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1.
Int J Cancer ; 146(4): 1031-1041, 2020 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-31304977

RESUMO

Accurate modeling of intratumor heterogeneity presents a bottleneck against drug testing. Flexibility in a preclinical platform is also desirable to support assessment of different endpoints. We established the model system, OHC-NB1, from a bone marrow metastasis from a patient diagnosed with MYCN-amplified neuroblastoma and performed whole-exome sequencing on the source metastasis and the different models and passages during model development (monolayer cell line, 3D spheroid culture and subcutaneous xenograft tumors propagated in mice). OHC-NB1 harbors a MYCN amplification in double minutes, 1p deletion, 17q gain and diploid karyotype, which persisted in all models. A total of 80-540 single-nucleotide variants (SNVs) was detected in each sample, and comparisons between the source metastasis and models identified 34 of 80 somatic SNVs to be propagated in the models. Clonal reconstruction using the combined copy number and SNV data revealed marked clonal heterogeneity in the originating metastasis, with four clones being reflected in the model systems. The set of OHC-NB1 models represents 43% of somatic SNVs and 23% of the cellularity in the originating metastasis with varying clonal compositions, indicating that heterogeneity is partially preserved in our model system.


Assuntos
Modelos Animais de Doenças , Neuroblastoma/genética , Neuroblastoma/patologia , Neoplasias Abdominais/genética , Neoplasias Abdominais/patologia , Animais , Feminino , Heterogeneidade Genética , Xenoenxertos , Humanos , Masculino , Camundongos , Camundongos SCID , Neoplasias Torácicas/genética , Neoplasias Torácicas/patologia , Células Tumorais Cultivadas
2.
Bull Cancer ; 107(3): 352-358, 2020 Mar.
Artigo em Francês | MEDLINE | ID: mdl-31882269

RESUMO

About 15 % of patients with familial adenomatous polyposis "PAF" develop one or more desmoid tumors in their lifetime. These are benign mesenchymal tumors with local aggressivity but with no potential for metastases. Most of the desmoids tumors result from a sporadic genetic anomaly in the ß catenin gene. When related to familial adenomatous polyposis or "PAF", this mutation is not present, and the patients must be sent in genetic counselling. The PAF is a dominant autosomic illness related to a germinal mutation in the APC gene. Sometimes, these tumors can be the first manifestation of the illness. The diagnosis in a context of PAF can be easily done by imaging, but a pathological confirmation is needed. These tumors raise a therapeutic problem because of their heterogeneity and the absence of predictive biomarkers along illness evolution. The identification of prognostic biological and clinical factors would make easier the selection of patients requiring first-line treatment, as spontaneous remissions have also been observed in patients with FAP whom which an active surveillance could also be a valid therapeutic option. The particularity of desmoids tumors associated to PAF lies in their predominantly intra-abdominal location and the risk of complication. In the last ten years, surgery has largely given way to conservative treatments such as chemotherapy and more recently to tyrosine kinase inhibitors that have shown their efficacy with a significant improvement in progression-free survival of patients.


Assuntos
Fibromatose Agressiva/genética , Síndrome de Gardner/genética , Neoplasias Abdominais/diagnóstico , Neoplasias Abdominais/genética , Neoplasias Abdominais/terapia , Parede Abdominal , Polipose Adenomatosa do Colo/genética , Feminino , Fibromatose Agressiva/diagnóstico , Fibromatose Agressiva/terapia , Síndrome de Gardner/diagnóstico , Síndrome de Gardner/terapia , Genes APC , Humanos , Masculino , Seleção de Pacientes , Gravidez , Complicações Neoplásicas na Gravidez/etiologia , Prognóstico , Inibidores de Proteínas Quinases/uso terapêutico , Conduta Expectante
3.
BMC Cancer ; 19(1): 1188, 2019 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-31805975

RESUMO

BACKGROUND: An extremely rare condition, radiation-induced angiosarcoma is characterized by a poor prognosis, high recurrence rate and lack of effective treatment. Herein, we present a case report of a 48-year-old female patient with radiation-induced abdominal wall angiosarcoma who showed a dramatic response to low-dose apatinib. CASE PRESENTATION: The patient, who was diagnosed with cervical squamous cell carcinoma 20 years ago, had received radiotherapy and chemotherapy after operation. Angiosarcomas of the abdominal wall appeared 9 years later. After repeated surgical operations and intravenous chemotherapy for the angiosarcomas, the patient developed tumor recurrence and pulmonary metastasis. The abdominal wall tumors showed repeated rupture and bleeding, with poor wound healing. On evaluation, laboratory findings detected the negative serum tumor markers CEA, CA 125, CA 15-3 and CA 19-9. Imaging showed multiple subcutaneous nodules and masses in the abdominal wall, accompanied by suspected small subpleural nodule at the lower lobe of the right lung. Immunohistochemistry of previous surgical pathology indicated that CD31, ERG and Vim were positive. The result of whole exome sequencing suggested the mutations of BRAF and HRAS, and the amplification of MYC. Based on the above results, the patient was clinically diagnosed with radiation-induced angiosarcoma of the abdominal wall with pulmonary metastasis. The patient was treated with low-dose apatinib and rejected reoperation or chemotherapy. RESULTS: At the 6-month follow-up visit, the abdominal wall lesions that had previously ruptured stopped bleeding and showed significant shrinkage. Imaging showed that most of the abdominal wall lesions had partially regressed, and some of the lesions on the abdominal wall and the suspected lesion of subpleural nodule at the lower lobe of the right lung had disappeared. CONCLUSIONS: We described this case and reviewed the literature on radiation-related angiosarcoma. Importantly, this case suggests that apatinib may be an effective and sensitive treatment for radiation-induced angiosarcoma even at the lowest dosage, without aggravating the bleeding of lesions.


