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1.
Rinsho Ketsueki ; 61(2): 103-109, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32147608

RESUMO

A 69-year-old woman with leukocytopenia and thrombocytopenia was referred to our hospital. Her bone marrow comprised 70.5% abnormal promyelocytes that were positive for myeloperoxidase/CD33/CD117 and CD13 (dim) and negative for CD2/CD34/CD56 and HLA-DR. Chromosome analysis of the bone marrow showed t (12;17;15) (p13;q21;q22), and fluorescence in situ hybridization revealed the PML-RARA fusion signal only on the derivative chromosome 15. The patient was diagnosed with acute promyelocytic leukemia (APL) with PML-RARA and was treated using all-trans retinoic acid (ATRA). In peripheral blood (PB), PML-RARA-positive polymorphonuclear cells (PMNs) appeared on the second week and became negative on the sixth week after treatment, whereas PML-RARA-negative PMNs started to increase in number on the sixth week. Molecular remission was confirmed on the 10th week. Quantitative evaluation of the differentiated leukemic cells of APL and recovered cells from normal hematopoiesis in PB can provide useful information for a safer induction therapy. No significant difference was noted in the kinetics of the leukemic cells under ATRA treatment as well as in the clinical features between our patient without RARA-PML and those with t (15;17), which is a cytogenetic evidence for the critical role of PML-RARA in the pathogenesis of APL.


Assuntos
Leucemia Promielocítica Aguda , Idoso , Cromossomos Humanos , Feminino , Humanos , Hibridização in Situ Fluorescente , Cinética , Leucemia Promielocítica Aguda/genética , Proteínas de Fusão Oncogênica , Translocação Genética , Tretinoína
2.
Ann Hematol ; 99(3): 487-500, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32006151

RESUMO

Fusion partners of KMT2A affect disease phenotype and influence the current World Health Organization classification of hematologic neoplasms. The t(11;16)(q23;p13)/KMT2A-CREBBP is considered presumptive evidence of a myelodysplastic syndrome (MDS) and a MDS-related cytogenetic abnormality in the classification of acute myeloid leukemia (AML). Here, we report 18 cases of hematologic neoplasms with t(11;16). There were 8 males and 10 females with a median age of 51.9 years at time of detection of t(11;16). Of 17 patients with enough clinical information and pathological materials for review, 16 had a history of cytotoxic therapies for various malignancies including 12/15 patients who received topoisomerase II inhibitors, and 15 were classified as having therapy-related neoplasms. The median interval from the diagnosis of primary malignancy to the detection of t(11;16) was 23.2 months. Dysplasia, usually mild, was observed in 7/17 patients. Blasts demonstrated monocytic differentiation in 8/8 patients who developed AML at the time or following detection of t(11;16). t(11;16) was observed as the sole chromosomal abnormality in 10/18 patients. KMT2A rearrangement was confirmed in 11/11 patients. The median survival from the detection of t(11;16) was 15.4 months. In summary, t(11;16)(q23;p13) is rare and overwhelmingly associated with prior exposure of cytotoxic therapy. Instead of being considered presumptive evidence of myelodysplasia, we suggest that the detection of t(11;16) should automatically prompt a search for a history of malignancy and cytotoxic therapy so that proper risk stratification and clinical management are made accordingly. The dismal outcome of patients with t(11;16) is in keeping with that of therapy-related neoplasms.


Assuntos
Proteína de Ligação a CREB/genética , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 16/genética , Bases de Dados Factuais , Neoplasias Hematológicas , Histona-Lisina N-Metiltransferase/genética , Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Proteína de Leucina Linfoide-Mieloide/genética , Segunda Neoplasia Primária , Proteínas de Fusão Oncogênica/genética , Inibidores da Topoisomerase II/administração & dosagem , Translocação Genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/mortalidade , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/mortalidade , Segunda Neoplasia Primária/tratamento farmacológico , Segunda Neoplasia Primária/genética , Segunda Neoplasia Primária/mortalidade , Medição de Risco
3.
Cancer Treat Rev ; 85: 101987, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32092619

