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2.
Am J Surg Pathol ; 44(9): 1224-1234, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32804454

RESUMO

This study determined the frequency and the clinicopathologic and genetic features of colorectal carcinomas driven by oncogenic fusions of the anaplastic lymphoma kinase gene (ALK). Of the 8150 screened tumors, 12 (0.15%) were immunohistochemically ALK-positive with D5F3 antibody. These cancers harbored CAD-ALK (n=1), DIAPH2-ALK (n=2), EML4-ALK (n=2), LOC101929227-ALK (n=1), SLMAP-ALK (n=1), SPTBN1-ALK (n=4), and STRN-ALK (n=1) fusions, as detected by an RNA-based next-generation sequencing assay. ALK fusion carcinomas were diagnosed mostly in older patients with a 9:3 female predominance (median age: 72 y). All tumors, except a rectal one, occurred in the right colon. Most tumors were stage T3 (n=7) or T4 (n=3). Local lymph node and distant metastases were seen at presentation in 9 and 2 patients. These tumors showed moderate (n=6) or poor (n=3) glandular differentiation, solid medullary growth pattern (n=2), and pure mucinous morphology (n=1). DNA mismatch repair-deficient phenotype was identified in 10 cases. Tumor-infiltrating lymphocytes were prominent in 9 carcinomas. In 4 carcinomas, tumor cells showed strong, focal (n=3), or diffuse programmed death-ligand 1 immunoreactivity. CDX2 expression and loss of CK20 and MUC2 expression were frequent. CK7 was expressed in 5 tumors. Four patients died of disease within 3 years, and 7 were alive with follow-up ranging from 1 to 8 years. No mutations in BRAF, RAS, and in genes encoding components of PI3K-AKT/MTOR pathway were identified. However, 1 tumor had a loss-of-function PTEN mutation. Aberration of p53 signaling, TP53 mutations, and/or nuclear accumulation of p53 protein was seen in 9 cases. ALK fusion colorectal carcinomas are a distinct and rare subtype of colorectal cancers displaying some features of mismatch repair-deficient tumors.


Assuntos
Adenocarcinoma/genética , Quinase do Linfoma Anaplásico/genética , Biomarcadores Tumorais/genética , Neoplasias Colorretais/genética , Fusão Gênica , Rearranjo Gênico , Adenocarcinoma/química , Adenocarcinoma/secundário , Adenocarcinoma/terapia , Idoso , Biomarcadores Tumorais/análise , Neoplasias Colorretais/química , Neoplasias Colorretais/patologia , Neoplasias Colorretais/terapia , Análise Mutacional de DNA , Europa (Continente) , Feminino , Predisposição Genética para Doença , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Japão , Metástase Linfática , Masculino , Mutação , Estadiamento de Neoplasias , Fenótipo , Resultado do Tratamento , Estados Unidos
3.
BMC Bioinformatics ; 21(Suppl 10): 352, 2020 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-32838759

RESUMO

BACKGROUND: The advent of Next Generation Sequencing (NGS) technologies and the concomitant reduction in sequencing costs allows unprecedented high throughput profiling of biological systems in a cost-efficient manner. Modern biological experiments are increasingly becoming both data and computationally intensive and the wealth of publicly available biological data is introducing bioinformatics into the "Big Data" era. For these reasons, the effective application of High Performance Computing (HPC) architectures is becoming progressively more recognized also by bioinformaticians. Here we describe HPC resources provisioning pilot programs dedicated to bioinformaticians, run by the Italian Node of ELIXIR (ELIXIR-IT) in collaboration with CINECA, the main Italian supercomputing center. RESULTS: Starting from April 2016, CINECA and ELIXIR-IT launched the pilot Call "ELIXIR-IT HPC@CINECA", offering streamlined access to HPC resources for bioinformatics. Resources are made available either through web front-ends to dedicated workflows developed at CINECA or by providing direct access to the High Performance Computing systems through a standard command-line interface tailored for bioinformatics data analysis. This allows to offer to the biomedical research community a production scale environment, continuously updated with the latest available versions of publicly available reference datasets and bioinformatic tools. Currently, 63 research projects have gained access to the HPC@CINECA program, for a total handout of ~ 8 Millions of CPU/hours and, for data storage, ~ 100 TB of permanent and ~ 300 TB of temporary space. CONCLUSIONS: Three years after the beginning of the ELIXIR-IT HPC@CINECA program, we can appreciate its impact over the Italian bioinformatics community and draw some considerations. Several Italian researchers who applied to the program have gained access to one of the top-ranking public scientific supercomputing facilities in Europe. Those investigators had the opportunity to sensibly reduce computational turnaround times in their research projects and to process massive amounts of data, pursuing research approaches that would have been otherwise difficult or impossible to undertake. Moreover, by taking advantage of the wealth of documentation and training material provided by CINECA, participants had the opportunity to improve their skills in the usage of HPC systems and be better positioned to apply to similar EU programs of greater scale, such as PRACE. To illustrate the effective usage and impact of the resources awarded by the program - in different research applications - we report five successful use cases, which have already published their findings in peer-reviewed journals.