Assuntos
Neoplasias Abdominais/tratamento farmacológico , Hemangiossarcoma/tratamento farmacológico , Neoplasias Pulmonares/secundário , Neoplasias Induzidas por Radiação/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Piridinas/administração & dosagem , Neoplasias Abdominais/etiologia , Neoplasias Abdominais/genética , Parede Abdominal/patologia , Feminino , Amplificação de Genes , Hemangiossarcoma/etiologia , Hemangiossarcoma/genética , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Pessoa de Meia-Idade , Mutação , Neoplasias Induzidas por Radiação/genética , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Piridinas/uso terapêutico , Resultado do Tratamento
4.
Cancer Metastasis Rev ; 38(4): 783-811, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31848768

RESUMO

Abdominal tumors (AT) in children account for approximately 17% of all pediatric solid tumor cases, and frequently exhibit embryonal histological features that differentiate them from adult cancers. Current molecular approaches have greatly improved the understanding of the distinctive pathology of each tumor type and enabled the characterization of novel tumor biomarkers. As seen in abdominal adult tumors, microRNAs (miRNAs) have been increasingly implicated in either the initiation or progression of childhood cancer. Moreover, besides predicting patient prognosis, they represent valuable diagnostic tools that may also assist the surveillance of tumor behavior and treatment response, as well as the identification of the primary metastatic sites. Thus, the present study was undertaken to compile up-to-date information regarding the role of dysregulated miRNAs in the most common histological variants of AT, including neuroblastoma, nephroblastoma, hepatoblastoma, hepatocarcinoma, and adrenal tumors. Additionally, the clinical implications of dysregulated miRNAs as potential diagnostic tools or indicators of prognosis were evaluated.


Assuntos
Neoplasias Abdominais/genética , MicroRNAs/genética , Neoplasias Abdominais/metabolismo , Animais , Criança , Humanos , MicroRNAs/biossíntese
5.
Ann Diagn Pathol ; 41: 102-105, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31202195

RESUMO

Based on histological findings, calcifying fibrous tumor (CFT) may be a late (burned out) stage of inflammatory myofibroblastic tumor (IMT). This concept, however, has not been proven by molecular means. Five CFTs were analyzed for IMT-related rearrangements in ALK, ROS1 and RET using fluorescence in situ hybridization (FISH). Additionally, genome-wide methylation patterns were investigated and compared with IMT (n = 7), leiomyoma (n = 7), angioleiomyoma (n = 9), myopericytoma (n = 7) and reactive soft tissue lesions (n = 10) using unsupervised hierarchical cluster analysis and t distributed stochastic neighbor embedding. CFT patients, 4 females and 1 male, had a median age of 20 years ranging from 7 to 43 years. Two patients were younger than 18 years old. The tumors originated in the abdomen (n = 4) and axilla (n = 1). Histologically, all lesions were (multi) nodular and hypocellular consisting of bland looking (myo)fibroblasts embedded in a collagenous matrix with calcifications. FISH analysis brought up negative results for ALK, RET and ROS1 rearrangements. However, genome-wide methylation analysis revealed overlapping methylation patterns of CFT and IMT forming a distinct homogeneous methylation cluster with exception of one case clustering with myopericytoma/angioleiomyoma. In conclusion, DNA methylation profiling supports the concept that CFT and IMT represent both ends of a spectrum of one entity with CFT being the burn out stage of IMT.