RESUMO

AIMS: To make recommendations on the indications for molecular testing regarding the diagnosis, prediction of prognosis, and treatment selection in adult patients with s oft tissue sarcomas (STS) excluding gastrointestinal stromal tumour. MATERIALS AND METHODS: This guideline was developed by the Cancer Care Ontario's Program in Evidence-Based Care (PEBC) and the Sarcoma Disease Site Group (DSG). The medline, embase, and Cochrane Library databases, main guideline websites, abstracts of relevant annual meetings, and PROSPERO databases were searched (January 2005 to October 2016). Internal and external reviews were conducted, with final approval by the PEBC and the Sarcoma DSG. RESULTS: Based on the available evidence, we made three S trong Recommendations, 14 Recommendations, 9 Qualified Statements, and seven No Recommendations. The three Strong Recommendations include: i) MDM2 amplification by fluorescence in situ hybridization (FISH) is recommended as a sensitive and specific test to differentiate patients with atypical lipomatous tumour/well-differentiated liposarcoma, or dedifferentiated liposarcoma from lipoma or other STS in the differential diagnosis; ii) SS18 (SYT) break-apart by FISH or SS18-SSX (SYT-SSX) fusion by reverse transcription-polymerase chain reaction is recommended as a sensitive and specific test to differentiate patients with synovial sarcoma from other sarcomas; iii) CTNNB1 S45F mutation by polymerase chain reaction is recommended as a prognostic factor for poor recurrence-free survival in patients with desmoid tumours. CONCLUSION: This guideline may serve as a framework for the thoughtful implementation of molecular studies at cancer centres and other jurisdictions. Some of the recommendations may need to be updated when new evidence appears in the future.


Assuntos
Biomarcadores Tumorais/genética , Proteínas de Fusão Oncogênica/genética , Guias de Prática Clínica como Assunto , Sarcoma/genética , Neoplasias de Tecidos Moles/genética , Medicina Baseada em Evidências , Feminino , Tumores do Estroma Gastrointestinal/diagnóstico , Tumores do Estroma Gastrointestinal/genética , Testes Genéticos , Humanos , Masculino , Ontário , Prognóstico , Sarcoma/diagnóstico , Sarcoma/terapia , Sensibilidade e Especificidade , Neoplasias de Tecidos Moles/diagnóstico , Neoplasias de Tecidos Moles/terapia
4.
Anticancer Res ; 40(2): 957-964, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32014940

RESUMO

BACKGROUND/AIM: To describe real clinical outcomes when using systemic therapy to treat non-small cell lung cancer (NSCLC) patients who have anaplastic lymphoma kinase (ALK) fusion gene mutation. PATIENTS AND METHODS: We performed a retrospective chart review from April 2008 to March 2019 sourced from 16 medical institutes that cover a population of three million people. RESULTS: There were 129 ALK rearranged NSCLC patients. Among them, 103 patients including 40 recurrent disease cases received ALK-tyrosine kinase inhibitors (TKI) and chemotherapy. Our treatment results were comparable to previously reported clinical trials and clinical practice studies. First-line alectinib, treatment sequence of ALK-TKI followed by another ALK-TKI, and pemetrexed-containing chemotherapy contributed to the outcome of treatment. CONCLUSION: By arrangement of treatment such as treatment sequence of ALK-TKI and chemotherapy regimen, it might be possible to obtain a treatment outcome almost equivalent to those of clinical trials even in real clinical practice.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/etiologia , Rearranjo Gênico , Neoplasias Pulmonares/etiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Quinase do Linfoma Anaplásico/genética , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/terapia , Gerenciamento Clínico , Feminino , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/terapia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Proteínas de Fusão Oncogênica/genética , Prognóstico , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Estudos Retrospectivos , Resultado do Tratamento , Carga Tumoral
5.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(1): 24-28, 2020 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-32027248

