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Recent studies have documented frequent evolution of clones carrying common cancer mutations in apparently normal tissues, which are implicated in cancer development1-3. However, our knowledge is still missing with regard to what additional driver events take place in what order, before one or more of these clones in normal tissues ultimately evolve to cancer. Here, using phylogenetic analyses of multiple microdissected samples from both cancer and non-cancer lesions, we show unique evolutionary histories of breast cancers harbouring der(1;16), a common driver alteration found in roughly 20% of breast cancers. The approximate timing of early evolutionary events was estimated from the mutation rate measured in normal epithelial cells. In der(1;16)(+) cancers, the derivative chromosome was acquired from early puberty to late adolescence, followed by the emergence of a common ancestor by the patient's early 30s, from which both cancer and non-cancer clones evolved. Replacing the pre-existing mammary epithelium in the following years, these clones occupied a large area within the premenopausal breast tissues by the time of cancer diagnosis. Evolution of multiple independent cancer founders from the non-cancer ancestors was common, contributing to intratumour heterogeneity. The number of driver events did not correlate with histology, suggesting the role of local microenvironments and/or epigenetic driver events. A similar evolutionary pattern was also observed in another case evolving from an AKT1-mutated founder. Taken together, our findings provide new insight into how breast cancer evolves.
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Neoplasias da Mama , Linhagem da Célula , Células Clonais , Evolução Molecular , Mutagênese , Mutação , Adolescente , Adulto , Feminino , Humanos , Adulto Jovem , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem da Célula/genética , Células Clonais/metabolismo , Células Clonais/patologia , Epigênese Genética , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Epitélio/patologia , Microdissecção , Taxa de Mutação , Pré-Menopausa , Microambiente TumoralRESUMO
INTRODUCTION: Gastric cancer with fusion genes involving the Rho GTPase-activating protein domain (RhoGAP-GC) is mainly included in the genomically stable type of The Cancer Genome Atlas classification. Clinical implications and histological characteristics of RhoGAP-GC in the early phase remain unclear. METHODS: We analyzed 878 consecutive pT1b GCs for RhoGAP and its partner genes using fluorescence in situ hybridization assay. RESULTS: RhoGAP fusion was detected in 57 (6.5%) GCs. Univariate analysis revealed that female sex, middle-lower third tumor location, advanced macroscopic type, tumor diameter > 2 cm, pT1b2, lymphatic invasion, venous invasion, negative EBER-ISH, and RhoGAP fusion were significantly associated with lymph node metastasis (LNM). Multivariate analysis presented RhoGAP fusion, lymphatic invasion, tumor diameter > 2 cm, advanced macroscopic type, venous invasion, and middle-lower third tumor location as independent risk factors for LNM. Notably, RhoGAP fusion had the highest odds ratio (3.92) for LNM among analyzed parameters (95% CI 2.12-7.27; p < 0.001). Compared to non-RhoGAP-GCs, RhoGAP-GCs were significantly frequent in younger females and showed the highest incidence of lymphatic invasion (56.2%) and LNM (49.1%) (p < 0.001). Histologically, microtubular architecture with pseudo-trabecular interconnection and small aggregations of tumor cells with a varied amount of cytoplasmic mucin, named "microtubular-mucocellular (MTMC) histology," was found in 93.0% (53 of 57) of RhoGAP-GCs in the intramucosal area. MTMC histology showed high sensitivity and negative predictive value (93.0% and 99.4%, respectively) for RhoGAP fusion, albeit positive predictive value is low (34.9%). CONCLUSION: RhoGAP-GC is linked to a characteristic MTMC histology and a high incidence of LNM.