Assuntos
Granuloma de Células Plasmáticas/genética , Neoplasias de Tecido Fibroso/genética , Neoplasias Abdominais/genética , Neoplasias Abdominais/patologia , Adolescente , Adulto , Axila/patologia , Calcinose/genética , Calcinose/patologia , Criança , Metilação de DNA , Epigênese Genética , Feminino , Estudo de Associação Genômica Ampla , Granuloma de Células Plasmáticas/patologia , Humanos , Masculino , Neoplasias de Tecido Fibroso/patologia , Adulto Jovem
6.
Intern Med J ; 49(4): 529-532, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30957378

RESUMO

Carriers of succinate dehydrogenase (SDHx) mutations are at risk of developing phaeochromocytomas, catecholamine secreting extra-adrenal paragangliomas and non-secretory head and neck paragangliomas and require lifelong surveillance. There is no current consensus on the optimal surveillance strategy. This study describes the outcomes of a cohort of 50 SDHx mutation carriers followed at a tertiary Australian hospital using a surveillance protocol involving annual clinical review with plasma/urine metanephrines and biennial magnetic resonance imaging from skull base to pelvis.


Assuntos
Mutação em Linhagem Germinativa , Paraganglioma/genética , Feocromocitoma/genética , Succinato Desidrogenase/genética , Neoplasias Abdominais/genética , Neoplasias das Glândulas Suprarrenais/genética , Adulto , Austrália , Estudos de Coortes , Feminino , Neoplasias de Cabeça e Pescoço/genética , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade
8.
Medicine (Baltimore) ; 97(40): e12718, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30290678

RESUMO

Neuroblastoma is a unique malignancy in infants often presenting with either localized or metastatic disease. The study was carried out to explore the risk stratification of the poor prognosis for patients underwent surgical treatment.60 patients diagnosed with neuroblastoma were primarily enrolled in the study from April 2008 to April 2016. All the patients underwent surgical treatment and received 5-year follow-up. Clinical variables, including age, International Neuroblastoma Staging System (INSS) stage, tumor size and site, histology, and MYCN status were retrospectively analyzed, and EFS was chosen as the endpoint.The median age of patients was 8.2 months and average follow-up period was 40.2 ±â€Š8.6 months. Among 60 patients, complete remission was achieved in 35 patients and partial remission in 14 subjects. Poor prognosis including patient death and tumor progression were overserved in 11 patients. Cox multifactor regression analysis revealed that age, histology and MYCN status had significant prognostic effect on event-free survival (EFS) rate for neuroblastoma patients underwent surgical treatment.In our study, we identified a series of prognostic factors including age, histology, and MYCN status predicting the prognosis of neuroblastoma patients after surgical treatment.


Assuntos
Neoplasias Abdominais/mortalidade , Neoplasias de Cabeça e Pescoço/mortalidade , Proteína Proto-Oncogênica N-Myc/análise , Neuroblastoma/mortalidade , Neoplasias Torácicas/mortalidade , Neoplasias Abdominais/genética , Neoplasias Abdominais/cirurgia , Pré-Escolar , Progressão da Doença , Intervalo Livre de Doença , Feminino , Seguimentos , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/cirurgia , Humanos , Lactente , Masculino , Estadiamento de Neoplasias , Neuroblastoma/genética , Neuroblastoma/cirurgia , Período Pós-Operatório , Prognóstico , Modelos de Riscos Proporcionais , Análise de Regressão , Indução de Remissão , Estudos Retrospectivos , Fatores de Risco , Neoplasias Torácicas/genética , Neoplasias Torácicas/cirurgia , Resultado do Tratamento
9.
Genes Chromosomes Cancer ; 57(10): 495-503, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29901254

RESUMO

A wait and see approach for desmoid tumors (DT) has become part of the routine treatment strategy. However, predictive factors to select the risk of progressive disease are still lacking. A translational project was run in order to identify genomic signatures in patients enrolled within an Italian prospective observational study. Among 12 DT patients (10 CTNNB1-mutated and 2 wild type) enrolled from our institution only two patients (17%) showed a progressive disease. Tumor biopsies were collected for whole exome sequencing. Overall, DT exhibited low somatic sequence mutation rate and no additional recurrent mutation was found. In the two wild type (WT) cases, two novel alterations were detected: a complex deletion of APC and a pathogenic mutation of LAMTOR2. Focusing on WT DT subtype, deep sequencing of CTNNB1, APC and LAMTOR2 was conducted on a retrospective series of 11 WT DT using a targeted approach. No other mutation of LAMTOR2 was detected, while APC was mutated in two cases. Low-frequency (mean reads of 16%) CTNNB1 mutations were discovered in five samples (45%) and two novel intra-genic deletions in CTNNB1 were detected in two cases. Both deletions and low frequency mutations of CTNNB1 were highly expressed. In conclusion, a minority of DT is WT for either CTNNB1, APC or any other gene involved in the WNT pathway. In this subgroup novel and hard to be detected molecular alterations in APC and CTNNB1 were discovered, contributing to explain a portion of the allegedly WT DT cases.