RESUMO

OBJECTIVE: To investigate the clinical manifestations and laboratory features of B-ALL patients with EP300-ZNF384 fusion gene positive, so as to improve the understanding of this subtype disease. METHODS: The clinical data of 3 B-ALL patients with EP300-ZNF384 fusion gene positive admitted in Department of Hematology, the first medical center of Chinese PLA general hospital from February 2017 to February 2018 were collected and analyzed retrospectively. The clinical and laboratory characteristics as well as the therapentic outcome in B-ALL patients with EP300-ZNF384 fusion gene positive were analyzed. RESULTS: The fusion gene of EP300-ZNF384 was detected in 8.1%(3/37) of B-ALL patients. All cases showed the normal karyotype and aberrant CD13 and/or CD33 expression for immunophenotype. 3 patients were sensitive to traditional chemotherapy. CONCLUSION: The B-ALL with EEP300-ZNF384 fusion gene positive may be a subgroup of B-ALL with a uniqe clinical characteristis and laboatorial features. EP300-ZNF384 positive patients show a good response to conventional chemotherapy, suggesting a favorable prognosis.


Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras , Proteína p300 Associada a E1A , Humanos , Proteínas de Fusão Oncogênica , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Estudos Retrospectivos , Transativadores , Fatores de Transcrição
6.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(1): 68-75, 2020 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-32027255

RESUMO

OBJECTIVE: To explore the clinical characteristics and therapeutic efficacy of patient with adult acute lymphoblastic leukemia(ALL). METHODS: Seventy-seven ALL patients diagnosed in the first affiliated hospital of Zhengzhou University from 2018 to 2019 were selected. The immunotyping, fusion gene and gene mutation were detected by flow cytometry, real-time quantitative polymerase chain reaction (RT-PCR) and next generation sequencing (NGS). RESULTS: Among 77 patients with ALL, 66 were B-ALL, 9 were T-ALL. CD7 and cCD3 were the most valuable for the diagnosis of T-ALL, CD19 and cCD79a were the most valuable for the diagnosis of B-ALL, and CD58, CD123 were highly expressed in B-ALL. Three fusion genes: BCR-ABL (20.8%), MLL-AF4 (5.19%) and E2A-PBX1 (2.60%) were detected by RT-PCR and 10 mutant genes were detected by NGS (the total detection rate was 33.47%). The highest mutation rates were IL-7R (6 cases), NOTCH1 (6 cases), TP53 (5 cases) and FLT-3 (4 cases). Patients with IL-7R, NOTCH1 and TP53 mutations showed poor response to induction chemotherapy. CONCLUSION: The CD123, IL-7R, NOTCH1 and TP53 may be risk factors for prognosis, however, the increase of case number and prolonging of follow-up time are needed to further confirm.


Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras , Adulto , Proteínas de Fusão bcr-abl , Humanos , Proteínas de Fusão Oncogênica , Prognóstico
7.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(1): 125-129, 2020 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-32027264

RESUMO

OBJECTIVE: To analyze relation of ASXL2 gene mutation with the clinical characteristics, prognosis and C-KIT gene mutation in acute myeloid leukemia (AML) patients with AML1-ETO fusion gene. METHODS: The clinical data of 63 primary AML patients with AML1-ETO fusion gene were collected and retrospectively analyzed. The mutation of ASXL2 gene was directly sequenced by PCR. The clinical characteristics, C-KIT mutation rate and prognosis were compared between the patients with ASXL2 gene mutation (group A) and non-mutation (group B). RESULTS: Among 63 patients, 8 (12.70%) cases of ASXL2 mutation gene was detected. Hemoglobin level in peripheral blood of patients in group A was significantly lower than that in group B (P<0.01). There was no significant difference in sex, ages proportion of bone marrow blasts, lymph node enlargement, peripheral blood leukocytes count and platelets between the two groups (P>0.05). The infiltration of central nervous system, liver and spleen was not found in both groups. The expression of CD33 in group A was significantly lower than that in group B (P<0.05), but the results of other immunophenotype analysis were not significantly different between the two groups (P>0.05). The remission rate and median survival time were not significantly different between two groups (P>0.05). The detection rate of C-KIT gene mutation were not significantly different between group A and group B (P>0.05). CONCLUSION: Among AML patients with AML1-ETO fusion gene, ASXL2 gene mutation accounts for a certain ratio, and the peripheral blood hemoglobin concentration and CD33 expression in these patients are often low. At the same time, ASXL2 gene mutation may not be closely related with C-KIT gene mutation.


