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1.
Gan To Kagaku Ryoho ; 46(10): 1595-1597, 2019 Oct.
Artigo em Japonês | MEDLINE | ID: mdl-31631147

RESUMO

Tropomyosin-related kinase(TRK)fusion proteins are oncogenic drivers in multiple tumors in adults and children.Larotrectinib, an orally administered selective TRK inhibitor approved in the US, exhibits inhibitory activity against tumors harboring TRK fusions and is well tolerated.Here, we report the case of an 8-year-old female child with recurrence of an NTRK fusion low-grade sarcoma treated with larotrectinib monotherapy.The patient previously underwent resection of low-grade sarcoma in the right brachialis at 6 years of age, but local recurrence occurred after 16 months.As re-operation likely required amputation, larotrectinib was commenced at a dose of 100 mg BID.Complete radiographic remission was achieved after 3 months.There were no adverse events attributed to larotrectinib treatment.After dosing for 6 months, we performed local resection, confirming pathological complete remission.The drug was stopped, and the patient showed no evidence of relapse at 4 months after resection.In this case, larotrectinib was obtained using Single Patient Expanded Access under the FDA.In this paper, we also discuss the issues faced while accessing unapproved drugs in the precision medicine era in Japan.


Assuntos
Recidiva Local de Neoplasia , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Sarcoma , Criança , Feminino , Fusão Gênica , Humanos , Japão , Lamina Tipo A , Receptor trkA , Sarcoma/tratamento farmacológico
2.
J Cancer Res Clin Oncol ; 145(12): 2901-2910, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31654122

RESUMO

INTRODUCTION: The nuclear pore complex is comprised of approximately 30 proteins named nucleoporins (Nups) and tightly regulates nucleocytoplasmic transport of macromolecules across the nuclear membrane. Genetic alterations in many NUP genes are associated with many human maladies, such as neurological disease, autoimmune disorders and cancer. METHODS: We reviewed the status quo of recent advancement of the knowledge of oncogenic role of nucleoporins in human carcinogenesis, focusing on major non-hematological malignancies in the recent literature. Both clinical study-derived and experiment-based reports were critically reviewed. We have also discussed the potential of nucleoporins as novel cancer biomarkers and promising therapeutic target against human malignancies. RESULTS: Several Nups such as Nup53, Nup88, Nup98, Nup160 and Nup214 modulated a plethora of cellular and physiological pathways involved in tumorigenesis such as GSK3ß-Snail, Wnt/ß-Catenin and RanGap1/RanBP2 signaling axes, DNA damage response, resistance to apoptosis and chemotherapy. CONCLUSION: Although classically, majority of studies have shown oncogenic roles of nucleoporins as genetic fusion partners in several types of leukemia, emerging evidence suggests that nucleoporins also modulate many cellular signaling pathways that are associated with several major non-hematological malignancies, such as carcinomas of skin, breast, lung, prostate and colon. Hence, nucleoporins are emerging as novel therapeutic targets in human tumors.


Assuntos
Cromossomos/genética , Fusão Gênica/genética , Neoplasias/genética , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Oncogenes/genética , Translocação Genética/genética , Animais , Humanos
3.
Zhonghua Bing Li Xue Za Zhi ; 48(9): 705-709, 2019 Sep 08.
Artigo em Chinês | MEDLINE | ID: mdl-31495091

RESUMO

Objective: To investigate histopathological characteristics, and differential diagnoses of childhood synovial sarcoma. Methods: HE staining, immunohistochemical staining and fusion gene detection by FISH were performed in 12 cases of synovial sarcoma in childhood at Beijing Children's Hospital from 2016 to 2018. Results: There were 6 cases of biphasic type, 1 case of monophasic epithelial type, 3 cases of monophasic spindle cell type and 2 cases of poorly differentiated synovial sarcomas. EMA, CKpan, bcl-2, CD99, TLE1 and CD34 immunostain positivities were observed in 10/12, 9/12, 12/12, 10/12, 10/12 and 0/12 cases respectively. Unique INI1 immunohistochemical staining was observed in 9/12 cases. SS18-SSX gene fusion was detected in 8 of 11 cases by FISH. Conclusions: Synovial sarcoma is rare in children. Histological morphology combined with immunohistochemistry and FISH SS18-SSX fusion gene detection are important for the diagnosis and differential diagnosis of synovial sarcoma in children.


