RESUMO
Chromosomal translocations frequently promote carcinogenesis by producing gain-of-function fusion proteins. Recent studies have identified highly recurrent chromosomal translocations in patients with endometrial stromal sarcomas (ESSs) and ossifying fibromyxoid tumors (OFMTs), leading to an in-frame fusion of PHF1 (PCL1) to six different subunits of the NuA4/TIP60 complex. While NuA4/TIP60 is a coactivator that acetylates chromatin and loads the H2A.Z histone variant, PHF1 is part of the Polycomb repressive complex 2 (PRC2) linked to transcriptional repression of key developmental genes through methylation of histone H3 on lysine 27. In this study, we characterize the fusion protein produced by the EPC1-PHF1 translocation. The chimeric protein assembles a megacomplex harboring both NuA4/TIP60 and PRC2 activities and leads to mislocalization of chromatin marks in the genome, in particular over an entire topologically associating domain including part of the HOXD cluster. This is linked to aberrant gene expression-most notably increased expression of PRC2 target genes. Furthermore, we show that JAZF1-implicated with a PRC2 component in the most frequent translocation in ESSs, JAZF1-SUZ12-is a potent transcription activator that physically associates with NuA4/TIP60, its fusion creating outcomes similar to those of EPC1-PHF1 Importantly, the specific increased expression of PRC2 targets/HOX genes was also confirmed with ESS patient samples. Altogether, these results indicate that most chromosomal translocations linked to these sarcomas use the same molecular oncogenic mechanism through a physical merge of NuA4/TIP60 and PRC2 complexes, leading to mislocalization of histone marks and aberrant Polycomb target gene expression.
Assuntos
Neoplasias do Endométrio , Sarcoma do Estroma Endometrial , Sarcoma , Cromatina , Proteínas de Ligação a DNA/metabolismo , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/metabolismo , Neoplasias do Endométrio/patologia , Feminino , Histonas/metabolismo , Humanos , Complexo Repressor Polycomb 2/genética , Complexo Repressor Polycomb 2/metabolismo , Proteínas do Grupo Polycomb/genética , Proteínas do Grupo Polycomb/metabolismo , Sarcoma/genética , Sarcoma do Estroma Endometrial/genética , Sarcoma do Estroma Endometrial/metabolismo , Sarcoma do Estroma Endometrial/patologia , Translocação Genética/genéticaRESUMO
We present two cases of malignant ossifying fibromyxoid tumor (OFMT) which eluded diagnosis due to compelling clinicopathologic mimicry, compounded by similarly elusive underlying molecular drivers. The first is of a clavicle mass in a 69 year-old female, which histologically showed an infiltrative nested and trabeculated proliferation of monomorphic cells giving rise to scattered spicules of immature woven bone. Excepting SATB2 positivity, the lesion showed an inconclusive immunoprofile which along with negative PHF1 FISH led to an initial diagnosis of high-grade osteosarcoma. Next generation sequencing (NGS) revealed a particularly rare CREBBP::BCORL1 fusion. The second illustrates the peculiar presentation of a dural-based mass in a 52 year-old female who presented with neurologic dyscrasias. Sections showed a sheeted monotonous proliferation of ovoid to spindle cells, but in contrast to Case #1, the tumor contained an exuberance of reticular osteoid and woven bone deposition mimicking malignant osteogenic differentiation. NGS showed a novel CREBZF::PHF1 fusion. Both tumors recurred locally less than 1 year post-operatively. As such we reiterate that careful morphologic examination is axiomatic to any diagnosis in our discipline, but this paradigm must shift to recognize that molecular diagnostics can provide closure where traditional tools have notable limitations.