Assuntos
Leucemia Mieloide Aguda , Proteínas Proto-Oncogênicas c-kit/genética , Proteínas Repressoras/genética , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Humanos , Leucemia Mieloide Aguda/genética , Mutação , Proteínas de Fusão Oncogênica/genética , Prognóstico , Proteína 1 Parceira de Translocação de RUNX1/genética , Estudos Retrospectivos
8.
Zhonghua Jie He He Hu Xi Za Zhi ; 43(2): 120-125, 2020 Feb 12.
Artigo em Chinês | MEDLINE | ID: mdl-32062881

RESUMO

Objective: To study the prevalence of c-ros oncogene 1 fusion in lung adenocarcinoma and to evaluate its relationship with clinical characteristics. Methods: We retrospectively analyzed epidermal growth factor receptor (EGFR) mutation, anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) fusion in 1 482 patients with adenocarcinoma from March 2014 to January 2017 in the first affiliated hospital of Zhejiang University. Furthermore, ROS1 fusion positive patients diagnosed between February 2017 and December 2017 were also included in ROS1 positive group. The data of age, sex, smoking history, TNM stage and chest computed tomography were collected by Electronic Medical Record (EMR). The clinical data were compared by the chi-squared test or Mann-Whitney test. Results: Of these 1 482 patients,54 cases were diagnosed with ROS1 rearrangement, including 19 males and 35 females, while 73 cases were diagnosed with ALK rearrangement, including 28 males and 45 females, and 679 cases diagnosed with EGFR mutation including 293 males and 386 females. And there were 676 patients without driven genes mutation. The mean age in ROS1 fusion group (54±12) was lower than EGFR mutation group (60±11, z=-3.982, P<0.001) and WT group (62±10, z=-4.944, P<0.001). Female proportion in ROS1 fusion group (64.8%, 35/54) was higher than WT group (28.4%, 192/676, χ(2)=30.94, P<0.001). Non-smoker percentages in ROS1 fusion group (72.2%, 39/54) was significantly higher than WT group (38.0%,257/676, χ(2)=24.27, P<0.001). ROS1 fusion group was similar to ALK fusion group in sex, age and smoking history, and there were no significant difference in TNM stage among these groups. On chest CT, adenocarcinomas with ROS1 fusion were found to be more peripheral in location (71.4%, 20/28) and solid in density (75%, 21/28), usually with lobulated margins (75.0%, 21/28) and spiculated in contour (57.1%,16/28). Conclusion: In our study lung adenocarcinoma with c-ROS oncogene 1 fusion was a rare subtype lung cancer and was usually detected in young, never smoking, and female patients.


Assuntos
Adenocarcinoma de Pulmão/diagnóstico , Quinase do Linfoma Anaplásico/genética , Receptores ErbB/genética , Neoplasias Pulmonares/diagnóstico , Proteínas Tirosina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Receptores Proteína Tirosina Quinases/genética , Adenocarcinoma de Pulmão/epidemiologia , Adenocarcinoma de Pulmão/genética , Adulto , Idoso , Quinase do Linfoma Anaplásico/metabolismo , China/epidemiologia , Feminino , Fusão Gênica/genética , Genes erbB-1 , Humanos , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Mutação/genética , Proteínas de Fusão Oncogênica , Prevalência , Proteínas Tirosina Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Espécies Reativas de Oxigênio , Estudos Retrospectivos
9.
Anticancer Res ; 40(1): 245-252, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31892573