Assuntos
Sarcoma Sinovial , Biomarcadores Tumorais , Criança , Fusão Gênica , Humanos , Imuno-Histoquímica , Proteínas de Fusão Oncogênica , Proteínas Repressoras
4.
Orv Hetil ; 160(33): 1319-1323, 2019 Aug.
Artigo em Húngaro | MEDLINE | ID: mdl-31401857

RESUMO

Ectomesenchymal chondromyxoid tumor is a rare benign intraoral soft tissue neoplasm. Till date, 93 cases have been reported in literature. Clinically, it presents as a slowly growing, painless, firm, submucosal swelling mainly occurring on the anterior two thirds of the dorsum of the tongue. Histopathologically, the tumor is characterized by a well circumscribed, lobular proliferation of round, polygonal, or fusiform cells in a net-like pattern in a myxoid to chondromyxoid background. Although it shows a morphological resemblance to myoepitheliomas of soft tissue and skin, the exact histogenesis remains unclear; a recent publication of a large series has demonstrated recurrent RREB1-MKL2 gene fusions in 90% of the cases, suggesting the possibility of a new entity. The diagnosis is largely supported by immunhistochemical investigations. Here, we present a new case of ECT occurring in a 62-year-old male who presented with a leading complaint of slowly growing painless mass arising from the anterior part of the tongue measuring about 3 cm. This lesion was diagnosed 4 years before recent admittance, but the patient did not undergo the scheduled surgical intervention and was lost to follow-up. As the tumor was still persisting and moderately enlarging, he came back to our clinic. Finally, the mass was completely resected; after 24 month of follow-up, he is doing well, with no signs of recurrence. Orv Hetil. 2019; 160(33): 1319-1323.


Assuntos
Proteínas de Ligação a DNA/genética , Mesenquimoma/patologia , Neoplasias da Língua/patologia , Língua/patologia , Fatores de Transcrição/genética , Proteínas de Ligação a DNA/metabolismo , Fusão Gênica , Humanos , Masculino , Mesenquimoma/cirurgia , Pessoa de Meia-Idade , Mioepitelioma , Recidiva Local de Neoplasia , Língua/cirurgia , Neoplasias da Língua/genética , Neoplasias da Língua/cirurgia , Fatores de Transcrição/metabolismo
5.
J Microbiol Biotechnol ; 29(8): 1299-1309, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31387340

RESUMO

As an opportunistic bacterial pathogen, Pseudomonas aeruginosa PAO1 contains two phenazineproducing gene operons, phzA1B1C1D1E1F1G1 (phz1) and phzA2B2C2D2E2F2G2 (phz2), each of which is independently capable of encoding all enzymes for biosynthesizing phenazines, including phenazine-1-carboxylic acid and its derivatives. Other previous study reported that the RpoS-deficient mutant SS24 overproduced pyocyanin, a derivative of phenazine-1- carboxylic acid. However, it is not known how RpoS mediates the expression of two phz operons and regulates pyocyanin biosynthesis in detail. In this study, with deletion of the rpoS gene in the PAΔphz1 mutant and the PAΔphz2 mutant respectively, we demonstrated that RpoS exerted opposite regulatory roles on the expression of the phz1and phz2 operons. We also confirmed that the phz1 operon played a critical role and especially biosynthesized much more phenazines than the phz2 operon when the rpoS gene was knocked out in P. aeruginosa. By constructing the translational reporter fusion vector lasR'-'lacZ and the chromosomal fusion mutant PAΔlasR::lacZ, we verified that RpoS deficiency caused increased expression of lasR, a transcription regulator gene in a first quorum sensing system (las) that activates overexpression of the phz1 operon, suggesting that in the absence of RpoS, LasR might act as an intermediate in overproduction of phenazine biosynthesis mediated by the phz1 operon in P. aeruginosa.