Assuntos
Proteínas Ativadoras de GTPase , Metástase Linfática , Neoplasias Gástricas , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Biomarcadores Tumorais/genética , Proteínas Ativadoras de GTPase/genética , Metástase Linfática/patologia , Metástase Linfática/genética , Proteínas de Fusão Oncogênica/genética , Prognóstico , Neoplasias Gástricas/patologia , Neoplasias Gástricas/genéticaRESUMO
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematological malignancy derived from the precursors of plasmacytoid dendritic cells. Diagnostic criteria for BPDCN have not been fully established. BPDCN is often diagnosed without other BPDCN markers than the 3 conventional markers (CD4, CD56, and CD123) in practice and case reports, although acute myeloid leukemia/myeloid sarcoma (AML/MS), which is always considered in the differential diagnosis of BPDCN, can express them. We reviewed published case reports on BPDCN and found that the diagnosis was made without any other BPDCN markers than the conventional markers in two-thirds of the cases. Next, 4 representative existing diagnostic criteria were applied to 284 cases of our cohort of BPDCN and mimics. The results differed in 20% (56/284) of the cases. The criterion based on the 3 conventional markers alone had a low concordance rate (80%-82%) with the other 3 criteria, which were almost concordant with each other. However, newly found minor limitations in these criteria prompted us to devise new diagnostic criterion for BPDCN composed of TCF4, CD123, TCL1, and lysozyme. We also revealed that CD123-positive AML/MS patients had a significantly poorer outcome than those with BPDCN and that 12% (24/205) of the cases were non-BPDCN even if all 3 conventional markers were positive, thus clarifying the risk of diagnosing BPDCN without more specific markers. In addition, histopathological features, such as the reticular pattern, which is not seen in BPDCN and suggests AML/MS, were also identified.
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AIMS: Angiofibroma of soft tissue (AFST) is a benign tumour characterised by prominent arborizing blood vessels throughout the lesion. Approximately two-thirds of AFST cases were reported to have AHRR::NCOA2 fusion, and only two cases have been reported to have other gene fusions: GTF2I::NCOA2 or GAB1::ABL1. Although AFST is included in fibroblastic and myofibroblastic tumours in the World Health Organization's 2020 classification, histiocytic markers, especially CD163, have been reported to be positive in almost all examined cases, and it still remains the possibility of a fibrohistiocytic nature of the tumour. Therefore, we aimed to clarify the genetic and pathological spectrum of AFST and identify whether histiocytic marker-positive cells were true neoplastic cells. METHODS AND RESULTS: We evaluated 12 AFST cases, which included 10 cases with AHRR::NCOA2 and two with AHRR::NCOA3 fusions. Pathologically, nuclear palisading, which has not been reported in AFST, was detected in two cases. Furthermore, one tumour resected by additional wide resection revealed severe infiltrative growth. Immunohistochemical analysis indicated varying levels of desmin-positive cells in nine cases, whereas CD163- and CD68-positive cells were diffusely distributed in all 12 cases. We also performed double immunofluorescence staining and immunofluorescence in situ hybridisation in four resected cases with >10% desmin-positive tumour cells. The results suggested that the CD163-positive cells differed from desmin-positive cells with AHRR::NCOA2 fusion in all four cases. CONCLUSION: Our findings suggested that AHRR::NCOA3 could be the second most frequent fusion gene, and histiocytic marker-positive cells are not genuine neoplastic cells in AFST.
Assuntos
Angiofibroma , Neoplasias de Cabeça e Pescoço , Neoplasias de Tecidos Moles , Humanos , Angiofibroma/genética , Angiofibroma/patologia , Desmina , Neoplasias de Tecidos Moles/genética , Neoplasias de Tecidos Moles/patologia , Hibridização In Situ , Fusão Gênica , Coativador 3 de Receptor Nuclear/genética , Proteínas Repressoras/genética , Fatores de Transcrição Hélice-Alça-Hélice BásicosRESUMO
Myxoid liposarcoma (MLPS) is genetically characterized by FUS-DDIT3 or EWSR1-DDIT3 gene fusion and the high frequency of hotspot mutations (C228T or C250T) in the promoter region of telomerase reverse transcriptase (TERT) that encodes the TERT protein. The latter leads to telomerase reactivation, a mechanism of telomere maintenance. Although the TERT promoter hotspot mutation is a poor prognostic factor in various tumors, its effect on MLPS has not been reported in detail. In the present study, we examined the clinicopathological characteristics, prognosis, and telomere maintenance mechanisms in 83 primary tumor samples of MLPS, which were resected surgically at the Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan, from 2008 to 2020. TERT promoter hotspot mutations were observed in 77% (63/82) cases, and alternative lengthening of telomeres (ALT) was absent in all cases. Among the cases without TERT promoter hotspot mutations, TERT rearrangements, and minor point mutations in the TERT promoter region were found in 3 and 2 cases, respectively. TERT mRNA expression was observed consistently even in patients for whom no genomic TERT aberrations were detected, and the presence of TERT promoter hotspot mutation did not correlate significantly with either overall and metastasis-free survival (P = .56, P = .83, respectively) or clinicopathological features. Therefore, patients with MLPS characteristically shows TERT expression and a high prevalence of TERT aberrations. Our findings suggest that TERT aberration is not prognostic factor, but might occur at an early stage and play a key role in tumorigenesis.