RESUMO

AIM: It has been shown that the integration of hepatitis B virus (HBV) gene into the host genome is a high-risk factor for development of hepatocellular carcinoma (HCC). However, the relationship between HBV S-integrated human extra spindle pole bodies-like 1 (ESPL1) gene and HCC is unknown. This study was designed to detect HBV S-integrated human ESPL1 fusion gene in patients with HCC for potentially using this fusion gene as a biomarker for HCC diagnosis. PATIENTS AND METHODS: Nineteen and 70 patients with chronic hepatitis B (CHB) were recruited to the experimental and control groups, respectively, and both groups underwent an effective nucleoside/nucleotide analog therapy and follow-up for HCC occurrence for up to 11 years. HCC tissues were obtained by surgical resection from the experimental group, while liver tissues were collected by liver biopsy in the control group prior to treatment with nucleoside/nucleotide analogs. Alu polymerase chain reaction was used to assess HBV S gene integration in the liver tissues from both groups. HBV S-integrated human ESPL1 fusion gene was then detected in patients with HBV S gene integration using a gene database. RESULTS: All patients in the experimental group developed HCC, whereas no HCC was diagnosed in the control group. HBV S gene integration was identified in 12 out of 19 HCC tissues in the experimental group, giving a detection rate of 63.2%, which was significantly greater than that of 15.7% (11/70) in the control group (p<0.001). We further showed that HBV S-integrated human ESPL1 fusion gene was detected in eight patients (rate of 66.7%) among the 12 patients with HCC with HBV S gene integration in the experimental group, whereas the fusion gene was not detectable in any of the patients in the control group (p=0.001). CONCLUSION: This research demonstrates a high detection rate of HBV S-integrated human ESPL1 fusion gene in patients with HBV-related HCC and shows that this fusion gene appears to be associated with HCC development in patients with CHB. These findings suggest that HBV S-integrated human ESPL1 fusion gene may potentially serve as a biomarker for early detection of HCC in HBV-infected populations.


Assuntos
Grupo com Ancestrais do Continente Asiático , Vírus da Hepatite B/genética , Neoplasias Hepáticas/genética , Proteínas de Fusão Oncogênica/genética , Separase/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Estudos de Casos e Controles , Feminino , Regulação Neoplásica da Expressão Gênica , Hepatite B Crônica/genética , Humanos , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Proteínas de Fusão Oncogênica/metabolismo , Separase/metabolismo , Proteínas do Envelope Viral/genética , Proteínas do Envelope Viral/metabolismo
11.
Virchows Arch ; 476(2): 317-322, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31385070

RESUMO

We here document a sarcoma with a recently reported MGA-NUTM1 fusion. A 49-year-old man presented with a nodule in the right lung, which grew to a giant mass in 5 years. The tumor showed uniform oval to spindle cell proliferation in a hypervascular stroma, associated with focal myxoid change and peculiar collagen deposition resembling an osteoid. The tumor showed an undifferentiated phenotype, including negativity for cytokeratin, although it was immunoreactive to BCOR and MUC4, and was initially suspected as BCOR-associated sarcoma. After complete resection, the tumor recurred in the mediastinal lymph node, and the patient died of the disease. RNA sequencing detected MGA (exon 22)-NUTM1 (exon 3), which was confirmed by reverse transcriptase-polymerase chain reaction, Sanger sequencing, fluorescence in situ hybridization, and NUT immunohistochemistry. Clinicopathological features of the present case were similar to some of the reported cases of MGA-NUTM1 sarcomas, suggesting the emergence of a distinct tumor subtype.