Assuntos
Biologia Computacional , Metodologias Computacionais , Software , Algoritmos , Animais , Linhagem Celular , Bases de Dados Genéticas , Fusão Gênica , Genoma , Humanos , Prunus persica/genética , Edição de RNA , Andorinhas/genética
4.
Brain Tumor Pathol ; 37(4): 165-170, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32740753

RESUMO

Solitary fibrous tumor/hemangiopericytoma is a mesenchymal tumor that originates from a common NAB2-STAT6 fusion gene and is known to very rarely demonstrate dedifferentiation in the pattern of local recurrence or distant metastasis. Here we describe for the first time a rare case of intracranial dedifferentiated solitary fibrous tumor/hemangiopericytoma with osteosarcoma components that developed in an 84-year-old man after frequent gamma knife radiosurgery over a 14-year period. We performed tumor-debulking and gamma knife radiosurgery, but unfortunately the patient died shortly after the development of dedifferentiation. There is no established treatment for dedifferentiated cases due to the rare histology and limited published data, and therefore further accumulation of histological and genetic profiles is necessary to develop novel target gene therapies.


Assuntos
Neoplasias Encefálicas/patologia , Desdiferenciação Celular , Hemangiopericitoma/patologia , Hemangiopericitoma/cirurgia , Segunda Neoplasia Primária , Osteossarcoma/patologia , Tumores Fibrosos Solitários/patologia , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/cirurgia , Procedimentos Cirúrgicos de Citorredução , Progressão da Doença , Evolução Fatal , Fusão Gênica , Hemangiopericitoma/genética , Humanos , Masculino , Procedimentos Neurocirúrgicos , Osteossarcoma/genética , Osteossarcoma/cirurgia , Radiocirurgia , Doenças Raras , Proteínas Repressoras/genética , Fator de Transcrição STAT6/genética , Tumores Fibrosos Solitários/genética , Tumores Fibrosos Solitários/cirurgia
5.
Brain Tumor Pathol ; 37(4): 159-164, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32754892

RESUMO

We report a case of 33-year-old Japanese male who presented with a headache and visual disturbances. Magnetic resonance imaging revealed a large tumor in the left frontal lobe, measuring 7 cm in diameter, which was diagnosed as supratentorial anaplastic ependymoma accompanied by extensive desmoplasia. The patient underwent a gross total resection. Histologically, the tumor cells had oval or short, spindle-shaped nuclei, and proliferating cells in perivascular pseudorosettes with anucleate zones and mitotic figures. Desmoplasia with abundant collagen fibers among the tumor cells was detected at numerous sites, and perinuclear dot- or ring-like immunoreactivity for epithelial membrane antigen was identified. Five years and six months after the initial procedure, a small recurrent tumor was identified at the removal site. The patient underwent a second total resection. The histology of the resected tumor showed decreased collagen production and more apparent anaplastic features as compared to those of the initial tumor. In addition to the histological findings, molecular examinations revealed ependymoma, RELA fusion positive. Although not commonly observed, this case suggests that desmoplasia could be associated with ependymomas, including RELA fusion-positive variant. Moreover, our findings indicate that high-grade ependymoma requires careful, long-term follow-up even if gross total resection is performed.