Assuntos
Neoplasias Ósseas , Fibroma Ossificante , Fibroma , Osteossarcoma , Sarcoma , Neoplasias de Tecidos Moles , Feminino , Humanos , Idoso , Pessoa de Meia-Idade , Proteínas de Ligação a DNA , Fibroma Ossificante/diagnóstico , Fibroma Ossificante/genética , Fibroma Ossificante/patologia , Osteogênese , Proteínas do Grupo Polycomb , Recidiva Local de Neoplasia , Fibroma/patologia , Osteossarcoma/diagnóstico , Osteossarcoma/genética , Neoplasias Ósseas/diagnóstico , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Neoplasias de Tecidos Moles/patologia , Fatores de Transcrição de Zíper de Leucina BásicaRESUMO
Polycomb repressive complex 2 (PRC2) is central to polycomb repression as it trimethylates lysine 27 on histone H3 (H3K27me3). How PRC2 is recruited to its targets to deposit H3K27me3 remains an open question. Polycomb-like (PCL) proteins, a group of conserved PRC2 accessory proteins, can direct PRC2 to its targets. In this report, we demonstrate that a PCL protein named PHF1 forms phase-separated condensates at H3K27me3 loci that recruit PRC2. Combining cellular observation and biochemical reconstitution, we show that the N-terminal domains of PHF1 cooperatively mediate target recognition, the chromo-like domain recruits PRC2, and the intrinsically disordered region (IDR) drives phase separation. Moreover, we reveal that the condensates compartmentalize PRC2, DNA, and nucleosome arrays by phase separation. Luciferase reporter assays confirm that PHF1 phase separation promotes transcription repression, further supporting a role of the condensates in polycomb repression. Based on our findings, we propose that these condensates create favorable microenvironments at the target loci for PRC2 to function.
Assuntos
Histonas , Complexo Repressor Polycomb 2 , Complexo Repressor Polycomb 2/genética , Complexo Repressor Polycomb 2/química , Complexo Repressor Polycomb 2/metabolismo , Histonas/genética , Histonas/metabolismo , Proteínas de Ligação a DNA/metabolismo , Proteínas do Grupo Polycomb/genética , Proteínas do Grupo Polycomb/metabolismo , NucleossomosRESUMO
Endometrial stromal sarcomas (ESS) are morphologically and molecularly heterogeneous. We report novel gene fusions (EPC1::EED, EPC1::EZH2, ING3::PHF1) identified by targeted RNA sequencing in five cases. The ING3::PHF1-fusion positive ESS presented in a 58-year-old female as extrauterine mesocolonic, ovarian masses, and displayed large, monomorphic ovoid-to-epithelioid cells arranged in solid sheets. The patient remained alive with disease 13 months after surgery. The three ESS with EPC1::EED occurred in the uterine corpus in patients with a median age of 58 years (range 27-62 years). One tumor showed a uniform epithelioid nested morphology, while the other two were composed of monomorphic spindle cells in fascicles with elevated mitotic figures, focal tumor cell necrosis, and lymphovascular invasion. At a median follow-up of 20 months, two patients developed local recurrence, including one with concomitant distant metastasis, while one patient remained free of disease. All three patients were alive at the last follow-up. The EPC1::EZH2-fusion positive ESS presented in a 52-year-old female in the uterus, and displayed uniform spindled cells arranged in short fascicles, with focally elevated mitotic activity but without necrosis. The patient remained free of disease 3 months after surgery. All cases were diffusely positive for CD10; four diffusely express estrogen and progesterone receptors. Our study expands the molecular spectrum of EPC1 and PHF1-related gene fusions in ESS to include additional novel subunits of the PRC2 and/or NuA4/TIP60 complexes. These cases displayed a monomorphic epithelioid or spindled phenotype, spanning low-grade and high-grade cytomorphology, all expressing CD10 and commonly ER and PR, and are prone to local and/or distant spread.
Assuntos
Neoplasias do Endométrio , Sarcoma do Estroma Endometrial , Feminino , Humanos , Sarcoma do Estroma Endometrial/genética , Sarcoma do Estroma Endometrial/cirurgia , Sarcoma do Estroma Endometrial/patologia , Montagem e Desmontagem da Cromatina , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/cirurgia , Neoplasias do Endométrio/patologia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Fusão Gênica , Proteínas de Homeodomínio/genética , Proteínas Supressoras de Tumor/genéticaRESUMO
AIMS: Ossifying fibromyxoid tumor (OFMT) is a rare enigmatic tumor of uncertain differentiation that can be classified as typical, atypical, and malignant subtypes based on cellularity, nuclear grade, and mitotic activity. The majority of OFMTs, regardless of the risk of malignancy, harbor genetic translocations. We report two malignant OFMTs, including one with evidence of dedifferentiation, with novel genefusions. METHODS AND RESULTS: Case 1 was a 63-year-old male with a dedifferentiated OFMT arising in the right wrist, while case 2 was a 41-year-old male with a malignant OFMT presenting as a posterior mediastinal mass. Case 2 showed multifocal expression with EMA and synaptophysin, while desmin and S100 were absent in both tumors. NGS sequencing studies detected PHF1::FOXR1 and PHF1::FOXR2 gene fusions in cases 1 and 2, respectively. Despite aggressive regimens, both progressed with wide spread metastases resulting in death within six years of diagnosis. CONCLUSIONS: We expand the genetic spectrum of OFMTs with two novel gene fusions, PHF1::FOXR1 and PHF1::FOXR2. These cases confirm the previously reported tendencies for OFMTs with rare variant fusions to demonstrate malignant behavior, unusual morphology, and non-specific immunophenotype.