Assuntos
Proteínas de Neoplasias/genética , Recidiva Local de Neoplasia/patologia , Proteínas Nucleares/genética , Proteínas de Fusão Oncogênica/genética , Sarcoma/patologia , Biomarcadores Tumorais/análise , Humanos , Hibridização in Situ Fluorescente/métodos , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/metabolismo , Recidiva Local de Neoplasia/genética , Proteínas Nucleares/metabolismo , Proteínas Repressoras/genética , Sarcoma/genética , Neoplasias de Tecidos Moles/patologia , Fatores de Transcrição/genética
12.
Virchows Arch ; 476(2): 295-305, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31423558

RESUMO

Secretory carcinoma of the salivary gland is a newly recognized entity that morphologically resembles breast secretory carcinoma and has a characteristic t(12;15)(p13;q25) ETV6-NTRK3 translocation. Fluorescence in situ hybridization (FISH) or reverse transcription polymerase chain reaction (RT-PCR) analyses can detect the ETV6-NTRK3 fusion; however, both tests are expensive and not widely available. In this study, we aimed to determine whether pan-Trk immunohistochemistry (IHC) could detect ETV6-NTRK3 fusions as reliably as RT-PCR and FISH. We performed pan-Trk IHC in 70 salivary gland cancer samples, including secretory carcinomas, acinic cell carcinomas, and hybrid carcinomas. Nineteen tumors exhibited positive pan-Trk staining, including 16 secretory carcinomas, 2 hybrid carcinomas with a secretory carcinoma component, and 1 acinic cell carcinoma. Pan-Trk IHC staining was localized in the nucleus in 16 (84.2%) cases and in the cytoplasm and/or membrane in 3 (15.8%) cases. RT-PCR analysis for the ETV6-NTRK3 transcript was conducted in 45 samples; the fusion transcript was present in 11 of 12 secretory carcinomas and absent in 32 acinic cell carcinomas and 1 mucoepidermoid carcinoma. Pan-Trk IHC was positive in 10 of 11 salivary tumors that were positive for ETV6-NTRK3 by RT-PCR and negative in all 34 tumors that were negative for the fusion by RT-PCR. Therefore, in comparison with RT-PCR, pan-Trk IHC had a sensitivity of 90.9% and specificity of 100%. In conclusion, our data showed that pan-Trk IHC is a reasonable screening test for diagnosing secretory carcinoma of the salivary gland.


Assuntos
Neoplasias da Mama/patologia , Carcinoma/patologia , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Neoplasias das Glândulas Salivares/patologia , Biomarcadores Tumorais/análise , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Carcinoma/diagnóstico , Carcinoma/genética , Carcinoma de Células Acinares/genética , Carcinoma de Células Acinares/patologia , Humanos , Imuno-Histoquímica/métodos , Hibridização in Situ Fluorescente/métodos , Proteínas Proto-Oncogênicas c-ets/genética , Proteínas Repressoras/genética , Neoplasias das Glândulas Salivares/diagnóstico , Neoplasias das Glândulas Salivares/genética , Glândulas Salivares/metabolismo
13.
Int J Cancer ; 146(7): 2036-2046, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-31732966

RESUMO

In prostate adenocarcinoma (PCa), distinction between indolent and aggressive disease is challenging. Around 50% of PCa are characterized by TMPRSS2-ERG (T2E)-fusion oncoproteins defining two molecular subtypes (T2E-positive/negative). However, current prognostic tests do not differ between both molecular subtypes, which might affect outcome prediction. To investigate gene-signatures associated with metastasis in T2E-positive and T2E-negative PCa independently, we integrated tumor transcriptomes and clinicopathological data of two cohorts (total n = 783), and analyzed metastasis-associated gene-signatures regarding the T2E-status. Here, we show that the prognostic value of biomarkers in PCa critically depends on the T2E-status. Using gene-set enrichment analyses, we uncovered that metastatic T2E-positive and T2E-negative PCa are characterized by distinct gene-signatures. In addition, by testing genes shared by several functional gene-signatures for their association with event-free survival in a validation cohort (n = 272), we identified five genes (ASPN, BGN, COL1A1, RRM2 and TYMS)-three of which are included in commercially available prognostic tests-whose high expression was significantly associated with worse outcome exclusively in T2E-negative PCa. Among these genes, RRM2 and TYMS were validated by immunohistochemistry in another validation cohort (n = 135), and several of them proved to add prognostic information to current clinicopathological predictors, such as Gleason score, exclusively for T2E-negative patients. No prognostic biomarkers were identified exclusively for T2E-positive tumors. Collectively, our study discovers that the T2E-status, which is per se not a strong prognostic biomarker, crucially determines the prognostic value of other biomarkers. Our data suggest that the molecular subtype needs to be considered when applying prognostic biomarkers for outcome prediction in PCa.