Assuntos
Neoplasias Abdominais/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteína da Polipose Adenomatosa do Colo/genética , Polipose Adenomatosa do Colo/genética , Fibromatose Agressiva/genética , beta Catenina/genética , Neoplasias Abdominais/patologia , Polipose Adenomatosa do Colo/patologia , Adulto , Feminino , Fibromatose Agressiva/metabolismo , Fibromatose Agressiva/patologia , Deleção de Genes , Genômica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Mutação
10.
BMC Res Notes ; 10(1): 413, 2017 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-28818093

RESUMO

BACKGROUND: Nephroblastoma and neuroblastoma belong to the most common abdominal malignancies in childhood. Similarities in the initial presentation may provide difficulties in distinguishing between these two entities, especially if unusual variations to prevalent patterns of disease manifestation occur. Because of the risk of tumor rupture, European protocols do not require biopsy for diagnosis, which leads to misdiagnosis in some cases. CASE PRESENTATION: We report on a 4½-year-old girl with a renal tumor displaying radiological and laboratory characteristics supporting the diagnosis of nephroblastoma. Imaging studies showed tumor extension into the inferior vena cava and bilateral lung metastases while urine catecholamines and MIBG-scintigraphy were negative. Preoperative chemotherapy with vincristine, actinomycine D and adriamycin according to the SIOP2001/GPOH protocol for the treatment of nephroblastoma was initiated and followed by surgical tumor resection. Histopathology revealed an undifferentiated tumor with expression of neuronal markers, suggestive of neuroblastoma. MYCN amplification could not be detected. DNA-microarray analysis was performed using Affymetrix genechip human genome U133 plus 2.0 and artificial neural network analysis. Results were confirmed by multiplex RT-PCR. RESULTS: Principal component analysis using 84 genes showed that the patient sample was clearly clustering with neuroblastoma tumors. This was confirmed by hierarchical clustering of the multiplex RT-PCR data. The patient underwent treatment for high-risk neuroblastoma comprising chemotherapy including cisplatin, etoposide, vindesine, dacarbacine, ifosfamide, vincristine, adriamycine and autologous stem cell transplantation followed by maintenance therapy with 13-cis retinoic acid (GPOH NB2004 High Risk Trial Protocol) and is in complete long-term remission. CONCLUSION: The use of gene expression profiling in an individual patient strongly contributed to clarification in a diagnostic dilemma which finally led to a change of diagnosis from nephroblastoma to neuroblastoma. This case underlines the importance of gene-expression profiling in the correct diagnosis of childhood neoplasms with atypical presentation to ensure that adequate treatment regimens can be applied.


Assuntos
Neoplasias Abdominais/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Regulação Neoplásica da Expressão Gênica , Neoplasias Renais/genética , Proteínas de Neoplasias/genética , Neuroblastoma/genética , Tumor de Wilms/genética , Neoplasias Abdominais/diagnóstico por imagem , Neoplasias Abdominais/tratamento farmacológico , Neoplasias Abdominais/cirurgia , Antineoplásicos/uso terapêutico , Pré-Escolar , Diagnóstico Diferencial , Feminino , Perfilação da Expressão Gênica , Humanos , Neoplasias Renais/diagnóstico por imagem , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/cirurgia , Imagem por Ressonância Magnética , Proteínas de Neoplasias/metabolismo , Neuroblastoma/diagnóstico por imagem , Neuroblastoma/tratamento farmacológico , Neuroblastoma/cirurgia , Tumor de Wilms/diagnóstico por imagem , Tumor de Wilms/tratamento farmacológico , Tumor de Wilms/cirurgia
11.
Pathol Res Pract ; 213(10): 1315-1321, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28645808

RESUMO

We experienced a 38-year-old Japanese male with t(10;19) CIC-DUX4 -positive undifferentiated small round cell sarcoma in the deep abdominal wall. Three months before his first visit to our hospital, he noticed a mass in his right abdominal wall. Computed tomography on admission revealed a solid abdominal tumor 70×53mm in size and multiple small tumors in both lungs. The biopsy of the abdominal tumor revealed undifferentiated small round cell sarcoma, suggestive of Ewing sarcoma. Under the clinical diagnosis of Ewing-like sarcoma of the abdominal wall with multiple lung metastases, several cycles of ICE (ifosfamide, carboplatin and etoposide) therapy were performed. After the chemotherapy, the lung metastases disappeared, while the primary lesion rapidly grew. Additional VDC (vincristine, doxorubicin and cyclophosphamide) therapy was carried out without apparent effect. Although the surgical removal of the primary lesion was done, peritoneal dissemination and a huge metastatic liver tumor appeared thereafter. The patient died of disease progression two months after the surgery. The total clinical course was approximately one year, showing that the tumor was extremely aggressive. The tumor cells of the surgical specimen were positive for CD99, WT1, calretinin, INI1, ERG and Fli1 by immunohistochemistry. Fusion gene analyses using the frozen surgical material revealed negativity for EWSR1-Fli1, EWSR1-ERG and t(4;19) CIC-DUX4 fusions, but positivity for t(10;19) CIC-DUX4 fusion. Thus, we made a final pathological diagnosis of t(10;19) CIC-DUX4-positive undifferentiated small round cell sarcoma. To our knowledge, this is the 13th case of t(10;19) CIC-DUX4 undifferentiated small round cell sarcoma with precise clinicopathological information. Especially in our case, two types of t(10;19) CIC-DUX4 fusion transcripts were observed, both of which are in-frame and novel.