Assuntos
Fibroma Ossificante , Fibroma , Neoplasias de Tecidos Moles , Masculino , Humanos , Pessoa de Meia-Idade , Adulto , Fibroma Ossificante/patologia , Neoplasias de Tecidos Moles/patologia , Fibroma/patologia , Fusão Gênica , Proteínas de Ligação a DNA/genética , Proteínas do Grupo Polycomb/genética , Proteínas do Grupo Polycomb/metabolismo , Fatores de Transcrição Forkhead/genéticaRESUMO
Low-grade endometrial stromal sarcoma (ESS) is a hormone-responsive low-grade sarcoma typically occurring in the uterine corpus in women. Their genetic hallmarks are recurrent gene fusions involving JAZF1, partnering with either SUZ12 gene or less commonly with PHF1. Low-grade ESS-like sarcoma, or endometrioid stromal sarcoma, is exceptionally rare in males and has been reported to date only in two cases, one in the paratesticular area and the other of prostatic stromal origin. We report herein two new cases of low-grade ESS-like sarcoma in male patients, one presenting as a periprostatic/peri-rectal mass with a JAZF1-GLI3 fusion, while the other as a paratesticular mass with a JAZF1-PHF1 fusion. As the GLI3 fusion appeared novel, we searched the transcriptional signature of 35 low-grade ESS from our archives and found a similar JAZF1-GLI3 fusion in a low-grade ESS arising from the uterine corpus, supporting a common pathogenesis. Histopathologically, both cases demonstrate cellular, monotonous proliferation of ovoid to fusiform cells with a background of arteriolar vascular network. Immunohistochemically, the neoplastic cells express ER, PR, and CD10, similar to ESS. One case also expresses diffuse and strong AR. On follow-up, the patient with the periprostatic mass recurred 2 years after initial surgery with peritoneal "sarcomatosis." We describe the salient diagnostic morphologic, immunohistochemical, and molecular features and discuss the differential diagnosis and possible pathogenesis of this unusual entity.
Assuntos
Proteínas Correpressoras/genética , Proteínas de Ligação a DNA/genética , Neoplasias dos Genitais Masculinos , Proteínas de Fusão Oncogênica/genética , Neoplasias Pélvicas , Sarcoma , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Ossifying fibromyxoid tumor (OFMT) is a rare mesenchymal neoplasm of uncertain line of differentiation that can be subdivided into typical, atypical, and malignant tumors. Cytogenetically, OFMT is characterized by recurrent gene rearrangement involving PHF1 in up to 85% of cases. The most common PHF1 fusion partner is EP400, present in approximately half of cases. Most recently, a novel fusion of PHF1-TFE3 was identified in about 10% of PHF1-rearranged OFMTs. Herein, we report a unique case of PHF1-TFE3 fusion atypical OFMT with prominent collagenous rosettes. A 50-year-old male patient presented with a slowly growing, painless mass in the right foot for 4 years. Gross examination showed a 3.5-cm, subcutaneous well-circumscribed, lobulated mass. Microscopic examination revealed a well-demarcated but un-encapsulated tumor without a peripheral bony shell. The neoplasm was composed of mildly atypical spindle to ovoid cells with increased mitosis (2 mitoses per 10 high-power fields) arranged in a multinodular manner within a fibromyxoid stroma, which contained numerous small, irregular collagenous rosettes surrounded by radiating growth of tumor cells. The neoplastic cells were diffusely positive for TFE3 and CD10. RNA sequencing revealed an in-frame fusion between PHF1 exon 12 and TFE3 exon 7. Subsequent Fluorescence in-situ hybridization analyses demonstrated positive for rearrangements of both the PHF1 and TFE3 loci. The patient was free of disease at 63 months' follow-up. Our case exhibits atypical features and prominent collagenous rosettes, expanding the morphological spectrum of OFMT with PHF1-TFE3 fusion.
