BCOR ITD is important in relation to primer design for detection by sequencing, and using RNA versus DNA for sequencing.
Asunto(s)
Neoplasias Renales , Sarcoma , Niño , Exones/genética , Humanos , Neoplasias Renales/patología , Mutación , Proteínas Proto-Oncogénicas/genética , ARN , Proteínas Represoras/genética , Sarcoma/genética , Sarcoma/patologíaRESUMEN
The hypoxic tumor microenvironment has been implicated in immune escape, but the underlying mechanism remains elusive. Using an in vitro culture system modeling human T cell dysfunction and exhaustion in triple-negative breast cancer (TNBC), we find that hypoxia suppresses immune effector gene expression, including in T and NK cells, resulting in immune effector cell dysfunction and resistance to immunotherapy. We demonstrate that hypoxia-induced factor 1α (HIF1α) interaction with HDAC1 and concurrent PRC2 dependency causes chromatin remolding resulting in epigenetic suppression of effector genes and subsequent immune dysfunction. Targeting HIF1α and the associated epigenetic machinery can reverse the immune effector dysfunction and overcome resistance to PD-1 blockade, as demonstrated both in vitro and in vivo using syngeneic and humanized mice models. These findings identify a HIF1α-mediated epigenetic mechanism in immune dysfunction and provide a potential strategy to overcome immune resistance in TNBC.
Asunto(s)
Neoplasias de la Mama Triple Negativas , Animales , Línea Celular Tumoral , Epigénesis Genética , Humanos , Hipoxia/genética , Inmunoterapia/métodos , Ratones , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/metabolismo , Neoplasias de la Mama Triple Negativas/terapia , Microambiente Tumoral/genéticaRESUMEN
The recently introduced, highly sensitive and specific SS18-SSX immunohistochemistry (IHC) is an attractive alternative to SS18 fluorescence in situ hybridization (FISH) testing in synovial sarcoma (SS). However, little is known about how SS18-SSX IHC correlates with SS18 FISH. We correlated the SS18 FISH results of SS from 36 patients with SS18-SSX IHC. Twenty-six tumours had a classic break-apart FISH pattern (1 fused, 1 red and 1 green signal) and all stained positive for the IHC. Ten had an atypical (non-classic) FISH pattern of which 5 stained positive for the IHC. Four of these (including two with novel atypical SS18 FISH patterns) were confirmed to harbour the SS18-SSX fusion on targeted RNA sequencing, while one had classic features of a biphasic SS. The remaining 5 tumours stained negative for the IHC. One had a TPM3-NTRK1 fusion, and one had no fusion, while the remaining three had insufficient tissue/RNA for sequencing. The sensitivity of the IHC was 91% (after excluding the 2 cases with confirmed absence of SS18-SSX fusion). Twenty histologic mimics of SS also stained negative for the IHC (100% specificity). Our study shows that the SS18-SSX IHC is more specific than SS18 FISH in diagnosing SS, especially in cases with atypical FISH patterns. It correlates well with RNA sequencing result and has the potential to replace SS18 FISH testing. A positive IHC result supports the diagnosis of SS, while a tumour with atypical FISH pattern and negative IHC result should undergo further molecular testing.
Asunto(s)
Proteínas de Fusión Oncogénica/genética , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Represoras/metabolismo , Sarcoma Sinovial/genética , Adulto , Biomarcadores de Tumor/genética , Femenino , Humanos , Inmunohistoquímica/métodos , Hibridación Fluorescente in Situ/métodos , Masculino , Persona de Mediana Edad , Proteínas Proto-Oncogénicas/inmunología , Proteínas Represoras/genética , Proteínas Represoras/inmunología , Sarcoma Sinovial/inmunología , Sarcoma Sinovial/metabolismoRESUMEN
ALK-positive histiocytosis was first described in 2008 as a systemic histiocytic disorder involving young infants and neonates. Subsequently, cases of local ALK-positive histiocytosis as well as clinical presentation in adult patients have been increasingly reported in the literature. The current case documented the hitherto largest local ALK-positive histiocytosis lesion involving the mesentery of a 20-year-old female patient, a clinical presentation that has not been previously reported in the medical literature. Of note was the presence of numerous lymphocytes, plasma cells, and eosinophils as well as the formation of lymphoid follicles in the lesion, mimicking an inflammatory myofibroblastic tumor. Other unique histologic aspects of the current case included the nested arrangement of the histiocytes, intravascular extension of the histiocytic proliferation into a large vein, and tumor necrosis. Notably, molecular studies revealed a novel TRIM33 (exon 12)-ALK (exon 20) gene fusion. Therefore, ALK-positive histiocytosis with TRIM33-ALK gene fusion expands the clinical, histologic, and molecular spectrum of local ALK-positive histiocytosis. Since ALK-positive histiocytosis associated with a significant inflammatory component can pose considerable diagnostic challenges, increased awareness of this peculiar variant of ALK-positive histiocytosis is essential to minimize the risk of misdiagnosis.