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Lipossarcoma Mixoide/genética , Telomerase/genética , Adulto , Idoso , Carcinogênese/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Prognóstico , Regiões Promotoras Genéticas , RNA Mensageiro/genética , Homeostase do Telômero/genéticaRESUMO
The rearrangement of anaplastic lymphoma kinase (ALK) occurs in 3%-5% of patients with non-small cell lung cancer (NSCLC) and confers sensitivity to ALK-tyrosine kinase inhibitors (TKIs). For the treatment of patients with ALK-rearranged NSCLC, various additional ALK-TKIs have been developed. Ceritinib is a second-generation ALK-TKI and has shown great efficacy in the treatment of patients with both newly diagnosed and crizotinib (a first-generation ALK-TKI)-refractory ALK-rearranged NSCLC. However, tumors can also develop ceritinib resistance. This may result from secondary ALK mutations, but other mechanisms responsible for this have not been fully elucidated. In this study, we explored the mechanisms of ceritinib resistance by establishing ceritinib-resistant, echinoderm microtubule-associated protein-like 4 (EML4)-ALK-positive H3122 cells and ceritinib-resistant patient-derived cells. We identified a mechanism of ceritinib resistance induced by bypass signals that is mediated by the overexpression and activation of fibroblast growth factor receptor 3 (FGFR3). FGFR3 knockdown by small hairpin RNA or treatment with FGFR inhibitors was found to resensitize the resistant cells to ceritinib in vitro and in vivo. FGFR ligands from either human serum or fetal bovine serum were able to activate FGFR3 and induce ceritinib resistance. A detailed analysis of ceritinib-resistant patient-derived specimens confirmed that tyrosine-protein kinase Met (cMET) amplification induces ceritinib resistance. Amplified cMET counteractivated EGFR and/or Her3 and induced ceritinib resistance. These results reveal multiple ceritinib resistance mechanisms and suggest that ceritinib resistance might be overcome by identifying precise resistance mechanisms.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos , Humanos , Quinase do Linfoma Anaplásico/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Mutação , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genéticaRESUMO
The recurrence risk of estrogen receptor (ER)-positive breast cancer remains high for a long period of time, unlike other types of cancer. Late recurrence reflects the ability of cancer cells to remain dormant through various events, including cancer stemness acquisition, but the detailed mechanism is unknown. ESR1 locus enhancing and activating noncoding RNAs (ELEANORS) are a cluster of nuclear noncoding RNAs originally identified in a recurrent breast cancer cell model. Although their functions as chromatin regulators in vitro are well characterized, their roles in vivo remain elusive. In this study, we evaluated the clinicopathologic features of ELEANORS, using primary and corresponding metastatic breast cancer tissues. The ELEANOR expression was restricted to ER-positive cases and well-correlated with the ER and progesterone receptor expression levels, especially at the metastatic sites. ELEANORS were detected in both primary and metastatic tumors (32% and 29%, respectively), and frequently in postmenopausal cases. Interestingly, after surgery, patients with ELEANOR-positive primary tumors showed increased relapse rates after, but not within, 5 years. Multivariate analysis showed that ELEANORS are an independent recurrence risk factor. Consistently, analyses with cell lines, mouse xenografts, and patient tissues revealed that ELEANORS upregulate a breast cancer stemness gene, CD44, and maintain the cancer stem cell population, which could facilitate tumor dormancy. Our findings highlight a new role of nuclear long noncoding RNAs and their clinical potential as predictive biomarkers and therapeutic targets for late recurrence of ER-positive breast cancer.