Assuntos
Ependimoma/genética , Ependimoma/patologia , Fusão Gênica/genética , Neoplasias Supratentoriais/genética , Neoplasias Supratentoriais/patologia , Fator de Transcrição RelA/genética , Adulto , Ependimoma/diagnóstico , Ependimoma/cirurgia , Lobo Frontal/diagnóstico por imagem , Lobo Frontal/patologia , Lobo Frontal/cirurgia , Humanos , Imagem por Ressonância Magnética , Masculino , Recidiva Local de Neoplasia , Procedimentos Neurocirúrgicos , Neoplasias Supratentoriais/diagnóstico , Neoplasias Supratentoriais/cirurgia
6.
Brain Tumor Pathol ; 37(4): 136-144, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32761533

RESUMO

Oncogenic gene fusions have been reported in diffuse gliomas and may serve as potential therapeutic targets. Here, using next-generation sequencing analysis (Illumina TruSight Tumor 170 panel), we analyzed a total of 356 diffuse gliomas collected from 2017 to 2019 to evaluate clinical, pathological, and genetic features of gene fusion. We found 53 cases of glioblastomas harboring the following oncogenic gene fusions: MET (n = 18), EGFR (n = 14), FGFR (n = 12), NTRK (n = 5), RET (n = 2), AKT3 (n = 1), and PDGFRA fusions (n = 1). Gene fusions were consistently observed in both IDH-wildtype and IDH-mutant glioblastomas (8.8% and 9.4%, p = 1.000). PTPRZ1-MET fusion was the only fusion that genetically resembled secondary glioblastomas (i.e., high frequency of IDH mutation, ATRX loss, TP53 mutation, and absence of EGFR amplification), whereas other gene fusion types were similar to primary glioblastomas (i.e., high frequency of IDH-wildtype, TERT mutation, EGFR amplification, and PTEN mutation). In IDH-wildtype glioblastoma patients, multivariable analysis revealed that the PTPRZ1-MET fusion was associated with poor progression-free survival (HR [95% CI]: 5.42 (1.72-17.05), p = 0.004). Additionally, we described two novel cases of CCDC6-RET fusion in glioma. Collectively, our findings indicate that targetable gene fusions are associated with aggressive biological behavior and can aid the clinical treatment strategy for glioma patients.


Assuntos
Neoplasias Encefálicas/genética , Fusão Gênica/genética , Estudos de Associação Genética , Glioblastoma/genética , Glioma/genética , Sequenciamento de Nucleotídeos em Larga Escala , Proteínas Proto-Oncogênicas c-met/genética , Proteínas Tirosina Fosfatases Classe 5 Semelhantes a Receptores/genética , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Proteínas do Citoesqueleto/genética , Feminino , Glioblastoma/mortalidade , Glioblastoma/patologia , Glioma/mortalidade , Glioma/patologia , Humanos , Isocitrato Desidrogenase/genética , Masculino , Pessoa de Meia-Idade , Prognóstico , Proteínas Proto-Oncogênicas c-ret/genética , Taxa de Sobrevida
7.
Hum Cell ; 33(4): 1302-1310, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32648033

RESUMO

Alveolar soft-part sarcoma is a mesenchymal malignancy characterized by the rearrangement of ASPSCR1 and TFE3 and a histologically distinctive pseudoalveolar pattern. Although alveolar soft-part sarcoma takes an indolent course, its long-term prognosis is poor because of late distant metastases. Currently, curative treatments have not been found for alveolar soft-part sarcoma, and hence, a novel therapeutic strategy has long been required. Patient-derived cell lines comprise an important tool for basic and preclinical research. However, few cell lines from alveolar soft-part sarcoma have been reported in the literature because it is an extremely rare malignancy, accounting for less than 1% of all soft-tissue sarcomas. This study aimed to establish a novel alveolar soft-part sarcoma cell line. Using surgically-resected tumor tissue of alveolar soft-part sarcoma, we successfully established a cell line and named it NCC-ASPS1-C1. The NCC-ASPS1-C1 cells harbored an ASPSCR1-TFE3 fusion gene and exhibited slow growth, and spheroid formation. On the other hand, NCC-ASPS1-C1 did not show the capability of invasion. We screened the antiproliferative effects of 195 anticancer agents, including Food and Drug Administration-approved anticancer drugs. We found that the MET inhibitor tivantinib and multi-kinase inhibitor orantinib inhibited the proliferation of NCC-ASPS1-C1 cells. The clinical utility and molecular mechanisms of antitumor effects of these drugs are worth investigating in the further studies, and NCC-ASPS1-C1 cells will be a useful tool for the in vitro study of alveolar soft-part sarcoma.