Asunto(s)
Quinasa de Linfoma Anaplásico/genética , Histiocitosis/diagnóstico , Mesenterio/patología , Proteínas de Fusión Oncogénica/genética , Factores de Transcripción/genética , Femenino , Histiocitosis/genética , Histiocitosis/patología , Histiocitosis/cirugía , Humanos , Mesenterio/diagnóstico por imagen , Mesenterio/cirugía , Tomografía Computarizada por Rayos X , Adulto JovenRESUMEN
Ependymomas are glial neoplasms with a wide morphological spectrum. The majority of supratentorial ependymomas are known to harbor ZFTA fusions, most commonly to RELA. We present an unusual case of a 9-year-old boy with a supratentorial ependymoma harboring a noncanonical ZFTA-MAML2 fusion. This case had unusual histomorphological features lacking typical findings of ependymoma and bearing resemblance to a primitive neoplasm with focal, previously undescribed myogenic differentiation. We discuss the diagnostic pitfalls in this case and briefly review the histological features of ependymoma with noncanonical gene fusions. Our report underscores the importance of molecular testing in such cases to arrive at the correct diagnosis. Supratentorial ependymomas with noncanonical fusions are rare, and more studies are necessary for better risk stratification and identification of potential treatment targets.
Asunto(s)
Neoplasias del Sistema Nervioso Central , Tumores Neuroectodérmicos Primitivos , Humanos , Factores de Transcripción/genética , Proteínas Nucleares/genética , Neoplasias del Sistema Nervioso Central/genética , Neoplasias del Sistema Nervioso Central/patología , Proteínas Represoras , Proteínas Proto-Oncogénicas/genética , Proteínas que Contienen Bromodominio , Proteínas de Ciclo Celular/genéticaRESUMEN
Tumor recurrence remains the main reason for breast cancer-associated mortality, and there are unmet clinical demands for the discovery of new biomarkers and development of treatment solutions to benefit patients with breast cancer at high risk of recurrence. Here we report the identification of chromosomal copy-number amplification at 1q21.3 that is enriched in subpopulations of breast cancer cells bearing characteristics of tumor-initiating cells (TICs) and that strongly associates with breast cancer recurrence. Amplification is present in â¼10-30% of primary tumors but in more than 70% of recurrent tumors, regardless of breast cancer subtype. Detection of amplification in cell-free DNA (cfDNA) from blood is strongly associated with early relapse in patients with breast cancer and could also be used to track the emergence of tumor resistance to chemotherapy. We further show that 1q21.3-encoded S100 calcium-binding protein (S100A) family members, mainly S100A7, S100A8, and S100A9 (S100A7/8/9), and IL-1 receptor-associated kinase 1 (IRAK1) establish a reciprocal feedback loop driving tumorsphere growth. Notably, this functional circuitry can be disrupted by the small-molecule kinase inhibitor pacritinib, leading to preferential impairment of the growth of 1q21.3-amplified breast tumors. Our study uncovers the 1q21.3-directed S100A7/8/9-IRAK1 feedback loop as a crucial component of breast cancer recurrence, serving as both a trackable biomarker and an actionable therapeutic target for breast cancer.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/patología , Cromosomas Humanos Par 1 , Recurrencia Local de Neoplasia/genética , Animales , Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Hidrocarburos Aromáticos con Puentes/uso terapéutico , Ácidos Nucleicos Libres de Células/genética , Progresión de la Enfermedad , Femenino , Xenoinjertos , Humanos , Hibridación Fluorescente in Situ , Ratones , Reacción en Cadena de la Polimerasa , Pirimidinas/uso terapéutico , Resultado del TratamientoRESUMEN