Assuntos
Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Proteínas de Ligação a DNA/genética , Fibroma Ossificante/genética , Fibroma/genética , Proteínas do Grupo Polycomb/genética , Fibroma/diagnóstico , Fibroma/patologia , Fibroma Ossificante/diagnóstico , Fibroma Ossificante/patologia , Rearranjo Gênico/genética , Humanos , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Proteínas de Fusão Oncogênica/genéticaRESUMO
Endometrial stromal nodule (ESN) and low-grade endometrial stromal sarcoma (LG-ESS) are rare uterine tumors known as endometrial stromal tumors (ESTs). In addition to their similarity in morphological features, recent studies have shown that these two tumors share common genetic alterations. In particular, JAZF1-SUZ12 fusion is found with high frequency in both ESN and LG-ESS. In LG-ESS, some minor fusions have also been described, which include rearrangements involving PHF1 and its partner genes, such as JAZF1, EPC1, MEAF6, BRD8, EPC2, and MBTD1. Because of the rarity of ESN, genetic alterations other than JAZF1 fusion have not been investigated in detail. In this study, we performed a next-generation sequencing-based analysis in a case of ESN with peripheral metaplastic bone formation and detected MEAF6-PHF1 fusion, which has been reported in a small subset of uterine LG-ESSs and soft tissue ossifying fibromyxoid tumors. The finding that MEAF6-PHF1 fusion is a background genetic abnormality detected both in ESN and LG-ESS, along with JAZF1-SUZ12, provides further support for the similarity and continuum between these two types of ESTs. Furthermore, the association between metaplastic bone formation and MEAF6-PHF1 fusion may not be limited to soft tissue tumors.
RESUMO
The classification of endometrial stromal sarcoma (ESS) has been refined and aided by the discovery of various recurrent gene translocations. Low-grade ESS (LG-ESS) is most commonly characterized by JAZF1-SUZ12 fusions followed by rearrangements involving PHD finger protein-1 (PHF1) and multiple fusion partners, including JAZF1, EPC1, EPC2, and MEAF6. In the present study, integrating anchored polymerase chain reaction and paired-end next-generation ribonucleic acid sequencing, we identified the presence of a novel malignant brain tumor domain-containing 1 (MBTD1)-PHF1 gene fusion in a case of LG-ESS. MBTD1 belongs to the Polycomb gene group, and its fusion with PHF1 is predicted to mediate tumorigenesis through aberrant transcriptional repression. Histology and immunohistochemical studies demonstrated conventional morphology for LG-ESS and clinical follow-up showed no progression of disease after 6 months. These findings help expand the current knowledge on the spectrum of gene rearrangements in the diagnosis of ESS.
Assuntos
Proteínas Cromossômicas não Histona/genética , Proteínas de Ligação a DNA/genética , Neoplasias do Endométrio/genética , Fusão Gênica , Proteínas do Grupo Polycomb/genética , Sarcoma do Estroma Endometrial/genética , Carcinogênese/genética , Neoplasias do Endométrio/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Pessoa de Meia-Idade , Sarcoma do Estroma Endometrial/patologiaRESUMO
Ossifying fibromyxoid tumor (OFMT) is a rare soft tissue neoplasm of uncertain differentiation and intermediate biologic potential. Up to 85% of OFMTs, including benign, atypical, and malignant forms, harbor fusion genes. Most commonly, the PHF1 gene localized to 6p21 is fused with EP400, but other fusion partners, such as MEAF6, EPC1, and JAZF1 have also been described. Herein, we present two rare cases of superficial OFMTs with ZC3H7B-BCOR and the very recently described PHF1-TFE3 fusions. The latter also exhibited moderate to strong diffuse immunoreactivity for TFE3. Reciprocally, this finding expands the entities with TFE3 rearrangements. Accumulation of additional data is necessary to determine if OFMTs harboring these rare fusions feature any reproducible clinicopathologic findings or carry prognostic and/or predictive implications.