Assuntos
Técnicas de Cultura de Células/métodos , Sarcoma Alveolar de Partes Moles , Antineoplásicos/farmacologia , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Linhagem Celular Tumoral , Descoberta de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Fusão Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Oncologia , Pessoa de Meia-Idade , Sarcoma Alveolar de Partes Moles/genética , Sarcoma Alveolar de Partes Moles/patologia
8.
Hum Cell ; 33(4): 1311-1320, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32715445

RESUMO

Alveolar rhabdomyosarcoma (aRMS) is a histological subtype of RMS, which is the most common pediatric and adolescent soft-tissue sarcoma, accounting for 3-4% of all pediatric malignancies. Patient-derived cells are essential tools for understanding the molecular mechanisms of poor prognosis and developing novel anti-cancer drugs. However, only a limited number of well-characterized cell lines for rhabdomyosarcoma from public cell banks is available. Therefore, we aimed to establish a novel cell line of aRMS from the tumor tissue of a patient with aRMS. The cell line was established from surgically resected tumor tissue from a 4-year-old male patient diagnosed with stage III, T2bN1M0 aRMS and was named as NCC-aRMS1-C1. The cells were maintained for more than 3 months under tissue culture conditions and passaged more than 20 times. We confirmed the presence of identical fusion gene such as PAX7-FOXO1 in both the original tumor and NCC-aRMS1-C1. The cells exhibited spheroid formation and invasion. We found that docetaxel, vincristine, ifosfamide, dacarbazine, and romidepsin showed remarkable growth-suppressive effects on the NCC-aRMS1-C1 cells. In conclusion, the NCC-aRMS1-C1 cell line exhibited characteristics that may correspond to the lymph node metastasis in aRMS and mirror its less aggressive features. Thus, it may be useful for innovative seeds for novel therapeutic strategies.


Assuntos
Técnicas de Cultura de Células/métodos , Rabdomiossarcoma Alveolar , Sarcoma Alveolar de Partes Moles , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Pré-Escolar , Desenvolvimento de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Proteína Forkhead Box O1/genética , Fusão Gênica , Humanos , Metástase Linfática , Masculino , Estadiamento de Neoplasias , Fator de Transcrição PAX7/genética , Rabdomiossarcoma Alveolar/genética , Rabdomiossarcoma Alveolar/patologia , Sarcoma Alveolar de Partes Moles/genética , Sarcoma Alveolar de Partes Moles/patologia
9.
Int J Hematol ; 112(5): 714-719, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32656633

RESUMO

PAX5-KIDINS220 (PAX5-K220) is a novel chimeric fusion gene identified in a pediatric Philadelphia chromosome (Ph)-like acute lymphoblastic leukemia (ALL) patient, but the function of the encoded fusion protein has not yet been analyzed. Here, we report the functional analysis of PAX5-K220 in vitro. We successfully generated PAX5-K220 expressing cells and demonstrate that PAX5-K220 is a nuclear protein. Luciferase reporter assay reveals that PAX5-K220 inhibits wild-type PAX5 transcriptional activity in a dominant-negative fashion like other PAX5-related fusion proteins, and may contribute to lymphocyte differentiation block. However, although identified in Ph-like ALL, PAX5-K220 does not induce IL-3-independent proliferation when transduced in the IL-3-dependent Ba/F3 murine leukemia cells, but rather attenuates growth. These results reveal that PAX5-K220 certainly shares the character with other PAX5-related fusion proteins rather than other fusion proteins with tyrosine kinase activity identified in Ph-like ALL, and did not contribute to proliferation activity. Precise functional analysis of each differently partnered PAX5 fusion protein is warranted in the future for better understanding of PAX5-related translocations and their effects.


Assuntos
Fusão Gênica , Proteínas de Membrana/análise , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/análise , Proteínas do Tecido Nervoso/genética , Fator de Transcrição PAX5/análise , Fator de Transcrição PAX5/genética , Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Animais , Linfócitos B/patologia , Diferenciação Celular/genética , Células Cultivadas , Criança , Células HEK293 , Humanos , Interleucina-3 , Camundongos , Proteínas Tirosina Quinases/metabolismo , Translocação Genética/genética
11.
J Clin Pathol ; 73(9): 527-530, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32699115