Assuntos
Proteínas de Bactérias/metabolismo , Fenazinas/metabolismo , Pseudomonas aeruginosa/metabolismo , Fator sigma/metabolismo , Transativadores/metabolismo , Proteínas de Bactérias/genética , Regulação Bacteriana da Expressão Gênica , Fusão Gênica , Óperon , Pseudomonas aeruginosa/genética , Piocianina/biossíntese , Fator sigma/genética
6.
Expert Rev Clin Pharmacol ; 12(10): 931-939, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31469968

RESUMO

Introduction: Detecting oncogenic drivers across multiple cancers has brought about a shift toward a more targeted therapeutic approach. Neurotrophic tyrosine receptor kinase (NTRK) gene fusions are genomic rearrangements containing the kinase domain of one of three tropomyosin receptor kinases (TRK) and a dimerization domain contributed by another gene, generating fusion proteins, which are oncogenic drivers, targetable with TRK inhibitors. Larotrectinib is a first-in-class TRK inhibitor, granted accelerated FDA approval for treating TRK fusion cancer. This breakthrough indication across cancer subtypes and ages, from infancy through adulthood, highlights the need to understand the heterogeneous patient population and cancer types studied in larotrectinib clinical trials. Areas covered: We provide a narrative review of preclinical, pharmacokinetic, efficacy, and safety data for larotrectinib from three clinical trials that led to regulatory approval. Expert opinion: Larotrectinib elicits impressive responses in most patients with TRK fusion cancer, regardless of tumor type and age. Treatment is well tolerated with a low rate of treatment-emergent grade 3-4 adverse events, dose reductions and discontinuations due to adverse events, and recent findings indicate patient-reported improvement in quality of life. This highlights the importance of early testing for NTRK gene fusions in cancers that may harbor them, even if rare.


Assuntos
Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Pirazóis/administração & dosagem , Pirimidinas/administração & dosagem , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Fusão Gênica , Humanos , Neoplasias/genética , Neoplasias/patologia , Proteínas de Fusão Oncogênica/genética , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/efeitos adversos , Pirazóis/farmacologia , Pirimidinas/efeitos adversos , Pirimidinas/farmacologia , Qualidade de Vida , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/genética
7.
Cancer Sci ; 110(9): 2973-2981, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31293054

RESUMO

Every year, approximately 1.2 million cases of colorectal carcinoma (CRC) are newly diagnosed worldwide. Although metastases to distant organs are often fatal complications of CRC, little information is known as to how such metastatic lesions are formed. To reveal the genetic profiles for CRC metastasis, we conducted whole-exome RNA sequencing on CRC tumors with liver metastasis (LM) (group A, n = 12) and clinical stage-matched larger tumors without LM (group B, n = 16). While the somatic mutation profiles were similar among the primary tumors and LM lesions in group A and the tumors in group B, the A-to-C nucleotide change in the context of "AAG" was only enriched in the LM regions in group A, suggesting the presence of a DNA damage process specific to metastasis. Genes already known to be associated with CRC were mutated in all groups at a similar frequency, but we detected somatic nonsynonymous mutations in a total of 707 genes in the LM regions, but not in the tumors without LM. Signaling pathways linked to such "LM-associated" genes were overrepresented for extracellular matrix-receptor interaction or focal adhesion. Further, fusions of the ADAP1 (ArfGAP with dual PH domain 1) were newly identified in our cohort (3 out of 28 patients), which activated ARF6, an ADAP1-substrate. Infrequently, mutated genes may play an important role in metastasis formation of CRC. Additionally, recurrent ADAP1 fusion genes were unexpectedly discovered. As these fusions activate small GTPase, further experiments are warranted to examine their contribution to CRC carcinogenesis.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Neoplasias Colorretais/genética , Fusão Gênica , Neoplasias Hepáticas/genética , Proteínas do Tecido Nervoso/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinogênese/genética , Neoplasias Colorretais/patologia , Análise Mutacional de DNA , Feminino , Perfilação da Expressão Gênica , Células HEK293 , Humanos , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Mutação Puntual , Sequenciamento Completo do Exoma
9.
BMC Genomics ; 20(1): 456, 2019 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-31170917