Protein-coding mutations in clear cell renal cell carcinoma (ccRCC) have been extensively characterized, frequently involving inactivation of the von Hippel-Lindau (VHL) tumor suppressor. Roles for noncoding cis-regulatory aberrations in ccRCC tumorigenesis, however, remain unclear. Analyzing 10 primary tumor/normal pairs and 9 cell lines across 79 chromatin profiles, we observed pervasive enhancer malfunction in ccRCC, with cognate enhancer-target genes associated with tissue-specific aspects of malignancy. Superenhancer profiling identified ZNF395 as a ccRCC-specific and VHL-regulated master regulator whose depletion causes near-complete tumor elimination in vitro and in vivoVHL loss predominantly drives enhancer/superenhancer deregulation more so than promoters, with acquisition of active enhancer marks (H3K27ac, H3K4me1) near ccRCC hallmark genes. Mechanistically, VHL loss stabilizes HIF2α-HIF1ß heterodimer binding at enhancers, subsequently recruiting histone acetyltransferase p300 without overtly affecting preexisting promoter-enhancer interactions. Subtype-specific driver mutations such as VHL may thus propagate unique pathogenic dependencies in ccRCC by modulating epigenomic landscapes and cancer gene expression.Significance: Comprehensive epigenomic profiling of ccRCC establishes a compendium of somatically altered cis-regulatory elements, uncovering new potential targets including ZNF395, a ccRCC master regulator. Loss of VHL, a ccRCC signature event, causes pervasive enhancer malfunction, with binding of enhancer-centric HIF2α and recruitment of histone acetyltransferase p300 at preexisting lineage-specific promoter-enhancer complexes. Cancer Discov; 7(11); 1284-305. ©2017 AACR.See related commentary by Ricketts and Linehan, p. 1221This article is highlighted in the In This Issue feature, p. 1201.
Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Carcinoma de Células Renales/genética , Proteínas de Unión al ADN/genética , Factores de Transcripción/genética , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/genética , Factores de Transcripción p300-CBP/genética , Carcinogénesis/genética , Carcinoma de Células Renales/patología , Línea Celular Tumoral , Cromatina , Elementos de Facilitación Genéticos/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Mutación , Oncogenes/genética , Regiones Promotoras Genéticas/genética , Secuencias Reguladoras de Ácidos Nucleicos/genéticaAsunto(s)
Reordenamiento Génico , Hemangioma , N-Metiltransferasa de Histona-Lisina , Proteínas Proto-Oncogénicas c-fos , Neoplasias Vasculares , Adulto , Células Epitelioides/patología , Femenino , Fusión Génica , Hemangioma/genética , Hemangioma/patología , N-Metiltransferasa de Histona-Lisina/genética , Humanos , Inmunohistoquímica , Reacción en Cadena de la Polimerasa Multiplex , Proteínas Proto-Oncogénicas c-fos/genética , Neoplasias de los Tejidos Blandos/genética , Neoplasias de los Tejidos Blandos/patología , Tórax/patología , Neoplasias Vasculares/genética , Neoplasias Vasculares/patologíaAsunto(s)
Neoplasias Encefálicas/genética , Carcinoma Papilar/genética , Subunidad RIIbeta de la Proteína Quinasa Dependiente de AMP Cíclico/genética , Ganglioglioma/genética , Proteínas Proto-Oncogénicas B-raf/genética , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/cirugía , Carcinoma Papilar/diagnóstico por imagen , Carcinoma Papilar/cirugía , Niño , Estudios de Seguimiento , Ganglioglioma/diagnóstico por imagen , Ganglioglioma/cirugía , Humanos , MasculinoRESUMEN
Metastatic tumour recurrence due to failed treatments remains a major challenge of breast cancer clinical management. Here we report that interleukin-1 receptor-associated kinase 1 (IRAK1) is overexpressed in a subset of breast cancers, in particular triple-negative breast cancer (TNBC), where it acts to drive aggressive growth, metastasis and acquired resistance to paclitaxel treatment. We show that IRAK1 overexpression confers TNBC growth advantage through NF-κB-related cytokine secretion and metastatic TNBC cells exhibit gain of IRAK1 dependency, resulting in high susceptibility to genetic and pharmacologic inhibition of IRAK1. Importantly, paclitaxel treatment induces strong IRAK1 phosphorylation, an increase in inflammatory cytokine expression, enrichment of cancer stem cells and acquired resistance to paclitaxel treatment. Pharmacologic inhibition of IRAK1 is able to reverse paclitaxel resistance by triggering massive apoptosis at least in part through inhibiting p38-MCL1 pro-survival pathway. Our study thus demonstrates IRAK1 as a promising therapeutic target for TNBC metastasis and paclitaxel resistance.