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Neoplasias da Mama , Receptores de Estrogênio , Animais , Neoplasias da Mama/patologia , Feminino , Humanos , Camundongos , Recidiva Local de Neoplasia/patologia , Células-Tronco Neoplásicas/metabolismo , RNA não Traduzido/genética , Receptores de Estrogênio/genética , Receptores de Estrogênio/metabolismoRESUMO
Histiocytes and dendritic cells may display cytological atypia and an aberrant immunophenotype even in reactive processes. Herein, we describe two cases of "Hodgkinoid histiocytosis" that show distinctive clinicopathological features, mimicking morphologically classic Hodgkin lymphoma (CHL), but suggesting reactive histiocytic/dendritic cell proliferation in lymph nodes. Both the patients presented with peripheral lymphadenopathy and blood eosinophilia with skin manifestations. Lymph node biopsy revealed scattered large histiocytes resembling Hodgkin cells with a round or stellate shape, abundant cytoplasm, and distinct nucleoli admixed in a predominant inflammatory background. The Hodgkinoid histiocytes occasionally showed emperipolesis. They expressed CD30, S100, and PD-L1 proteins but lacked PAX5 and CD1a expressions, Epstein-Barr association, BRAF V600E mutation, and PD-L1 gene amplification. Neither of the patients showed overt progression to malignant haematopoietic neoplasms during the disease course. An identical case series of four patients has been reported to date. Both these series highlight the potential of being interpreted as CHL due to the presence of Hodgkinoid histiocytes with CD30 positivity.
Assuntos
Eosinofilia , Histiocitose , Doença de Hodgkin , Antígeno B7-H1 , Eosinofilia/complicações , Eosinofilia/patologia , Histiócitos/patologia , Histiocitose/complicações , Histiocitose/patologia , Doença de Hodgkin/diagnóstico , Doença de Hodgkin/patologia , Humanos , Antígeno Ki-1 , Proteínas S100RESUMO
Serum prostate-specific antigen (PSA) test is the current gold standard for screening and diagnosis of prostate cancer (PCa), while overdiagnosis and overtreatment are social problems. In order to improve the specificity and exclude a false positive diagnosis in PSA test, PCa-specific glycosylation subtypes of PSA were explored using in-depth quantitative profiling of PSA glycoforms based on mass spectrometric oxonium ion monitoring technology. As a result of analysis using sera from 15 PCa or 15 benign prostate hyperplasia (BPH) patients whose PSA levels were in the "gray zone" (4.0-10.0 ng/mL), 52 glycan structures on PSA were quantitatively observed. We found that abundance of multisialylated LacdiNAc (GalNAcß1-4GlcNAc) structures were significantly upregulated in the PCa group compared to the BPH group. A couple of those glycoforms were then extracted and subjected to establish a novel PCa-specific diagnosis model (PSA G-index). When the diagnostic power was assessed using an independent validation sample set (15 PCa and 15 BPH patients in the PSA gray zone), an AUC of PSA G-index was 1.00, while that of total PSA or PSA f/T ratio was 0.50 or 0.60, respectively. Moreover, both PSA glycoforms showed significant correlation with Gleason scores. Lectin histochemical staining analysis also showed that PCa cells overexpressed glycoproteins containing LacdiNAc and sialic acids moieties. Thus, PSA G-index could serve as not only an effective secondary screening method to exclude false positive diagnosis in PSA screening, but also a potential grading biomarker for PCa.
Assuntos
Biomarcadores Tumorais/análise , Calicreínas/sangue , Calicreínas/química , Polissacarídeos/sangue , Antígeno Prostático Específico/sangue , Antígeno Prostático Específico/química , Neoplasias da Próstata/diagnóstico , Sialoglicoproteínas/sangue , Idoso , Algoritmos , Biomarcadores Tumorais/química , Humanos , Lactose/análogos & derivados , Lactose/química , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Polissacarídeos/química , Próstata/patologia , Neoplasias da Próstata/patologia , Curva ROC , Ácidos Siálicos/química , Sialoglicoproteínas/químicaRESUMO
Overexpression of the BCL2 is associated with a poor prognosis in diffuse large B-cell lymphoma (DLBCL). The assessment of MYC immunohistochemistry (IHC) is becoming optimized, whereas the criteria for BCL2 positivity are highly variable. Furthermore, data on the frequency and prognostic value of BCL2 positivity are conflicting. We aimed to evaluate BCL2 expression by IHC and assess the prognostic significance of the histopathologically scored BCL2 expression in 456 patients with DLBCL uniformly treated with standard immunochemotherapy (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone, R-CHOP). We initially designed 4-grade BCL2 scoring criteria, from 0 to 3+, and found that â¼40% of DLBCL showed strong BCL2 expression (score 3+). The scores from the pathologist's visual estimation were confirmed to be reliable using a digital image analysis. A retrospective survival analysis revealed that BCL2 score 3+ was a significant prognostic factor independent of the international prognostic index (IPI), the IHC-determined cell of origin, and the MYC protein/rearrangement status in a training set (n = 218). The adverse prognostic impact of BCL2 score 3+ was confirmed in a validation set (n = 238). We also developed a prognostic model consisting of 3 groups with a combined BCL2 score and MYC protein/rearrangement status. Patients with BCL2 score 3+ showed a higher treatment failure rate; therefore, alternative therapeutic strategies should be considered for these patients. A highly selective BCL2 inhibitor, venetoclax, was recently introduced as breakthrough therapy. Our BCL2 scoring system could readily be used by pathologists to evaluate patients with DLBCL who might benefit from BCL2-targeted therapies.