Assuntos
Fibroma Ossificante/patologia , Fibroma/genética , Fibroma/patologia , Proteínas Proto-Oncogênicas/genética , Proteínas de Ligação a RNA/genética , Proteínas Repressoras/genética , Neoplasias de Tecidos Moles/patologia , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Proteínas de Ligação a DNA/genética , Feminino , Fibroma/diagnóstico , Fibroma/cirurgia , Fusão Gênica/genética , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/patologia , Proteínas do Grupo Polycomb/genética , Neoplasias de Tecidos Moles/cirurgia , Fatores de Transcrição/metabolismo , Resultado do TratamentoRESUMO
Ossifying fibromyxoid tumor (OFMT) is an uncommon mesenchymal neoplasm of uncertain differentiation and intermediate malignant potential. Recurrent PHF1 gene rearrangements are detected in up to 80% of OFMTs. We describe the clinicopathologic features of five OFMTs harboring a novel PHF1-TFE3 fusion. In two cases, RNA sequencing identified a fusion transcript composed of PHF1 exon 11 fused to TFE3 exon 3, whereas in a third case PHF1 exon 12 was fused to TFE3 exon 7. A FISH break-apart assay revealed rearrangements in both PHF1 and TFE3 genes in all cases. The cohort included three males and two females with a median age of 64 years. One OFMT originated in the scapula, while four occurred in the deep soft tissues. Two OFMTs had typical features, whereas three were classified as malignant. Despite uniform cytologic features and fibromyxoid stroma compatible with an OFMT diagnosis, none showed a peripheral shell of lamellar bone. S100 expression was focally present in only one case, while desmin was positive in three cases. All tumors showed strong nuclear immunopositivity for TFE3. All three malignant OFMTs developed metastases, either regionally or to the lung. One patient died of disease 1 year after diagnosis, while the remaining two are alive with disease. In summary, we report novel recurrent PHF1-TFE3 fusions in a subset of OFMTs with aggressive clinical behavior. The PHF1-TFE3 fusions resulted in consistent protein TFE3 overexpression which can be used as a reliable screening tool, adding OFMT as another tumor driven by TFE3 oncogenic activation pathway.
Assuntos
Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Biomarcadores Tumorais/genética , Proteínas de Ligação a DNA/genética , Fibroma Ossificante/genética , Fusão Oncogênica , Proteínas do Grupo Polycomb/genética , Neoplasias de Tecidos Moles/genética , Idoso , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Biomarcadores Tumorais/metabolismo , Proteínas de Ligação a DNA/metabolismo , Desmina/genética , Desmina/metabolismo , Feminino , Fibroma Ossificante/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Proteínas do Grupo Polycomb/metabolismo , Proteínas S100/genética , Proteínas S100/metabolismo , Neoplasias de Tecidos Moles/patologiaRESUMO
OBJECTIVE: To report the exceptional occurrence of ossifying fibromyxoid tumour (OFMT) as a primary bone lesion. OFMT is a rare soft tissue tumour of uncertain differentiation and variable malignant potential, that occurs in adults with a slight male predominance. It is typically located in the subcutis or in the skeletal muscles of the extremities, followed by trunk or head and neck. METHODS: Two cases of OFMT proven to arise from bone are presented. The first is a 65-year old female with a history of rib "osteosarcoma", presenting with an inferior lobe left lung mass. The second is a man with a lytic lesion of the 5th cervical vertebra that recurred shortly after resection. Following H&E and immunohistochemical examination, tumour samples were analysed by NGS and by break-apart FISH to detect rearrangement of the PHF1 and TFE3 genes. RESULTS: PHF1 gene-rearrangement was identified by FISH on both the primary and the metastatic lesion of first patient. NGS identified a PHF1(intron1) and EPC1 (exon 10) fusion transcript later confirmed by positive PHF1 rearrangement on FISH in the second case. CONCLUSIONS: The demonstration of PHF1 gene rearrangements represents a fundamental ancillary diagnostic test when presented with challenging examples of OFMT.
Assuntos
Neoplasias Ósseas , Proteínas de Ligação a DNA/genética , Fibroma Ossificante , Proteínas do Grupo Polycomb/genética , Adulto , Idoso , Biomarcadores Tumorais/análise , Neoplasias Ósseas/diagnóstico , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , DNA de Neoplasias/análise , Feminino , Fibroma Ossificante/diagnóstico , Fibroma Ossificante/genética , Fibroma Ossificante/patologia , Rearranjo Gênico , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Masculino , Recidiva Local de Neoplasia/patologia , Neoplasias de Tecidos Moles/diagnóstico , Neoplasias de Tecidos Moles/genética , Neoplasias de Tecidos Moles/patologia , Fatores de Transcrição/genéticaRESUMO
Tau pathology in Alzheimer's disease (AD) includes hyperphosphorylation and truncation of tau. Phosphorylation at S422 is found to suppress truncation of tau at D421 that leading to the generation of ΔTau. However, the interrelation between hyperphosphorylation and generation of ΔTau in AD remains elusive. In current study, staurosporine (Stau) induced ΔTau generation by caspases in SH-SY5Y cells with tau overexpression was found to be accompanied by a dramatic dephosphorylation at S422 and the epitope of the diagnostic antibody AT8 (S199â¯+â¯S202â¯+â¯T205), but a moderate dephosphorylation of PHF1 (S396â¯+â¯S404) epitope. Therefore, to explore the effect of AT8 epitope on tau truncation, the residues in AT8 epitope were mutated to produce "pseudo-phosphorylated" (AT8E) or "pseudo-unphosphorylated" (AT8A) tau constructs. With Stau treatment, the generation of ΔTau from tau-AT8E was significantly attenuated comparing with that from tau-AT8A, which was S422-independent in that addition of S422A mutation still preserved this effect. Interestingly, this modulatory effect was able to be reversed by addition of PHF1E mutation. Moreover, treating the crude tau extracts with recombinant caspase-3 in vitro, also showed that ΔTau level was suppressed by AT8E, and potentiated by AT8E + PHF1E. The results primarily revealed the modulating effects of phosphorylation on ΔTau generation which may have potential implications in tau pathological processes and therapeutic intervention.