Assuntos
Adenocarcinoma/genética , Adenocarcinoma/mortalidade , Biomarcadores Tumorais , Proteínas de Fusão Oncogênica/genética , Neoplasias da Próstata/genética , Neoplasias da Próstata/mortalidade , Adenocarcinoma/diagnóstico , Biologia Computacional , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Masculino , Gradação de Tumores , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , Neoplasias da Próstata/diagnóstico
14.
Hematol Oncol ; 38(1): 82-88, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31875988

RESUMO

Identification of gene fusion is an essential part in the management of patients with acute leukemia, not only for diagnosis but also in predicting the treatment outcome and selecting appropriate treatment. Adopting next-generation sequencing (NGS) technology for identification of gene fusion in patients with acute leukemia can be a good alternative to conventional tests. In the present study, the NGS RNA fusion gene panel test was applied to diagnostic samples of patients with acute leukemia to identify fusion genes more efficiently. Among 134 patients with acute leukemia, 53 gene fusions were detected in 52 patients. In addition to the recurrent gene fusions specified in the WHO diagnostic criteria, 11 rare or novel gene fusions were identified. Of those, two were gene fusions associated with Philadelphia-like acute lymphoblastic leukemia (Ph-like ALL), two were novel gene fusions, three were gene fusions with novel partner genes, and six were rare gene fusions from previous reports. We confirmed the clinical utility of the NGS test in identifying clinically significant gene fusions such as gene fusions involving KMT2A that has a large number of partners. Notably, Ph-like ALL-associated gene fusions could be easily identified despite the wide variety of genes involved. The results from the present study may contribute toward a better understanding of the genomic landscape of acute leukemia as well as patient management.


Assuntos
Biomarcadores Tumorais/genética , Fusão Gênica , Genômica/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Leucemia Mieloide Aguda/genética , Proteínas de Fusão Oncogênica , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Humanos , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Prognóstico , Recidiva , Adulto Jovem
16.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 27(6): 1767-1773, 2019 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-31839036

RESUMO

OBJECTIVE: To analyze the related factors affecting the long-term prognosis of acute myeloid leukemia (AML) children with positive RUNX1-RUNX1T1. METHODS: The clinical data of 63 chlidren with positive RUNX1-RUNX1T1 AML treated by BCH-AML 05 regimen in our hospital from January 2010 to December 2015 were collected and analyzed retrospectively. The level of RUNX1-RUNX1T1 was detected at the time of initial diagnosis (T1), after the first induction treatment (T2), after the second induction treatment (T3), after the first consolidation treatment (T4), after the second consolidation treatment (T5) and after the third consolidation treatment (T6). According to the fusion transcript levels of RUNX1-RUNX1T1 the AML children were divided into low-expression group and high-expression group; the threshold values for grouping were 104 copies/104 ß-glucuronidase (GUS), 103 copies/104 GUS, 102 copies/104 GUS, 10 copies/104 GUS, 1 copies/104 GUS and 0 copies respectively. The gained data were enrolled in the statistical analysis. RESULTS: 23 cases of 63 children died during the follow-up period, and the median follow-up time of the remaining 40 children were 30.04 (11-60) months. There were statistically significant differences in CD15 positive rate between low-expression group and high-expression group (P<0.05), however, there were no statistically significant differences in sex, age, FAB typing, platelet (Plt) count, hemoglobin (Hb) and white blood cell (WBC) count and the ratio of bone marrow immature cells at T2 between the two groups (P>0.05). Univariate analysis showed that sex, Plt counts at T1 and fusion transcript levels at T1, T2 and T6 correlated with the 5-year overall survival rate (P<0.05). Multivariate analysis showed that fusion transcript level >103 copies/104 GUS at T2 was an independent risk factor for 5-year overall survival rate (HR=2.13, 95%CI: 1.04-7.78)(P<0.05). CONCLUSION: The fusion transcript level after the first induction therapy in RUNX1-RUNX1T1-positive AML children is an independent factor influencing the long-term prognosis.