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Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Biomarcadores Tumorais , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Linfoma Difuso de Grandes Células B , Proteínas Proto-Oncogênicas c-bcl-2 , Idoso , Anticorpos Monoclonais Murinos/administração & dosagem , Biomarcadores Tumorais/biossíntese , Biomarcadores Tumorais/genética , Ciclofosfamida/administração & dosagem , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Feminino , Rearranjo Gênico , Humanos , Imuno-Histoquímica , Linfoma Difuso de Grandes Células B/sangue , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Estudos Retrospectivos , Rituximab , Taxa de Sobrevida , Vincristina/administração & dosagemAssuntos
Receptor IGF Tipo 1 , Trombospondina 1 , Humanos , Trombospondina 1/genética , Trombospondina 1/metabolismo , Receptor IGF Tipo 1/metabolismo , Receptor IGF Tipo 1/genética , Masculino , Feminino , Proteínas de Fusão Oncogênica/genética , Neoplasias de Tecidos Moles/patologia , Neoplasias de Tecidos Moles/genéticaRESUMO
A 35-year-old Japanese man who had experienced hoarseness for 10 years presented with a vocal cord lesion. A gross examination revealed a left vocal cord polyp occupying two-thirds of the vocal space. The endoscopically resected lesion contained scattered atypical fibroblastic, stellate, or ganglion-like cells with mucoid stroma. Vacuolated cells were also seen. Lymphoplasmacytic infiltrate was largely undetectable. A vocal cord polyp was first suspected, but well-differentiated liposarcoma and inflammatory myofibroblastic tumor (IMT) were included in the differential diagnoses. The tumor cells were positive for anaplastic lymphoma kinase (ALK), calponin, and vimentin, and negative for other smooth muscle markers by immunohistochemistry. Structures resembling myofibroblasts were not observed by electron microscopy, which confirmed abundant rough endoplasmic reticulum in the tumor cells and accumulated lipid droplets in some tumor cells. ALK gene rearrangement was detected by fluorescence in situ hybridization, and TIMP3-ALK fusion was confirmed by 5' rapid ampliï¬cation of cDNA ends. We diagnosed the lesion as an IMT, and an ALK-rearranged stellate cell tumor may be postulated. This is the first report of a fusion partner gene of ALK in a case of laryngeal IMT.
Assuntos
Quinase do Linfoma Anaplásico/metabolismo , Granuloma de Células Plasmáticas/patologia , Miofibroblastos/patologia , Inibidor Tecidual de Metaloproteinase-3/metabolismo , Adulto , Biomarcadores Tumorais/genética , Granuloma de Células Plasmáticas/diagnóstico , Humanos , Masculino , Receptores Proteína Tirosina Quinases/genética , Prega Vocal/metabolismoRESUMO
MYB-NFIB and MYBL1-NFIB have been reported in ~60% of adenoid cystic carcinoma cases, but driver alterations in the remaining ~40% of adenoid cystic carcinoma remain unclear. We examined 100 adenoid cystic carcinoma cases for MYB and MYBL1 locus rearrangements by fluorescence in situ hybridization (FISH) with originally designed probe sets using formalin-fixed paraffin-embedded materials. Approximately one-third of samples were also analyzed by fusion transcript-specific RT-PCR and capture RNA sequencing. In the 27 cases with frozen materials, MYB-NFIB and MYBL1-NFIB fusion transcripts were detected in 9 (33%) and 6 cases (22%) by RT-PCR, respectively. Meanwhile, high expression of MYB (18 cases, 67%) or MYBL1 (9 cases, 33%) was detected in all 27 cases in a mutually exclusive manner, regardless of its form (full-length, truncation, or fusion transcript). Interestingly, genomic rearrangements around the corresponding highly-expressed gene were observed in all 27 cases by FISH, suggesting a causative relationship between genomic rearrangements and gene expression. Among the 100 cases, including additional 73 cases, 97 harbored genomic rearrangements in the MYB (73 cases) or MYBL1 locus (24 cases) including 10 cases with atypical FISH patterns undetectable through ordinary split FISH approaches: breakpoints far distant from MYB (5 cases) and a small NFIB locus insertion into the MYB (3 cases) or MYBL1 locus (2 cases). In clinicopathological analyses, histological grade, primary tumor size, and lymph node metastasis were identified as prognostic factors, whereas MYB/MYBL1 rearrangements were not, but were associated with histological grade. In the present study, MYB or MYBL1 locus rearrangement was detected in nearly all adenoid cystic carcinoma cases, and therefore it would be a good diagnostic marker for adenoid cystic carcinoma. However, fusion transcript-specific RT-PCR for MYB-NFIB and MYBL1-NFIB and ordinary split FISH assays for MYB and MYBL1 were less sensitive, and thus detection methods should be judiciously designed because of the diversity of rearrangement modes in adenoid cystic carcinoma.