RESUMO

The GLIS 1-3 genes belong to a family of transcription factors, the Krüppel-like zinc finger proteins. The GLIS proteins function primarily as activators of transcription (GLIS 1 and 3), while GLIS 2 functions as a repressor. Collectively, the GLIS proteins are involved in a variety of diseases in several organs ranging from Alzheimer's disease, facial dysmorphism, neonatal diabetes mellitus, breast and colon cancers and leukaemia. In particular, loss-of-function mutations in GLIS2 are responsible for an autosomal recessive cystic kidney disease called nephronophthisis, which is characterised by tubular atrophy, interstitial fibrosis and corticomedullary cysts.Of diagnostic value in current practice are the presence of GLIS 3 and 1 fusions with PAX8 in almost 100% of hyalinising trabecular tumours of the thyroid gland. This enables its separation from papillary thyroid cancer.


Assuntos
Proteínas de Ligação a DNA/genética , Fatores de Transcrição Kruppel-Like/genética , Proteínas Repressoras/genética , Câncer Papilífero da Tireoide/genética , Neoplasias da Glândula Tireoide/genética , Transativadores/genética , Fatores de Transcrição/genética , Proteínas de Ligação a DNA/metabolismo , Fusão Gênica , Humanos , Fatores de Transcrição Kruppel-Like/metabolismo , Mutação com Perda de Função , Fator de Transcrição PAX8/genética , Fator de Transcrição PAX8/metabolismo , Proteínas Repressoras/metabolismo , Glândula Tireoide/patologia , Transativadores/metabolismo , Fatores de Transcrição/metabolismo
12.
Virchows Arch ; 477(5): 725-732, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32556562

RESUMO

The WHO Classification of Tumors of Soft Tissue and Bone divides rhabdomyosarcoma (RMS) into alveolar, embryonal, pleomorphic, and spindle cell/sclerosing types. Advances in molecular diagnostics have allowed for further refinement of RMS classification including the identification of new subtypes. Very rare RMS with epithelioid and spindle cell morphology, female predominance, marked osseous predilection, ALK expression, EWSR1/FUS-TFCP2 gene fusions, and highly aggressive clinical behavior have recently been recognized with only 23 cases reported in the English language literature. Herein, we report two additional cases with detailed clinicopathologic description and molecular confirmation. In brief, two young women presented each with a primary bone tumor-one with a frontal bone tumor and another with an osseous pelvic tumor. Both tumors showed epithelioid to spindle cell morphology, ALK expression, and EWSR1/FUS-TFCP2 gene fusions. Both patients died of disease less than 17 months from diagnosis despite administration of multiple lines of aggressive treatment. In addition, we review the literature and discuss differential diagnostic and potential treatment considerations.


Assuntos
Biomarcadores Tumorais/genética , Proteínas de Ligação a DNA/genética , Fusão Gênica , Neoplasias Pélvicas/genética , Proteína EWS de Ligação a RNA/genética , Proteína FUS de Ligação a RNA/genética , Rabdomiossarcoma/genética , Neoplasias Cranianas/genética , Fatores de Transcrição/genética , Adulto , Progressão da Doença , Células Epitelioides/patologia , Evolução Fatal , Feminino , Osso Frontal/patologia , Predisposição Genética para Doença , Humanos , Neoplasias Pélvicas/diagnóstico por imagem , Neoplasias Pélvicas/patologia , Neoplasias Pélvicas/terapia , Fenótipo , Rabdomiossarcoma/diagnóstico por imagem , Rabdomiossarcoma/secundário , Rabdomiossarcoma/terapia , Neoplasias Cranianas/diagnóstico por imagem , Neoplasias Cranianas/patologia , Neoplasias Cranianas/terapia , Adulto Jovem
13.
Medicine (Baltimore) ; 99(26): e20725, 2020 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-32590748