RESUMO

BACKGROUND: Ricinus communis is a highly economically valuable oil crop plant from the spurge family, Euphorbiaceae. However, the available reference genomes are incomplete and to date studies on ricinoleic acid biosynthesis at the transcriptional level are limited. RESULTS: In this study, we combined PacBio single-molecule long read isoform and Illumina RNA sequencing to identify the alternative splicing (AS) events, novel isoforms, fusion genes, long non-coding RNAs (lncRNAs) and alternative polyadenylation (APA) sites to unveil the transcriptomic complexity of castor beans and identify critical genes related to ricinoleic acid biosynthesis. Here, we identified 11,285 AS-variants distributed in 21,448 novel genes and detected 520 fusion genes, 320 lncRNAs and 9511 (APA-sites). Furthermore, a total of 6067, 5983 and 4058 differentially expressed genes between developing beans of the R. communis lines 349 and 1115 with extremely different oil content were identified at 7, 14 and 21 days after flowering, respectively. Specifically, 14, 18 and 11 DEGs were annotated encoding key enzymes related to ricinoleic acid biosynthesis reflecting the higher castor oil content of 1115 compared than 349. Quantitative real-time RT-PCR further validated fifteen of these DEGs at three-time points. CONCLUSION: Our results significantly improved the existed gene models of R. communis, and a putative model of key genes was built to show the differences between strains 349 and 1115, illustrating the molecular mechanism of castor oil biosynthesis. A multi-transcriptome database and candidate genes were provided to further improve the level of ricinoleic acid in transgenic crops.


Assuntos
Ácidos Ricinoleicos/metabolismo , Ricinus/genética , Transcriptoma , Processamento Alternativo , Perfilação da Expressão Gênica , Fusão Gênica , Genes de Plantas , Sequenciamento de Nucleotídeos em Larga Escala , Poliadenilação , RNA Longo não Codificante/genética , Ricinus/metabolismo , Análise de Sequência de RNA , Fatores de Transcrição/genética
10.
Clin Cancer Res ; 25(15): 4674-4681, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31068372

RESUMO

PURPOSE: Gene fusions involving neuregulin 1 (NRG1) have been noted in multiple cancer types and have potential therapeutic implications. Although varying results have been reported in other cancer types, the efficacy of the HER-family kinase inhibitor afatinib in the treatment of NRG1 fusion-positive pancreatic ductal adenocarcinoma is not fully understood. EXPERIMENTAL DESIGN: Forty-seven patients with pancreatic ductal adenocarcinoma received comprehensive whole-genome and transcriptome sequencing and analysis. Two patients with gene fusions involving NRG1 received afatinib treatment, with response measured by pretreatment and posttreatment PET/CT imaging. RESULTS: Three of 47 (6%) patients with advanced pancreatic ductal adenocarcinoma were identified as KRAS wild type by whole-genome sequencing. All KRAS wild-type tumors were positive for gene fusions involving the ERBB3 ligand NRG1. Two of 3 patients with NRG1 fusion-positive tumors were treated with afatinib and demonstrated a significant and rapid response while on therapy. CONCLUSIONS: This work adds to a growing body of evidence that NRG1 gene fusions are recurrent, therapeutically actionable genomic events in pancreatic cancers. Based on the clinical outcomes described here, patients with KRAS wild-type tumors harboring NRG1 gene fusions may benefit from treatment with afatinib.See related commentary by Aguirre, p. 4589.


Assuntos
Neoplasias Pulmonares/genética , Neoplasias Pancreáticas , Feminino , Fusão Gênica , Rearranjo Gênico , Humanos , Neuregulina-1 , Proteínas de Fusão Oncogênica/genética , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Proteínas Proto-Oncogênicas p21(ras)
11.
Nat Commun ; 10(1): 2198, 2019 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-31097696

RESUMO

Many gene fusions are reported in tumours and for most their role remains unknown. As fusions are used for diagnostic and prognostic purposes, and are targets for treatment, it is crucial to assess their function in cancer. To systematically investigate the role of fusions in tumour cell fitness, we utilized RNA-sequencing data from 1011 human cancer cell lines to functionally link 8354 fusion events with genomic data, sensitivity to >350 anti-cancer drugs and CRISPR-Cas9 loss-of-fitness effects. Established clinically-relevant fusions were identified. Overall, detection of functional fusions was rare, including those involving cancer driver genes, suggesting that many fusions are dispensable for tumour fitness. Therapeutically actionable fusions involving RAF1, BRD4 and ROS1 were verified in new histologies. In addition, recurrent YAP1-MAML2 fusions were identified as activators of Hippo-pathway signaling in multiple cancer types. Our approach discriminates functional fusions, identifying new drivers of carcinogenesis and fusions that could have clinical implications.