Assuntos
Neoplasias Abdominais/genética , Biomarcadores Tumorais/genética , Diferenciação Celular , Cromossomos Humanos Par 10 , Cromossomos Humanos Par 19 , Fusão Gênica , Proteínas de Fusão Oncogênica/genética , Sarcoma de Células Pequenas/genética , Neoplasias Abdominais/química , Neoplasias Abdominais/patologia , Neoplasias Abdominais/terapia , Adulto , Biomarcadores Tumorais/análise , Biópsia , Western Blotting , Progressão da Doença , Evolução Fatal , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Masculino , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sarcoma de Células Pequenas/química , Sarcoma de Células Pequenas/secundário , Sarcoma de Células Pequenas/terapia , Tomografia Computadorizada por Raios X , Resultado do Tratamento
12.
Methods ; 121-122: 138-145, 2017 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-28522325

RESUMO

Recurrent chromosomal translocations often lead to expression of fusion proteins associated with oncogenic transformation. To study translocations and downstream events, genome editing techniques have been developed to generate chromosomal translocations through non-homologous end joining of DNA double-strand breaks introduced at the two participating endogenous loci. However, the frequencies at which these events occur is usually too low to efficiently clone cells carrying the translocation. This article provides a detailed method using CRISPR-Cas9 technology and homology-directed repair to efficiently isolate cells harboring a chromosomal translocation. For an additional level of control, the resulting fusion protein is conditionally expressed to allow early events in oncogenic transformation to be studied. We focus on the generation of the EWSR1-WT1 fusion using human mesenchymal cells, which is associated with the translocation found in desmoplastic small round cell tumors.


Assuntos
Neoplasias Abdominais/genética , Proteínas de Bactérias/genética , Sistemas CRISPR-Cas , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Tumor Desmoplásico de Pequenas Células Redondas/genética , Endonucleases/genética , RNA Guia/genética , Neoplasias Abdominais/metabolismo , Neoplasias Abdominais/patologia , Proteínas de Bactérias/metabolismo , Proteína 9 Associada à CRISPR , Linhagem Celular , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Cromossomos Humanos Par 11 , Cromossomos Humanos Par 22 , Quebras de DNA de Cadeia Dupla , Tumor Desmoplásico de Pequenas Células Redondas/metabolismo , Tumor Desmoplásico de Pequenas Células Redondas/patologia , Endonucleases/metabolismo , Genoma Humano , Humanos , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/patologia , Mutagênese Sítio-Dirigida/métodos , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , RNA Guia/metabolismo , Proteína EWS de Ligação a RNA/genética , Proteína EWS de Ligação a RNA/metabolismo , Reparo de DNA por Recombinação , Translocação Genética , Proteínas WT1/genética , Proteínas WT1/metabolismo
13.
Oncotarget ; 8(26): 41866-41875, 2017 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-28418912

RESUMO

Desmoid tumors (DT) are rare, benign, fibroblastic neoplasm with challenging histological diagnosis. DTs can occur sporadically or associated with the familial adenomatous polyposis coli (FAP). Most sporadic DTs are associated with ß-catenin gene (CTNNB1) mutations, while mutated APC gene causes FAP disease. microRNAs (miRNAs) are involved in many human carcinogenesis.The miRNA profile was analyzed by microarray in formalin-fixed, paraffin-embedded (FFPE) specimens of 12 patients (8 sporadic, 4 FAP-associated) and 4 healthy controls. One hundred and one mRNAs resulted dysregulated, of which 98 in sporadic DTs and 8 in FAP-associated DTs, 5 were shared by both tumors. Twenty-six miRNAs were then validated by RT-qPCR in 23 sporadic and 7 FAP-associated DT samples matched with healthy controls. The qPCR method was also used to evaluate the CTNNB1 mutational status in sporadic DTs. The correlation between sporadic DTs and miRNA expression showed that miR-21-3p increased in mutated versus wild-type DTs, while miR-197-3p was decreased. The mRNA expression of Tetraspanin3 and Serpin family A member 3, as miR-21-3p targets, and L1 Cell Adhesion Molecule, as miR-197-3p target, was also evaluate. CTNNB1 mutations associated to miRNA dysregulation could affect the genesis and the progression of this disease and help histological diagnosis of sporadic DTs.