RESUMO

RATIONALE: Malignant peripheral nerve sheath tumor (MPNST) is a rare sarcoma. Owing to the lack of specific histological criteria, immunohistochemical, and molecular diagnostic markers, several differential diagnoses must be considered. Advances in molecular testing can provide significant insights for management of rare tumor. PATIENT CONCERNS: The patient was a 50-year-old man with a history of lumpectomy on the right back 30 years ago. He felt a stabbing pain at the right iliac fossa and went to the local hospital. DIAGNOSIS: By immunohistochemistry, the tumor cells stained positively for S-100 (focal +), CD34 (strong +++) and Ki-67 (20%), and negatively for smooth muscle actin, pan-cytokeratin, neurofilament, pan-cytokeratin-L, GFAP, CD31, STAT6, ERG, myogenin, and MyoD1. Combined with the histopathology and immunohistochemistry results, our initial diagnosis was solitary fibrous tumor (SFT) or MPNST. The tissue biopsy was sent for next-generation sequencing. neurofibromatosis type 1 Q1395Hfs*22 somatic mutation, neurofibromatosis type 1 D483Tfs*15 germline mutation, and amplifications of BTK, MDM2, ATF1, BMPR1A, EBHA2, GNA13, PTPN11, RAD52, RPTOR, and SOX9, as well as TJP1-ROS1 fusion, CDKN2A-IL1RAPL2 fusion and CDKN2A/UBAP1 rearrangement were identified. Given that NAB2-STAT6 fusion, a specific biomarker of SFT, was not identified in our patient's tumor, the SFT was excluded by through genetic testing results. Therefore, our finally diagnosis was a MPNST by 2 or more pathologists. INTERVENTIONS AND OUTCOMES: Subsequently, the patient received crizotinib therapy for 2 months and showed stable disease. However, after crizotinib continued treatment for 4 months, the patient's disease progressed. Soon after, the patient stopped crizotinib treatment and died in home. LESSONS: To our knowledge, this is the first report of the TJP1-ROS1 fusion, which expands the list of gene fusions and highlights new targets for targeted therapy. Also, our case underlines the value of multi-gene panel next-generation sequencing for diagnosis of MPNST.


Assuntos
Crizotinibe/administração & dosagem , Fusão Gênica/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Neurofibrossarcoma , Proteínas Tirosina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Proteína da Zônula de Oclusão-1/genética , Antineoplásicos/administração & dosagem , Diagnóstico Diferencial , Progressão da Doença , Monitoramento de Medicamentos , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Neoplasias de Tecido Fibroso/diagnóstico , Neurofibrossarcoma/tratamento farmacológico , Neurofibrossarcoma/genética , Neurofibrossarcoma/patologia , Resultado do Tratamento
14.
Cytogenet Genome Res ; 160(5): 255-263, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32544910

RESUMO

Fusions of the Runt-related transcription factor 1 (RUNX1) with different partner genes have been associated with various hematological disorders. Interestingly, the C-terminally truncated form of RUNX1 and RUNX1 fusion proteins are similarly considered important contributors to leukemogenesis. Here, we describe a 59-year-old male patient who was initially diagnosed with acute myeloid leukemia, inv(16)(p13;q22)/CBFB-MYH11 (FAB classification M4Eo). He achieved complete remission and negative CBFB-MYH11 status with daunorubicin/cytarabine combination chemotherapy but relapsed 3 years later. Cytogenetic analysis of relapsed leukemia cells revealed CBFB-MYH11 negativity and complex chromosomal abnormalities without inv(16)(p13;q22). RNA-seq identified the glutamate receptor, ionotropic, kinase 2 (GRIK2) gene on 6q16 as a novel fusion partner for RUNX1 in this case. Specifically, the fusion of RUNX1 to the GRIK2 antisense strand (RUNX1-GRIK2as) generated multiple missplicing transcripts. Because extremely low levels of wild-type GRIK2 were detected in leukemia cells, RUNX1-GRIK2as was thought to drive the pathogenesis associated with the RUNX1-GRIK2 fusion. The truncated RUNX1 generated from RUNX1-GRIK2as induced the expression of the granulocyte colony-stimulating factor (G-CSF) receptor on 32D myeloid leukemia cells and enhanced proliferation in response to G-CSF. In summary, the RUNX1-GRIK2as fusion emphasizes the importance of aberrantly truncated RUNX1 in leukemogenesis.