Assuntos
Biomarcadores Tumorais/genética , Sistemas CRISPR-Cas/genética , Fusão Gênica/genética , Neoplasias/genética , Antineoplásicos/farmacologia , Carcinogênese/genética , Linhagem Celular Tumoral , Conjuntos de Dados como Assunto , Resistencia a Medicamentos Antineoplásicos/genética , Detecção Precoce de Câncer/métodos , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Genômica/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neoplasias/diagnóstico , Análise de Sequência de RNA
12.
Nat Med ; 25(5): 767-775, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31011208

RESUMO

Anti-tumor immunity is driven by self versus non-self discrimination. Many immunotherapeutic approaches to cancer have taken advantage of tumor neoantigens derived from somatic mutations. Here, we demonstrate that gene fusions are a source of immunogenic neoantigens that can mediate responses to immunotherapy. We identified an exceptional responder with metastatic head and neck cancer who experienced a complete response to immune checkpoint inhibitor therapy, despite a low mutational load and minimal pre-treatment immune infiltration in the tumor. Using whole-genome sequencing and RNA sequencing, we identified a novel gene fusion and demonstrated that it produces a neoantigen that can specifically elicit a host cytotoxic T cell response. In a cohort of head and neck tumors with low mutation burden, minimal immune infiltration and prevalent gene fusions, we also identified gene fusion-derived neoantigens that generate cytotoxic T cell responses. Finally, analyzing additional datasets of fusion-positive cancers, including checkpoint-inhibitor-treated tumors, we found evidence of immune surveillance resulting in negative selective pressure against gene fusion-derived neoantigens. These findings highlight an important class of tumor-specific antigens and have implications for targeting gene fusion events in cancers that would otherwise be less poised for response to immunotherapy, including cancers with low mutational load and minimal immune infiltration.


Assuntos
Antígenos de Neoplasias/genética , Imunoterapia/métodos , Neoplasias/imunologia , Neoplasias/terapia , Linfócitos T Citotóxicos/imunologia , Proteínas Cromossômicas não Histona/genética , Proteínas Cromossômicas não Histona/imunologia , Fusão Gênica , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/imunologia , Neoplasias de Cabeça e Pescoço/terapia , Humanos , Fatores de Transcrição NFI/genética , Fatores de Transcrição NFI/imunologia , Neoplasias/genética , Proteínas Nucleares/genética , Proteínas Nucleares/imunologia , Proteínas Oncogênicas/genética , Proteínas Oncogênicas/imunologia , Proteínas de Ligação a Poli-ADP-Ribose/genética , Proteínas de Ligação a Poli-ADP-Ribose/imunologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-myb/genética , Proteínas Proto-Oncogênicas c-myb/imunologia , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia , Sequenciamento Completo do Genoma
13.
Brain Tumor Pathol ; 36(3): 121-128, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31011918

RESUMO

Here, we report a highly unusual case of high-grade glioneuronal tumor with a neurotrophic tropomyosin receptor kinase (NTRK) fusion gene. A 13-year-old girl presented with headache and vomiting and MRI detected two cystic lesions bilaterally in the frontal areas with surrounding edema. The left larger tumor was removed by left frontal craniotomy. The tumor was diagnosed as a high-grade glioneuronal tumor, unclassified. Methylation profiling classified it as a diffuse leptomeningeal glioneuronal tumor (DLGNT) with low confidence. This tumor showed genotypes frequently found in DLGNT such as 1p/19q codeletion without IDH mutation and, however, did not have the typical DLGNT clinical and histological features. RNA sequencing identified an ARHGEF2 (encoding Rho/Rac guanine nucleotide exchange factor 2)-NTRK1 fusion gene. The presence of recurrent NTRK fusion in glioneuronal tumors has an important implication in the clinical decision making and opens up a possibility of novel targeted therapy.