Assuntos
Neoplasias Abdominais/genética , Polipose Adenomatosa do Colo/genética , Fibromatose Agressiva/genética , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Mutação , beta Catenina/genética , Neoplasias Abdominais/metabolismo , Neoplasias Abdominais/patologia , Polipose Adenomatosa do Colo/metabolismo , Polipose Adenomatosa do Colo/patologia , Adolescente , Adulto , Idoso , Análise Mutacional de DNA , Feminino , Fibromatose Agressiva/metabolismo , Fibromatose Agressiva/patologia , Perfilação da Expressão Gênica , Genes APC , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Interferência de RNA , RNA Mensageiro/genética , Serpinas/genética , Tetraspaninas/genética , Transcriptoma , Carga Tumoral , Adulto Jovem , beta Catenina/metabolismo
14.
Acta Med Iran ; 55(2): 134-138, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28282712

RESUMO

Desmoids tumors, characterized by monoclonal proliferation of myofibroblasts, could occur in 5-10% of patients with familial adenomatous polyposis (FAP) as an extra-colonic manifestation of the disease. FAP can develop when there is a germ-line mutation in the adenomatous polyposis coli gene. Although mild or attenuated FAP may follow mutations in 5΄ extreme of the gene, it is more likely that 3΄ extreme mutations haveamore severe manifestation of thedisease. A 28-year-old woman was admitted to the Cancer Institute of Iran with an abdominal painful mass. She had strong family history of FAP and underwent prophylactic total colectomy. Pre-operative CT scans revealed a large mass. Microscopic observation showed diffuse fibroblast cell infiltration of the adjacent tissue structures. Peripheral blood DNA extraction followed by adenomatous polyposis coli gene exon by exon sequencing was performed to investigate the mutation in adenomatous polyposis coli gene. Analysis of DNA sequencing demonstrated a mutation of 4 bpdeletions at codon 1309-1310 of the exon 16 of adenomatous polyposis coli gene sequence which was repeated in 3 members of the family. Some of them had desmoid tumor without classical FAP history. Even when there is no familial history of adenomatous polyposis, the adenomatous polyposis coli gene mutation should be investigated in cases of familial desmoids tumors for a suitable prevention. The 3΄ extreme of the adenomatous polyposis coli gene is still the best likely location in such families.


Assuntos
Neoplasias Abdominais/genética , Polipose Adenomatosa do Colo/genética , Fibromatose Abdominal/genética , Mutação da Fase de Leitura , Genes APC , Adulto , Feminino , Predisposição Genética para Doença , Humanos
15.
Clin Nucl Med ; 42(3): 211-213, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28033222

RESUMO

Pheochromocytomas/paragangliomas are somatostatin receptor 2-overexpressing tumors. Ga-DOTA-peptide imaging has recently shown excellent results in the detection of metastatic lesions in these tumors. However, currently used Ga-DOTA peptides show different somatostatin receptor affinities. Here, we report the remarkable differences in a patient who was imaged with Ga-DOTANOC and Ga-DOTATATE PET/CT within a 7-month period. The patient presented with a nearly negative Ga-DOTANOC PET/CT scan, whereas on Ga-DOTATATE PET/CT, multiple highly positive lesions were identified.


Assuntos
Neoplasias Abdominais/diagnóstico por imagem , Neoplasias Pulmonares/secundário , Compostos Organometálicos , Paraganglioma/diagnóstico por imagem , Compostos Radiofarmacêuticos , Receptores de Somatostatina/metabolismo , Neoplasias Abdominais/genética , Neoplasias Abdominais/patologia , Criança , Feminino , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Metástase Neoplásica , Paraganglioma/genética , Paraganglioma/patologia , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Ligação Proteica , Succinato Desidrogenase/genética
16.
Hum Genomics ; 10(1): 36, 2016 11 18.
Artigo em Inglês | MEDLINE | ID: mdl-27863505

RESUMO

BACKGROUND: Genome-wide profiling of rare tumors is crucial for improvement of diagnosis, treatment, and, consequently, achieving better outcomes. Desmoplastic small round cell tumor (DSRCT) is a rare type of sarcoma arising from mesenchymal cells of abdominal peritoneum that usually develops in male adolescents and young adults. A specific translocation, t(11;22)(p13;q12), resulting in EWS and WT1 gene fusion is the only recurrent molecular hallmark and no other genetic factor has been associated to this aggressive tumor. Here, we present a comprehensive genomic profiling of one DSRCT affecting a 26-year-old male, who achieved an excellent outcome. METHODS: We investigated somatic and germline variants through whole-exome sequencing using a family based approach and, by array CGH, we explored the occurrence of genomic imbalances. Additionally, we performed mate-paired whole-genome sequencing for defining the specific breakpoint of the EWS-WT1 translocation, allowing us to develop a personalized tumor marker for monitoring the patient by liquid biopsy. RESULTS: We identified genetic variants leading to protein alterations including 12 somatic and 14 germline events (11 germline compound heterozygous mutations and 3 rare homozygous polymorphisms) affecting genes predominantly involved in mesenchymal cell differentiation pathways. Regarding copy number alterations (CNA) few events were detected, mainly restricted to gains in chromosomes 5 and 18 and losses at 11p, 13q, and 22q. The deletions at 11p and 22q indicated the presence of the classic translocation, t(11;22)(p13;q12). In addition, the mapping of the specific genomic breakpoint of the EWS-WT1 gene fusion allowed the design of a personalized biomarker for assessing circulating tumor DNA (ctDNA) in plasma during patient follow-up. This biomarker has been used in four post-treatment blood samples, 3 years after surgery, and no trace of EWS-WT1 gene fusion was detected, in accordance with imaging tests showing no evidence of disease and with the good general health status of the patient. CONCLUSIONS: Overall, our findings revealed genes with potential to be associated with risk assessment and tumorigenesis of this rare type of sarcoma. Additionally, we established a liquid biopsy approach for monitoring patient follow-up based on genomic information that can be similarly adopted for patients diagnosed with a rare tumor.