Assuntos
Subunidade alfa 2 de Fator de Ligação ao Core/genética , DNA Antissenso/genética , Fusão Gênica/genética , Fator Estimulador de Colônias de Granulócitos/farmacologia , Leucemia Mieloide Aguda/genética , Receptores de Ácido Caínico/genética , Deleção de Sequência/genética , Translocação Genética/genética , Proliferação de Células/efeitos dos fármacos , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , RNA Mensageiro/análise , RNA Mensageiro/genética , Receptores de Fator Estimulador de Colônias de Granulócitos/biossíntese , Receptores de Fator Estimulador de Colônias de Granulócitos/metabolismo
15.
Brain Tumor Pathol ; 37(3): 105-110, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32556925

RESUMO

Central nervous system (CNS) ganglioneuroblastoma is a rare neuroectodermal neoplasm and little is known about its clinical and biological features. Herein, we report a pediatric case of CNS ganglioneuroblastoma harboring MYO5A-NTRK3 fusion. The patient, a 4-year-old boy, underwent a partial resection of a supratentorial tumor that was histopathologically diagnosed as a CNS ganglioneuroblastoma. Treatment with radiotherapy was started per the St Jude Medulloblastoma 03 (SJMB03) protocol; however, the tumor progressed rapidly and radiotherapy was temporally discontinued. Meanwhile, the patient underwent a second surgery, in which a gross total resection was successfully performed, following which he completed the remaining protocol-based therapy. Although an early focal recurrence was detected for which he received additional radiotherapy and oral temozolomide, the patient remained in complete remission for 14 months after the completion of the treatment. A central pathological review and molecular analysis were performed that revealed a MYO5A-NTRK3 fusion. Interestingly, the MYO5A-NTRK3 fusion has been recurrently detected in melanocytic tumors but not in other types of tumors. Therefore, it can be speculated that our case might partly share tumorigenesis mechanisms with MYO5A-NTRK3-positive melanocytic tumors. In addition, our case may enable an improved understanding of the pathogenesis and clinical features of CNS ganglioneuroblastomas.


Assuntos
Neoplasias Encefálicas/genética , Ganglioneuroblastoma/genética , Fusão Gênica , Cadeias Pesadas de Miosina/genética , Miosina Tipo V/genética , Receptor trkC/genética , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/patologia , Pré-Escolar , Imagem de Difusão por Ressonância Magnética , Ganglioneuroblastoma/diagnóstico por imagem , Ganglioneuroblastoma/patologia , Humanos , Masculino
16.
Proc Natl Acad Sci U S A ; 117(25): 14561-14571, 2020 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-32518116

RESUMO

Recombination between homeologous chromosomes, also known as homeologous exchange (HE), plays a significant role in shaping genome structure and gene expression in interspecific hybrids and allopolyploids of several plant species. However, the molecular mechanisms that govern HEs are not well understood. Here, we studied HE events in the progeny of a nascent allotetraploid (genome AADD) derived from two diploid progenitors of hexaploid bread wheat using cytological and whole-genome sequence analyses. In total, 37 HEs were identified and HE junctions were mapped precisely. HEs exhibit typical patterns of homologous recombination hotspots, being biased toward low-copy, subtelomeric regions of chromosome arms and showing association with known recombination hotspot motifs. But, strikingly, while homologous recombination preferentially takes place upstream and downstream of coding regions, HEs are highly enriched within gene bodies, giving rise to novel recombinant transcripts, which in turn are predicted to generate new protein fusion variants. To test whether this is a widespread phenomenon, a dataset of high-resolution HE junctions was analyzed for allopolyploid Brassica, rice, Arabidopsis suecica, banana, and peanut. Intragenic recombination and formation of chimeric genes was detected in HEs of all species and was prominent in most of them. HE thus provides a mechanism for evolutionary novelty in transcript and protein sequences in nascent allopolyploids.


Assuntos
Cromossomos de Plantas/genética , Genes de Plantas/genética , Proteínas de Plantas/genética , Poliploidia , Recombinação Genética , Arabidopsis/genética , Arachis/genética , Brassica/genética , Biologia Computacional , Evolução Molecular , Fusão Gênica , Cariotipagem , Musa/genética , Oryza/genética , Transcrição Genética , Triticum/genética
18.
Nat Commun ; 11(1): 2861, 2020 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-32504042

RESUMO

Fusion genes are hallmarks of various cancer types and important determinants for diagnosis, prognosis and treatment. Fusion gene partner choice and breakpoint-position promiscuity restricts diagnostic detection, even for known and recurrent configurations. Here, we develop FUDGE (FUsion Detection from Gene Enrichment) to accurately and impartially identify fusions. FUDGE couples target-selected and strand-specific CRISPR-Cas9 activity for fusion gene driver enrichment - without prior knowledge of fusion partner or breakpoint-location - to long read nanopore sequencing with the bioinformatics pipeline NanoFG. FUDGE has flexible target-loci choices and enables multiplexed enrichment for simultaneous analysis of several genes in multiple samples in one sequencing run. We observe on-average 665 fold breakpoint-site enrichment and identify nucleotide resolution fusion breakpoints within 2 days. The assay identifies cancer cell line and tumor sample fusions irrespective of partner gene or breakpoint-position. FUDGE is a rapid and versatile fusion detection assay for diagnostic pan-cancer fusion detection.