Assuntos
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Glioma/genética , Glioma/patologia , Proteínas de Fusão Oncogênica/genética , Receptor trkA/genética , Fatores de Troca de Nucleotídeo Guanina Rho/genética , Adolescente , Deleção Cromossômica , Cromossomos Humanos Par 1 , Cromossomos Humanos Par 19 , Feminino , Fusão Gênica , Humanos , Neoplasias Meníngeas/genética , Neoplasias Meníngeas/patologia , Mutação , Oligodendroglioma/genética , Oligodendroglioma/patologia , Proteínas de Fusão Oncogênica/metabolismo , Receptor trkA/metabolismo , Fatores de Troca de Nucleotídeo Guanina Rho/metabolismo
14.
Diagn Pathol ; 14(1): 32, 2019 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-31027501

RESUMO

BACKGROUND: Uterine leiomyomas, in contrast to sarcomas, tend to cease growth following menopause. In the setting of a rapidly enlarging uterine mass in a postmenopausal patient, clinical distinction of uterine leiomyoma from sarcoma is difficult and requires pathologic examination. CASE PRESENTATION: A 74-year-old woman presented with postmenopausal bleeding and acute blood loss requiring transfusion. She was found to have a rapidly enlarging uterine mass clinically suspicious for sarcoma. An abdominal hysterectomy and bilateral salpingo-oophorectomy were performed. A 15.5 cm partially necrotic intramural mass was identified in the uterine corpus. The tumor was classified as a cellular leiomyoma. RNA sequencing identified a KAT6B-KANSL1 fusion that was confirmed by RT-PCR and Sanger sequencing. After 6 months of follow-up, the patient remains asymptomatic without evidence of disease. CONCLUSION: Prior studies of uterine leiomyomas have identified KAT6B (previously MORF) rearrangements in uterine leiomyomas, but this case is the first to identify a KAT6B-KANSL1 gene fusion in a uterine leiomyoma. While alterations of MED12 and HMGA2 are most common in uterine leiomyomas, a range of other genetic pathways have been described. Our case contributes to the evolving molecular landscape of uterine leiomyomas.


Assuntos
Histona Acetiltransferases/genética , Leiomioma/genética , Proteínas Nucleares/genética , Neoplasias Uterinas/genética , Idoso , Feminino , Fusão Gênica , Humanos , Leiomioma/diagnóstico por imagem , Leiomioma/patologia , Neoplasias Uterinas/diagnóstico por imagem , Neoplasias Uterinas/patologia
15.
Clin Cancer Res ; 25(16): 4966-4972, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-30988082

RESUMO

PURPOSE: NRG1 gene fusions are rare but potentially actionable oncogenic drivers that are present in some solid tumors. Details regarding the incidence of these gene rearrangements are lacking. Here, we assessed the incidence of NRG1 fusions across multiple tumor types and described fusion partners. EXPERIMENTAL DESIGN: Tumor specimens submitted for molecular profiling at a Clinical Laboratory Improvement Amendments (CLIA)-certified genomics laboratory and that underwent fusion testing by anchored multiplex PCR for targeted RNA sequencing were retrospectively identified. The overall and tumor-specific incidence was noted, as was the specific fusion partner. RESULTS: Out of 21,858 tumor specimens profiled from September 2015 to December 2018, 41 cases (0.2%) harbored an NRG1 fusion. Multiple fusion partners were identified. Fusion events were seen across tumor types. The greatest incidence was in non-small cell lung cancer (NSCLC, 25), though this represented only 0.3% of NSCLC cases tested. Other tumor types harboring an NRG1 fusion included gallbladder cancer, renal cell carcinoma, bladder cancer, ovarian cancer, pancreatic cancer, breast cancer, neuroendocrine tumor, sarcoma, and colorectal cancer. CONCLUSIONS: NRG1 fusions can be detected at a low incidence across multiple tumor types with significant heterogeneity in fusion partner.See related commentary by Dimou and Camidge, p. 4865.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Fusão Gênica , Humanos , Neuregulina-1/genética , Proteínas de Fusão Oncogênica/genética , Estudos Retrospectivos
16.
BMC Genomics ; 20(1): 307, 2019 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-31014245