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Carcinoma Adenoide Cístico/genética , Rearranjo Gênico , Proteínas Proto-Oncogênicas c-myb/genética , Proteínas Proto-Oncogênicas/genética , Neoplasias das Glândulas Salivares/genética , Transativadores/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Adenoide Cístico/patologia , Feminino , Humanos , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Proteínas de Fusão Oncogênica , Neoplasias das Glândulas Salivares/patologia , Adulto JovemRESUMO
Hyalinizing clear cell carcinoma of the bronchial glands is a very rare tumor. Since only five reports describing six tumors have been published to date, only a little is known about specific histologic findings and clinical features. Because of its rarity, hyalinizing clear cell carcinoma has not been described in the latest WHO classification of pulmonary tumors yet. Here we present three cases of bronchial hyalinizing clear cell carcinomas, confirmed by both fluorescence in situ hybridization (FISH) and RT-PCR, focusing on histologic and immunohistochemical characteristics in a comparison with three cases of salivary gland origin. In addition, we compared immunohistochemical features with bronchial mucoepidermoid carcinoma, a lesion that needs to be taken into account in differential diagnosis of hyalinizing clear cell carcinoma. All our bronchial hyalinizing clear cell carcinoma cases were surgically resected. Histologically, tumor cells showed clear to eosinophilic cytoplasm with hyalinizing stroma in various proportions, resembling those of salivary gland origin. Immunohistochemically, tumor cells were positive for CK7, CK5/6, p40, p63, and ATF1, while they were negative for TTF1, Napsin A, HMB45, and SOX10. The CK5/6 staining pattern varied in mucoepidermoid carcinomas, while that of hyalinizing clear cell carcinoma was uniformly positive. FISH revealed EWSR1-ATF1 fusion, and RT-PCR with sequencing confirmed specificity of the chimeric gene for hyalinizing clear cell carcinoma. Clinically, bronchial hyalinizing clear cell carcinoma was characterized by occurrence in the fourth to sixth decades, no link with smoking history, and a predilection for the right lung, in line with previous reports. In summary, our study confirmed that the bronchial hyalinizing clear cell carcinoma is a histologically and genetically identical tumor to that of salivary gland origin, and that gene rearrangement analysis can play a critical role in distinction from mucoepidermoid carcinoma.
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Adenocarcinoma de Células Claras/patologia , Neoplasias Brônquicas/patologia , Carcinoma Mucoepidermoide/patologia , Neoplasias das Glândulas Salivares/patologia , Adenocarcinoma de Células Claras/metabolismo , Adulto , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Neoplasias Brônquicas/metabolismo , Carcinoma Mucoepidermoide/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Neoplasias das Glândulas Salivares/metabolismoRESUMO
Extranodal natural killer (NK)/T-cell lymphoma, nasal type (ENKTL) is an extranodal aggressive T or NK-cell lymphoma that is characteristically associated with Epstein-Barr virus (EBV) infection and cytotoxic tissue-destructive features. Although ENKTL is described as a distinct entity according to the 2008 WHO classification, a considerable complexity is associated with the differential diagnosis of other T-cell lymphomas with respect to tumour cell origins, locations, and the presence of EBV infection, as well as molecular and cytogenetic abnormalities. Here, we report a rare case of EBV-negative ENKTL, where the absence of EBV in the true NK-lineage cells was confirmed by extensive phenotypic and genotypic analyses. Furthermore, using the next-generation sequencing approach, we identified mutations in the tumour suppressor genes KDM6A and TP53. The clinicopathological characteristics were almost similar to those of EBV-positive ENKTL, except for the absence of EBV and histologically apparent angioinvasiveness. This is the first reported ENKTL case with mutations in the KDM6A gene. KDM6A is one of the histone-modifying genes that are mutated in many human diseases including haematological cancers. Epigenetic regulation of gene expression has recently been demonstrated in ENKTL, and a similar pathway is thought to play an oncogenic role in EBV-negative ENKTL. Our report shows the extent of comprehensive examination required before making a definitive diagnosis for NK- and T-cell neoplasms and broadens the therapeutic options for potential targets.