Assuntos
Ácido Aspártico/metabolismo , Epitopos/metabolismo , Fosforilação/fisiologia , Proteínas tau/metabolismo , Doença de Alzheimer/metabolismo , Caspases/metabolismo , Linhagem Celular Tumoral , Humanos , Neurônios/metabolismoRESUMO
The Tudor domain comprises a family of motifs that mediate protein-protein interactions required for various DNA-templated biological processes. Emerging evidence demonstrates a versatility of the Tudor family domains by identifying their specific interactions to a wide variety of histone methylation marks. Here, we discuss novel functions of a number of Tudor-containing proteins [including Jumonji domain-containing 2A (JMJD2A), p53-binding protein 1 (53BP1), SAGA-associated factor 29 (SGF29), Spindlin1, ubiquitin-like with PHD and RING finger domains 1 (UHRF1), PHD finger protein 1 (PHF1), PHD finger protein 19 (PHF19), and SAWADEE homeodomain homolog 1 (SHH1)] in 'reading' unique methylation events on histones in order to facilitate DNA damage repair or regulate transcription. This review covers our recent understanding of the molecular bases for histone-Tudor interactions and their biological outcomes. As deregulation of Tudor-containing proteins is associated with certain human disorders, pharmacological targeting of Tudor interactions could provide new avenues for therapeutic intervention.
Assuntos
Metilação de DNA , Proteínas de Drosophila/metabolismo , Histonas/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Animais , Drosophila , Proteínas de Drosophila/química , Proteínas de Drosophila/genética , Proteínas de Membrana Transportadoras/química , Proteínas de Membrana Transportadoras/genética , Modelos MolecularesRESUMO
AIMS: Endometrial stromal sarcomas (ESSs) are divided into low-grade and high-grade subtypes, with the latter showing more aggressive clinical behaviour. Although histology and immunophenotype can aid in the diagnosis of these tumours, genetic studies can provide additional diagnostic insights, as low-grade ESSs frequently harbour fusions involving JAZF1/SUZ12 and/or JAZF1/PHF1, whereas high-grade ESSs are defined by YWHAE-NUTM2A/B fusions. The aim of this study was to evaluate the utility of a next-generation sequencing (NGS)-based assay in identifying ESS fusions in archival formalin-fixed paraffin-embedded tumour samples. METHODS AND RESULTS: We applied an NGS-based fusion transcript detection assay (Archer FusionPlex Sarcoma Panel) that targets YWHAE and JAZF1 fusions in a series of low-grade ESSs (n = 11) and high-grade ESSs (n = 5) that were previously confirmed to harbour genetic rearrangements by fluorescence in-situ hybridization (FISH) and/or reverse transcription polymerase chain reaction (RT-PCR) analyses. The fusion assay identified junctional fusion transcript sequences that corresponded to the known FISH/RT-PCR results in all cases. Four low-grade ESSs harboured JAZF1-PHF1 fusions with different junctional sequences, and all were correctly identified because of the open-ended nature of the assay design, using anchored multiplex polymerase chain reaction. Seven non-ESS sarcomas were also included as negative controls, and no strong ESS fusion candidates were identified in these cases. CONCLUSIONS: Our findings demonstrate good sensitivity and specificity of an NGS-based gene fusion assay in the detection of ESS fusion transcripts.