RESUMO

BACKGROUND: Protein kinases are enzymes controlling different cellular functions. Genetic alterations often result in kinase dysregulation, making kinases a very attractive class of druggable targets in several human diseases. Existing approved drugs still target a very limited portion of the human 'kinome', demanding a broader functional knowledge of individual and co-expressed kinase patterns in physiologic and pathologic settings. The development of novel rapid and cost-effective methods for kinome screening is therefore highly desirable, potentially leading to the identification of novel kinase drug targets. RESULTS: In this work, we describe the development of KING-REX (KINase Gene RNA EXpression), a comprehensive kinome RNA targeted custom assay-based panel designed for Next Generation Sequencing analysis, coupled with a dedicated data analysis pipeline. We have conceived KING-REX for the gene expression analysis of 512 human kinases; for 319 kinases, paired assays and custom analysis pipeline features allow the evaluation of 3'- and 5'-end transcript imbalances as readout for the prediction of gene rearrangements. Validation tests on cell line models harboring known gene fusions demonstrated a comparable accuracy of KING-REX gene expression assessment as in whole transcriptome analyses, together with a robust detection of transcript portion imbalances in rearranged kinases, even in complex RNA mixtures or in degraded RNA. CONCLUSIONS: These results support the use of KING-REX as a rapid and cost effective kinome investigation tool in the field of kinase target identification for applications in cancer biology and other human diseases.


Assuntos
Perfilação da Expressão Gênica/métodos , Proteínas Quinases/genética , Fusão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Proteínas Quinases/metabolismo , Estabilidade de RNA
17.
Diagn Pathol ; 14(1): 26, 2019 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-30922345

RESUMO

BACKGROUD: Myeloid sarcoma (MS) is a rare neoplasm of immature myeloid precursors that form tumor mass outside the bone marrow. The diagnosis of de novo MS can be challenging, particularly in patients with no prior history of hematologic malignancies or when MS involves unusual anatomic sites. CASE PRESENTATION: The patient was a 53-year-old woman with a history of uterine fibroids and vaginal bleeding for many years who presented with a vaginal wall mass. The tumor had histologic and phenotypic features of histiocytic sarcoma, however, overlapping with a possible extramedullary MS. Using a comprehensive genomic profiling, we were able to identify recurrent chromosomal aberrations associated with MS including a rare KMT2A-ELL fusion, losses of chromosomes 1p, 9, 10, 15, 18, and gain of chromosome 1q and mutations in FLT3 and PTPN11, and achived the final diagnosis of a de novo MS. The patient received standard treatment for acute myeloid leukemia regimen with stem cell transplantation and achieved complete remission. CONCLUSION: Our case illustrates the clinical utility of comprehensive genomic profiling in assisting the diagnosis or differential diagnosis of challenging MS or histiocytic sarcoma cases, and in providing important information in tumor biology for appropriate clinical management.


Assuntos
Aberrações Cromossômicas , Histona-Lisina N-Metiltransferase/genética , Leucemia Mieloide Aguda/diagnóstico , Proteína de Leucina Linfoide-Mieloide/genética , Sarcoma Mieloide/diagnóstico , Fatores de Elongação da Transcrição/genética , Feminino , Fusão Gênica , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/cirurgia , Pessoa de Meia-Idade , Sarcoma Mieloide/genética , Sarcoma Mieloide/patologia , Sarcoma Mieloide/cirurgia , Transplante de Células-Tronco , Resultado do Tratamento , Vagina/patologia , Vagina/cirurgia
18.
Nat Commun ; 10(1): 1388, 2019 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-30918253

RESUMO

Fusion genes are a major cause of cancer. Their rapid and accurate diagnosis can inform clinical action, but current molecular diagnostic assays are restricted in resolution and throughput. Here, we show that targeted RNA sequencing (RNAseq) can overcome these limitations. First, we establish that fusion gene detection with targeted RNAseq is both sensitive and quantitative by optimising laboratory and bioinformatic variables using spike-in standards and cell lines. Next, we analyse a clinical patient cohort and improve the overall fusion gene diagnostic rate from 63% with conventional approaches to 76% with targeted RNAseq while demonstrating high concordance for patient samples with previous diagnoses. Finally, we show that targeted RNAseq offers additional advantages by simultaneously measuring gene expression levels and profiling the immune-receptor repertoire. We anticipate that targeted RNAseq will improve clinical fusion gene detection, and its increasing use will provide a deeper understanding of fusion gene biology.