Assuntos
Neoplasias Abdominais/diagnóstico por imagem , Tumor Desmoplásico de Pequenas Células Redondas/diagnóstico por imagem , Neoplasias Abdominais/genética , Neoplasias Abdominais/terapia , Adulto , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Cromossomos Humanos Par 11/genética , DNA de Neoplasias/sangue , DNA de Neoplasias/genética , Tumor Desmoplásico de Pequenas Células Redondas/genética , Tumor Desmoplásico de Pequenas Células Redondas/terapia , Humanos , Masculino , Técnicas de Diagnóstico Molecular , Polimorfismo Genético , Translocação Genética
17.
Cancer Lett ; 383(1): 73-84, 2016 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-27693633

RESUMO

The epithelial-mesenchymal transition (EMT) plays a crucial role in pancreatic ductal adenocarcinoma (PDAC) development and progression. TWIST activated by intra-tumoral hypoxia functions to promote the EMT. We hypothesized that TWIST and the downstream gene pathway could mediate PDAC progression under hypoxia. Therefore, 90 PDAC tissue specimens were immunostained for TWIST and other proteins. Pancreatic cancer cell lines were used for in vitro experiments and nude mice were used to confirm the in vivo data. Expression of TWIST and HIF-1α proteins was significantly upregulated, whereas expression of E-cadherin and p16 was down-regulated in PDAC tissues compared to that of non-tumor tissues and in tumor tissues obtained from patients with tumor involving splenic artery than those without splenic artery involvement. Up-regulated TWIST in tumor tissues were associated with worse prognosis in PDAC patients. The in vitro data showed that HIF-1α-induced TWIST overexpression promoted tumor cell growth and EMT under a hypoxic condition via TWIST interaction with Ring1B and EZH2. In vivo data showed that TWIST overexpression or a hypoxic condition induce xenograft growth, abdominal metastasis and low mouse survival, whereas knockdown of either Ring1B or EZH2 expression suppressed tumor xenograft growth and metastasis and prolonged survival of nude mice. TWIST was the key player in promotion of pancreatic cancer development and metastasis under a hypoxic condition through interaction with Ring1B and EZH2 to regulate expression of E-cadherin and p16 proteins in pancreatic cancer cells.


Assuntos
Proliferação de Células , Transição Epitelial-Mesenquimal , Proteínas Nucleares/metabolismo , Neoplasias Pancreáticas/metabolismo , Hipóxia Tumoral , Proteína 1 Relacionada a Twist/metabolismo , Neoplasias Abdominais/genética , Neoplasias Abdominais/metabolismo , Neoplasias Abdominais/secundário , Idoso , Animais , Antígenos CD , Sítios de Ligação , Caderinas/genética , Caderinas/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Inibidor p16 de Quinase Dependente de Ciclina/genética , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Invasividade Neoplásica , Proteínas Nucleares/genética , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Complexo Repressor Polycomb 1/genética , Complexo Repressor Polycomb 1/metabolismo , Regiões Promotoras Genéticas , Interferência de RNA , Transdução de Sinais , Fatores de Tempo , Transfecção , Carga Tumoral , Proteína 1 Relacionada a Twist/genética , Regulação para Cima
18.
Br J Cancer ; 115(8): 1000-1007, 2016 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-27607470