Assuntos
Neoplasias do Endométrio/diagnóstico , Tumores do Estroma Endometrial/diagnóstico , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Proteínas de Fusão Oncogênica/análise , Sarcoma do Estroma Endometrial/diagnóstico , Adulto , Idoso , Neoplasias do Endométrio/genética , Tumores do Estroma Endometrial/genética , Feminino , Humanos , Pessoa de Meia-Idade , Patologia Molecular , Sarcoma do Estroma Endometrial/genética , Sensibilidade e Especificidade , Adulto JovemRESUMO
Ossifying fibromyxoid tumor (OFMT) is a soft tissue neoplasm of uncertain differentiation and intermediate (rarely metastasizing) biologic potential, with typical morphologic features, of an encapsulated, lobulated tumor comprising uniform polygonal cells within fibromyxoid stroma, which is surrounded by or contains metaplastic bone, classically as a peripheral rim of lamellar bone. Ossifying fibromyxoid tumor can arise at almost any site, although most frequently occurs within the extremities and trunk. Although most behave in a benign fashion, tumors can rarely show atypical or malignant features. It is now established that OFMTs represent translocation-associated tumors, with up to 85% associated with recurrent gene rearrangements, mostly involving the PHF1 gene (including in typical, atypical, and malignant neoplasms), with EP400-PHF1 in approximately 40% of tumors, and ZC3H7B-BCOR, MEAF6-PHF1, and EPC1-PHF1 fusions also described. Correct diagnosis is clinically important to ensure correct treatment and prognostication, both to avoid overdiagnosing OFMT as a malignant neoplasm such as osteosarcoma and also because of the propensity for aggressive behavior in a small number of OFMT. We review OFMT, with emphasis on the morphologic spectrum, recent molecular genetic findings, and the differential diagnosis.
Assuntos
Fibroma/diagnóstico , Ossificação Heterotópica/diagnóstico , Neoplasias de Tecidos Moles/diagnóstico , Diagnóstico Diferencial , Fibroma/genética , Humanos , Ossificação Heterotópica/genética , Neoplasias de Tecidos Moles/genéticaRESUMO
INTRODUCTION: Ossifying fibromyxoid tumor (OFMT) is rare and may present diagnostic difficulty. We describe 26 subcutaneous examples of OFMT emphasizing differential diagnosis and prognostic features. METHODS: Histopathology and follow-up data from archival/consultation cases were reviewed. Prognostic features were assessed according to proposed criteria. RESULTS: Patients (16 female, 10 male) ranged from 26 to 88 years (median 54). The tumors (median 2.3 cm, range 0.8-8.5) involved lower limb (11), trunk (7), head/neck (4), or arm (4). All showed combinations of corded, nested and trabecular patterns in a fibromyxoid stroma. Out of 26 cases 13 had peripheral ossification. Sixteen of 22 cases showed S100 protein expression. Nuclear grade was low (14); intermediate (8) and high (4) while cellularity was low (14); moderate (7) and high (5), with overall good interobserver agreement. Median mitotic rate was 3/50HPF (0-61). Five met criteria for malignant OFMT showing high nuclear grade or high cellularity and mitotic rate >2/50HPF or both. Thirteen OFMTs were atypical. Follow-up (16/26, median 45.5 months, range 8-108) showed that patients with typical OFMT (3) and atypical OFMT (9) remained disease-free. Three malignant examples of OFMT recurred and one metastasized to the lung. No deaths were recorded. CONCLUSIONS: Our results validate proposed prognostic classification of OFMT. Dermatopathologists should be aware of this unusual superficial tumor given its potentially aggressive behavior.
Assuntos
Neoplasias Ósseas/patologia , Fibroma Ossificante/patologia , Neoplasias de Tecidos Moles/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Ósseas/diagnóstico , Neoplasias Ósseas/metabolismo , Proteínas de Ligação a DNA/metabolismo , Diagnóstico Diferencial , Feminino , Fibroma Ossificante/diagnóstico , Fibroma Ossificante/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Variações Dependentes do Observador , Proteínas do Grupo Polycomb/metabolismo , Prognóstico , Doenças Raras , Proteínas S100/metabolismo , Neoplasias de Tecidos Moles/diagnóstico , Neoplasias de Tecidos Moles/metabolismo , Tela Subcutânea/metabolismo , Tela Subcutânea/patologiaRESUMO
Tau phosphorylated at the PHF-1 epitope (S396/S404) is likely involved in the pathogenesis of Alzheimer's disease (AD). However, the molecular mechanisms by which tau phosphorylated at these sites negatively impacts neuronal functions are still under scrutiny. Previously, we showed that expression of tau truncated at D421 enhances mitochondrial dysfunction induced by Aß in cortical neurons. To extend these findings, we expressed tau pseudo-phosphorylated at S396/404 (T42EC) in mature and young cortical neurons and evaluated different aspects of mitochondrial function in response to Aß. Expression of T42EC did not induce significant changes in mitochondrial morphology, mitochondrial length, or mitochondrial transport, compared to GFP and full-length tau. However, T42EC expression enhanced Aß-induced mitochondrial membrane potential loss and increased superoxide levels compared to what was observed in mature neurons expressing full-length tau. The same effect was observed in mature neurons that expressed both pseudo-phosphorylated and truncated tau when they were treated with Aß. Interestingly, the mitochondrial failure induced by Aß in mature neurons that expressed T42EC, was not observed in young neurons expressing T42EC. These novel findings suggest that phosphorylated tau (PHF-1 epitope) enhances Aß-induced mitochondrial injury, which contributes to neuronal dysfunction and to the pathogenesis of AD.