Assuntos
Fusão Gênica/genética , Técnicas de Diagnóstico Molecular/métodos , Neoplasias/genética , Análise de Sequência de RNA/métodos , Linhagem Celular Tumoral , Perfilação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neoplasias/diagnóstico , Fusão Oncogênica/genética
19.
APMIS ; 127(5): 288-302, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30803032

RESUMO

Over the last decade, anaplastic lymphoma kinase (ALK), a receptor tyrosine kinase (RTK), has been identified as a fusion partner in a diverse variety of translocation events resulting in oncogenic signaling in many different cancer types. In tumors where the full-length ALK RTK itself is mutated, such as neuroblastoma, the picture regarding the role of ALK as an oncogenic driver is less clear. Neuroblastoma is a complex and heterogeneous tumor that arises from the neural crest derived peripheral nervous system. Although high-risk neuroblastoma is rare, it often relapses and becomes refractory to treatment. Thus, neuroblastoma accounts for 10-15% of all childhood cancer deaths. Since most cases are in children under the age of 2, understanding the role and regulation of ALK during neural crest development is an important goal in addressing neuroblastoma tumorigenesis. An impressive array of tyrosine kinase inhibitors (TKIs) that act to inhibit ALK have been FDA approved for use in ALK-driven cancers. ALK TKIs bind differently within the ATP-binding pocket of the ALK kinase domain and have been associated with different resistance mutations within ALK itself that arise in response to therapeutic use, particularly in ALK-fusion positive non-small cell lung cancer (NSCLC). This patient population has highlighted the importance of considering the relevant ALK TKI to be used for a given ALK mutant variant. In this review, we discuss ALK in neuroblastoma, as well as the use of ALK TKIs and other strategies to inhibit tumor growth. Current efforts combining novel approaches and increasing our understanding of the oncogenic role of ALK in neuroblastoma are aimed at improving the efficacy of ALK TKIs as precision medicine options in the clinic.


Assuntos
Quinase do Linfoma Anaplásico/antagonistas & inibidores , Neoplasias Encefálicas/tratamento farmacológico , Neuroblastoma/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Quinase do Linfoma Anaplásico/genética , Neoplasias Encefálicas/genética , Fusão Gênica , Humanos , Terapia de Alvo Molecular , Neuroblastoma/genética , Mutação Puntual
20.
FEMS Microbiol Lett ; 366(4)2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30772899

RESUMO

Enterotoxigenic Escherichia coli (ETEC) producing type Ib heat-stable toxin (STa) are a main cause of children's diarrhea and travelers' diarrhea, thus STa needs to be targeted in ETEC vaccine development. However, because this 19-amino acid STa is poorly immunogenic, attempts to genetically fuse or chemically couple it to carrier proteins have been made to enhance STa immunogenicity. In this study, we selected one genetic fusion and one chemical conjugate to comparatively evaluate STa immunogenicity. The genetic fusion is 3xSTaN12S-mnLTR192G/L211A carrying three toxoid (STaN12S) genetically fused to a double mutant LT monomer (mnLTR192G/L211A); the chemical conjugate is BSA-STaA14T, which has toxoid STaA14T chemically coupled to bovine serum albumin (BSA). We immunized mice with the STa toxoid fusion and chemical conjugates, and examined antibody responses. Furthermore, we immunized pigs and evaluated derived antibodies for efficacy to passively provide protection against ETEC diarrhea using a piglet model. Data showed that mice subcutaneously immunized with BSA-STaA14T or 3xSTaN12S-mnLTR192G/L211A developed a strong anti-STa antibody, and the induced antibodies exhibited equivalent toxin-neutralizing activities. Pigs immunized with 3xSTaN12S-mnLTR192G/L211A or BSA-STaA14T developed similar levels of anti-STa antibodies; piglets with passively acquired antibodies induced by the genetic fusion appeared better protected against STa + ETEC. Results from the current study indicate that the fusion and conjugate approaches are viable options for facilitating STa immunogenicity and developing ETEC vaccines.


Assuntos
Infecções por Escherichia coli/imunologia , Imunogenicidade da Vacina , Toxoides/imunologia , Animais , Anticorpos Antibacterianos/sangue , Conjugação Genética/imunologia , Escherichia coli Enterotoxigênica/genética , Escherichia coli Enterotoxigênica/imunologia , Infecções por Escherichia coli/prevenção & controle , Fusão Gênica/imunologia , Camundongos , Suínos
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