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Histona Desmetilases/imunologia , Linfoma Extranodal de Células T-NK/imunologia , Proteínas Nucleares/imunologia , Feminino , Humanos , Linfoma Extranodal de Células T-NK/tratamento farmacológico , Linfoma Extranodal de Células T-NK/patologia , Pessoa de Meia-Idade , MutaçãoRESUMO
We report the discovery of a novel benzylpiperidine derivative with serotonin transporter (SERT) inhibitory activity and 5-HT1A receptor weak partial agonistic activity showing the antidepressant-like effect. The 3-methoxyphenyl group and the phenethyl group of compound 1, which has weak SERT binding activity, but potent 5-HT1A binding activity, were optimized, leading to compound 35 with potent and balanced dual SERT and 5-HT1A binding activity, but also potent CYP2D6 inhibitory activity. Replacement of the methoxy group in the left part of compound 35 with a larger alkoxy group, such as ethoxy, isopropoxy or methoxy-ethoxy group ameliorated CYP2D6 inhibition, giving SMP-304 as a candidate. SMP-304 with serotonin uptake inhibitory activity and 5-HT1A weak partial agonistic activity, which could work as a 5-HT1A antagonist, displayed faster onset of antidepressant-like effect than a representative SSRI paroxetine in an animal model.
Assuntos
Antidepressivos/farmacologia , Dioxanos/farmacologia , Piperidinas/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Animais , Antidepressivos/administração & dosagem , Antidepressivos/síntese química , Antidepressivos/farmacocinética , Inibidores do Citocromo P-450 CYP2D6/administração & dosagem , Inibidores do Citocromo P-450 CYP2D6/síntese química , Inibidores do Citocromo P-450 CYP2D6/farmacocinética , Inibidores do Citocromo P-450 CYP2D6/farmacologia , Dioxanos/administração & dosagem , Dioxanos/síntese química , Dioxanos/farmacocinética , Agonismo Parcial de Drogas , Humanos , Masculino , Piperidinas/administração & dosagem , Piperidinas/síntese química , Piperidinas/farmacocinética , Ratos Wistar , Agonistas do Receptor 5-HT1 de Serotonina/administração & dosagem , Agonistas do Receptor 5-HT1 de Serotonina/síntese química , Agonistas do Receptor 5-HT1 de Serotonina/farmacocinética , Inibidores Seletivos de Recaptação de Serotonina/administração & dosagem , Inibidores Seletivos de Recaptação de Serotonina/síntese química , Inibidores Seletivos de Recaptação de Serotonina/farmacocinéticaRESUMO
Extranodal natural killer/T cell lymphoma (ENKTL) is a rare subtype of lymphoma. Recurrent mutations in the JAK-STAT pathway, recently reported in ENKTL cases, are interesting in terms of both pathogenesis and inhibitor therapy. However, the frequencies of these mutations are low and variable among reports, and other pathognomonic mutations in ENKTL remain to be elucidated. In the present study, targeted capture sequencing of 602 cancer-related genes from 25 frozen ENKTL samples was performed, 11 of which were matched to normal samples. Several recurrent somatic mutations involving BCOR (32%), TP53 (16%), DDX3X (12%), FAT4 (8%), NRAS (8%), MLL3 (12%), and MIR17HG (8%) were identified. The pattern of BCOR aberrations (1 nonsense and 5 frame-shift mutations, a mutation leading to a splicing error, and gene loss) suggested that loss of function of BCOR was the functionally important outcome of such changes. The literature was reviewed and the public data on BCOR aberrations was reanalyzed and it was found that the aberrations were frequently found in myeloid neoplasms, but, interestingly, were highly specific to ENKTL among lymphoid malignancies. Given the high frequency and pattern of aberration, BCOR is likely to play an important role in ENKTL pathogenesis as a tumor suppressor gene.