Assuntos
Doenças Mitocondriais/induzido quimicamente , Neurônios/efeitos dos fármacos , Proteínas tau/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animais , Células Cultivadas , Córtex Cerebral/citologia , Embrião de Mamíferos , Proteínas de Fluorescência Verde/genética , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Doenças Mitocondriais/metabolismo , Mutação/genética , Fosforilação/genética , Presenilina-1/genética , Ratos , Superóxidos/metabolismo , TransfecçãoRESUMO
Ossifying fibromyxoid tumor (OFMT) is a rare soft tissue neoplasm of uncertain histogenesis, primarily arising in subcutaneous tissues of the extremities, head and neck, or trunk. Most cases present as well-circumscribed masses with a characteristic morphologic appearance, comprising cytologically bland ovoid cells with fibromyxoid stroma, a peripheral rim of metaplastic bone, and lobulated architecture. Nevertheless, tumors displaying unusual morphologic characteristics pose significant diagnostic challenges, requiring the detection of a pathogenic fusion for a definitive diagnosis. The majority of OFMTs exhibits PHF1 gene rearrangements. Herein, we present six cases of molecularly confirmed OFMTs with uncommon histomorphologic features, including the absence of myxoid stroma, extensive chondroid differentiation, prominent clear cell morphology, collagen entrapment, interdigitating fibrocollagenous and fibromyxoid stromal elements, and conspicuous red blood cell extravasation. One case harbored a novel fusion (EPC1::SUZ12). This study emphasizes the broad range of morphologic manifestations that can be encountered in OFMT and the crucial role of molecular testing in establishing a conclusive diagnosis in such cases.
RESUMO
OBJECTIVES: Ossifying fibromyxoid tumor (OFMT) is a rare soft tissue neoplasm of uncertain histogenesis. Most OFMTs have benign behavior, and many harbor gene fusions involving the PHD finger protein 1 (PHF1), such as EP400::PHF1, MEAF6::PHF1, EPC1::PHF1, and PHF1::TFE3. The PHF1::TFE3 fusion is unique because PHF1 is at 5' instead of residing at 3' in the other fusions. In this study, we describe 2 cases of OFMT harboring PHF1::TFE3 fusions and review 13 published cases. METHODS: Two cases of PHF1::TFE3-positive OFMT were investigated using RNA Next-Generation Sequencing and immunohistochemistry. RESULTS: Most (12/15) of the PHF1::TFE3 OFMTs we studied were located at proximal and distal extremities, with a multinodular growth pattern. Only 1 case (1/10) had a shell of bone at the periphery. Areas morphologically similar to sclerosing epithelioid fibrosarcoma or low-grade fibromyxoid sarcoma were found in 8 of 12 (66.7%) cases. Eleven cases (11/15 [73.3%]) were regarded as malignant based on more than 2/50 high-power field mitotic figures, increased cellularity, or the presence of necrosis. Among the 9 cases with follow-up data, 2 patients died of disease (with metastases), 1 patient is alive with metastases, and 1 patient had multiple local recurrences. CONCLUSIONS: Because PHF1 is located at 3' in all the PHF1 fusions in OFMTs except PHF1::TFE3, the different driver molecular alterations suggest that OFMTs with 3'-PHF1 fusions and OFMTs with PHF1::TFE3 are different tumors. Immunohistochemistry confirmed TFE3 expression in all PHF1::TFE3 OFMTs. Because PHF1::TFE3-positive OFMTs have increased mitotic figures and tumor cellularity, with a high rate of metastasis, using the name PHF1::TFE3 positive fibromyxoid sarcoma may be appropriate.