RESUMO

BACKGROUND: Soft tissue sarcomas are heterogeneous and a major complication in their management is that the existing classification scheme is not definitive and is still evolving. Leiomyosarcomas, a major histologic category of soft tissue sarcomas, are malignant tumours displaying smooth muscle differentiation. Although defined as a single group, they exhibit a wide range of clinical behaviour. We aimed to carry out molecular classification to identify new molecular subgroups with clinical relevance. METHODS: We used gene expression profiling on 20 extra-uterine leiomyosarcomas and cross-study analyses for molecular classification of leiomyosarcomas. Clinical significance of the subgroupings was investigated. RESULTS: We have identified two distinct molecular subgroups of leiomyosarcomas. One group was characterised by high expression of 26 genes that included many genes from the sub-classification gene cluster proposed by Nielsen et al. These sub-classification genes include genes that have importance structurally, as well as in cell signalling. Notably, we found a statistically significant association of the subgroupings with tumour grade. Further refinement led to a group of 15 genes that could recapitulate the tumour subgroupings in our data set and in a second independent sarcoma set. Remarkably, cross-study analyses suggested that these molecular subgroups could be found in four independent data sets, providing strong support for their existence. CONCLUSIONS: Our study strongly supported the existence of distinct leiomyosarcoma molecular subgroups, which have clinical association with tumour grade. Our findings will aid in advancing the classification of leiomyosarcomas and lead to more individualised and better management of the disease.


Assuntos
Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Leiomiossarcoma/classificação , Neoplasias Abdominais/genética , Idoso , Conjuntos de Dados como Assunto , Extremidades , Feminino , Humanos , Leiomiossarcoma/genética , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Neoplasias Retroperitoneais/genética , Neoplasias Torácicas/genética , Análise Serial de Tecidos
19.
BMC Cancer ; 16: 686, 2016 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-27565718

RESUMO

BACKGROUND: The efficacy of the classical treatment modalities surgery and radiotherapy in the treatment of aggressive fibromatosis is presently disputed and there is a shift towards a more conservative approach. The aim of the present study is to objectify tumor growth in patients with extra-abdominal or abdominal wall aggressive fibromatosis, while adhering to a "watchful waiting" policy. Other objectives are to investigate quality of life and to identify factors associated with tumor growth, in particular the relation with the presence of a CTNNB1-gene mutation in the tumor. DESIGN AND METHODS: GRAFITI is a nationwide, multicenter, prospective registration trial. All patients with extra-abdominal or abdominal wall aggressive fibromatosis are eligible for inclusion in the study. Main exclusion criteria are: history of familiar adenomatous polyposis, severe pain, functional impairment, life/limb threating situations in case of progressive disease. Patients included in the study will be treated with a watchful waiting policy during a period of 5 years. Imaging studies with ultrasound and magnetic resonance imaging scan will be performed during follow-up to monitor possible growth: the first years every 3 months, the second year twice and the yearly. In addition patients will be asked to complete a quality of life questionnaire on specific follow-up moments. The primary endpoint is the rate of progression per year, defined by the Response Evaluation Criteria In Solid Tumors (RECIST). Secondary endpoints are quality of life and the rate of influence on tumor progression for several factors, such as CTNNB1-mutations, age and localization. DISCUSSION: This study will provide insight in tumor behavior, the effect on quality of life and clinicopathological factors predictive of tumor progression. TRIAL REGISTRATION: The GRAFITI trial is registered in the Netherlands National Trial Register (NTR), number 4714 .


Assuntos
Neoplasias Abdominais/complicações , Neoplasias Abdominais/patologia , Polipose Adenomatosa do Colo/complicações , Polipose Adenomatosa do Colo/patologia , Fibromatose Agressiva/complicações , Fibromatose Agressiva/patologia , Projetos de Pesquisa , Neoplasias Abdominais/genética , Polipose Adenomatosa do Colo/genética , Adulto , Idoso , Análise Mutacional de DNA , Progressão da Doença , Feminino , Fibromatose Agressiva/genética , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Países Baixos , Qualidade de Vida , Conduta Expectante , beta Catenina/genética
20.
Nat Genet ; 48(8): 848-55, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27348297

RESUMO

Recent studies have detailed the genomic landscape of primary endometrial cancers, but the evolution of these cancers into metastases has not been characterized. We performed whole-exome sequencing of 98 tumor biopsies including complex atypical hyperplasias, primary tumors and paired abdominopelvic metastases to survey the evolutionary landscape of endometrial cancer. We expanded and reanalyzed The Cancer Genome Atlas (TCGA) data, identifying new recurrent alterations in primary tumors, including mutations in the estrogen receptor cofactor gene NRIP1 in 12% of patients. We found that likely driver events were present in both primary and metastatic tissue samples, with notable exceptions such as ARID1A mutations. Phylogenetic analyses indicated that the sampled metastases typically arose from a common ancestral subclone that was not detected in the primary tumor biopsy. These data demonstrate extensive genetic heterogeneity in endometrial cancers and relative homogeneity across metastatic sites.


Assuntos
Neoplasias Abdominais/genética , Biomarcadores Tumorais/genética , Hiperplasia Endometrial/genética , Neoplasias do Endométrio/genética , Evolução Molecular , Mutação/genética , Neoplasias Pélvicas/genética , Neoplasias Abdominais/secundário , Progressão da Doença , Hiperplasia Endometrial/patologia , Neoplasias do Endométrio/patologia , Exoma/genética , Feminino , Genômica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neoplasias Pélvicas/secundário , Filogenia
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