Assuntos
Sistemas CRISPR-Cas/genética , Fusão Gênica , Testes Genéticos/métodos , Sequenciamento por Nanoporos , Neoplasias/diagnóstico , Linhagem Celular Tumoral , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Neoplasias/genética , Análise de Sequência de DNA
19.
Nucleic Acids Res ; 48(W1): W415-W426, 2020 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-32392343

RESUMO

Genetics data visualization plays an important role in the sharing of knowledge from cancer genome research. Many types of visualization are widely used, most of which are static and require sufficient coding experience to create. Here, we present Oviz-Bio, a web-based platform that provides interactive and real-time visualizations of cancer genomics data. Researchers can interactively explore visual outputs and export high-quality diagrams. Oviz-Bio supports a diverse range of visualizations on common cancer mutation types, including annotation and signatures of small scale mutations, haplotype view and focal clusters of copy number variations, split-reads alignment and heatmap view of structural variations, transcript junction of fusion genes and genomic hotspot of oncovirus integrations. Furthermore, Oviz-Bio allows landscape view to investigate multi-layered data in samples cohort. All Oviz-Bio visual applications are freely available at https://bio.oviz.org/.


Assuntos
Genômica/métodos , Neoplasias/genética , Software , Gráficos por Computador , Visualização de Dados , Fusão Gênica , Variação Genética , Haplótipos , Humanos , Internet , Mutação , Retroviridae/genética , Integração Viral
20.
Virchows Arch ; 477(5): 625-636, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32417965

RESUMO

Heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) is a ubiquitous RNA splicing factor that is overexpressed and prognostically relevant in various human cancer types. To study the impact of hnRNPA1 expression in prostate cancer, we analyzed a tissue microarray containing 17,747 clinical prostate cancer specimens by immunohistochemistry. hnRNPA1 was expressed in normal prostate glandular cells but often overexpressed in cancer cells. hnRNPA1 immunostaining was interpretable in 14,258 cancers and considered strong in 33.4%, moderate in 45.9%, weak in 15.3%, and negative in 5.4%. Moderate to strong hnRNPA1 immunostaining was strongly linked to adverse tumor features including high classical and quantitative Gleason score, lymph node metastasis, advanced tumor stage, positive surgical margin, and early biochemical recurrence (p < 0.0001 each). The prognostic impact of hnRNPA1 immunostaining was independent of established preoperatively or postoperatively available prognostic parameters (p < 0.0001). Subset analyses revealed that all these associations were strongly driven by the fraction of cancers lacking the TMPRSS2:ERG gene fusion. Comparison with other key molecular data that were earlier obtained on the same TMA showed that hnRNPA1 overexpression was linked to high levels of androgen receptor (AR) expression (p < 0.0001) as well as presence of 9 of 11 chromosomal deletions (p < 0.05 each). A strong association between hnRNPA1 upregulation and tumor cell proliferation that was independent from the Gleason score supports a role for tumor cell aggressiveness. In conclusion, hnRNPA1 overexpression is an independent predictor of poor prognosis in ERG-negative prostate cancer. hnRNPA1 measurement, either alone or in combination, might provide prognostic information in ERG-negative prostate cancer.


Assuntos
Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Fusão Gênica , Ribonucleoproteína Nuclear Heterogênea A1/análise , Proteínas de Fusão Oncogênica/genética , Neoplasias da Próstata/química , Idoso , Biomarcadores Tumorais/sangue , Proliferação de Células , Humanos , Imuno-Histoquímica , Calicreínas/sangue , Metástase Linfática , Masculino , Margens de Excisão , Pessoa de Meia-Idade , Gradação de Tumores , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Valor Preditivo dos Testes , Antígeno Prostático Específico/sangue , Prostatectomia , Neoplasias da Próstata/sangue , Neoplasias da Próstata/genética , Neoplasias da Próstata/cirurgia , Fatores de Risco , Análise Serial de Tecidos , Resultado do Tratamento , Regulação para Cima
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