Assuntos
Linfoma Extranodal de Células T-NK/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Repressoras/genética , Variações do Número de Cópias de DNA , Humanos , Splicing de RNARESUMO
Antagonism of the dopamine D3 receptor has been hypothesized to be beneficial for schizophrenia cognitive deficits, negative symptoms and extrapyramidal symptoms. However, recent animal and human studies have shown that most antipsychotics do not occupy D3 receptors in vivo, despite their considerable binding affinity for this receptor in vitro. In the present study, we investigated the D3 receptor binding of blonanserin, a dopamine D2/D3 and serotonin 5-HT2A receptors antagonist, in vitro and in vivo. Blonanserin showed the most potent binding affinity for human D3 receptors among the tested atypical antipsychotics (risperidone, olanzapine and aripiprazole). Our GTPγS-binding assay demonstrated that blonanserin acts as a potent full antagonist for human D3 receptors. All test-drugs exhibited antipsychotic-like efficacy in methamphetamine-induced hyperactivity in rats. Treatment with blonanserin at its effective dose blocked the binding of [(3)H]-(+)-PHNO, a D2/D3 receptor radiotracer, both in the D2 receptor-rich region (striatum) and the D3 receptor-rich region (cerebellum lobes 9 and 10). On the other hand, the occupancies of other test-drugs for D3 receptors were relatively low. In conclusion, we have shown that blonanserin, but not other tested antipsychotics, extensively occupies D3 receptors in vivo in rats.
Assuntos
Antipsicóticos/metabolismo , Antipsicóticos/farmacologia , Antagonistas dos Receptores de Dopamina D2/metabolismo , Antagonistas dos Receptores de Dopamina D2/farmacologia , Piperazinas/metabolismo , Piperazinas/farmacologia , Piperidinas/metabolismo , Piperidinas/farmacologia , Receptores de Dopamina D3/antagonistas & inibidores , Receptores de Dopamina D3/metabolismo , Antagonistas do Receptor 5-HT2 de Serotonina/metabolismo , Antagonistas do Receptor 5-HT2 de Serotonina/farmacologia , Animais , Antipsicóticos/uso terapêutico , Células Cultivadas , Cricetinae , Cricetulus , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Hipercinese/tratamento farmacológico , Masculino , Piperazinas/uso terapêutico , Piperidinas/uso terapêutico , Ligação Proteica , Ratos Sprague-DawleyRESUMO
The 18 kDa translocator protein (TSPO) was identified as a discrete receptor for diazepam (1). Since TSPO in the central nervous system (CNS) is believed to regulate neurosteroids biosynthesis, selective TSPO ligands are expected to be useful in the treatment of psychiatric disorders. We synthesized three novel tricyclic benzimidazolone derivatives, and selected the dihydroimidazoquinolinone derivative 27 as a lead TSPO ligand. Study of the structure-activity relationship (SAR) of dihydroimidazoquinolinone derivatives revealed compounds with potent affinity for TSPO (subnanomolar K(i) values), but poor metabolic stability. The optimization of these compounds led to compound 48 with potent affinity for TSPO and good in vitro PK profile.
Assuntos
Acetanilidas/síntese química , Benzimidazóis/química , Proteínas de Transporte/química , Desenho de Fármacos , Compostos Heterocíclicos com 3 Anéis/síntese química , Receptores de GABA-A/química , Acetanilidas/química , Acetanilidas/farmacocinética , Animais , Benzimidazóis/síntese química , Benzimidazóis/farmacocinética , Proteínas de Transporte/metabolismo , Meia-Vida , Compostos Heterocíclicos com 3 Anéis/química , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Ligantes , Masculino , Camundongos , Ligação Proteica , Ratos , Ratos Sprague-Dawley , Receptores de GABA-A/metabolismo , Relação Estrutura-AtividadeRESUMO
Selective 18 kDa translocator protein (TSPO) ligands are expected to be therapeutic agents with a wide spectrum of action on psychiatric disorders and fewer side effects. We designed novel benzoxazolone derivatives and examined the structure-activity relationship (SAR) of a series of compounds with various substituents at the amide part and C-5 position. Although a number of the synthesized compounds showed high TSPO binding affinity, these compounds had poor drug-like properties. Further optimization of pharmacokinetic properties of these compounds led to discovery of compound 74, which exhibited anxiolytic effect in the rat Vogel conflict model.