Assuntos
Leucemia Mieloide Aguda , Criança , Subunidade alfa 2 de Fator de Ligação ao Core , Humanos , Proteínas de Fusão Oncogênica , Prognóstico , Proteína 1 Parceira de Translocação de RUNX1 , Estudos Retrospectivos
17.
Crit Rev Oncol Hematol ; 144: 102826, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31707223

RESUMO

NMC is a recently recognized cancer type hallmarked by chromosomal translocation involving the NUT gene, a catastrophic event leading to fusion oncoprotein responsible for malignant transformation and tumor progression. The aggressiveness of disease together with a poor response to conventional treatment make NMC one of the most lethal cancer. Moreover, although until recently NMC has been poorly understood and largely neglected, the number of reported cases is steadily rising. Recently, in addition to its pathogenetic and diagnostic role, NUT-fusion oncoprotein has been shown to be amenable to targeted inhibition using BET inhibitors. Future clinical trials are warranted with the aim of investigate the incorporation of targeted agent into multimodal therapeutic strategy. Since new promising NUT-targeting drugs are emerging that may affect the clinical course, the correct and prompt recognition of NMC is key to improve patients' outcome.


Assuntos
Carcinoma , Proteínas Nucleares , Transformação Celular Neoplásica , Humanos , Proteínas de Fusão Oncogênica , Translocação Genética
19.
Hematol Oncol ; 37(5): 617-625, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31701557

RESUMO

Immortalized cell lines are useful for deciphering the pathogenesis of acute leukemia and developing novel therapeutic agents against this malignancy. In this study, a new human myeloid leukemia cell line YBT-5 was established. After more than 1-year cultivation from the bone marrow of a patient with acute monocytic leukemia, YBT cell line was established. Then a subclone, YBT-5, was isolated from YBT using single cell sorting. Morphological and cytogenetical characterizations of the YBT-5 cell line were determined by cytochemical staining, flow cytometry analysis, and karyotype analysis. Molecular features were identified by transcriptomic analysis and reverse transcription-polymerase chain reaction. To establish a tumor model, 5 × 106 YBT-5 cells were injected subcutaneously in nonobese diabetic/severe combined immune-deficiency (NOD/SCID) mice. DOT1L has been proposed as a potential therapeutic target for KMT2A-related leukemia; therefore, to explore the potential application of this new cell line, its sensitivity to a specific DOT1L inhibitor, EPZ004777 was measured ex vivo. The growth of YBT-5 does not depend on granulocyte-macrophage colony-stimulating factor. Cytochemical staining showed that α-naphthyl acetate esterase staining was positive and partially inhibited by sodium fluoride, while peroxidase staining was negative. Flow cytometry analysis of YBT-5 cells showed positive myeloid and monocytic markers. Karyotype analysis of YBT-5 showed 48,XY,+8,+8. The breakpoints between KMT2A exon 10 and exon 11 (KMT2A exon 10/11) and MLLT3 exon 5 and exon 6 (MLLT3 exon 5/6) were identified, which was different from all known breakpoint locations, and a novel fusion transcript KMT2A exon 10/MLLT3 exon 6 was formed. A tumor model was established successfully in NOD/SCID mice. EPZ004777 could inhibit the proliferation and induce the differentiation of YBT-5 cells. Therefore, a new acute monocytic leukemia cell line with clear biological and molecular features was established and may be used in the research and development of new agents targeting KMT2A-associated leukemia.


Assuntos
Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Histona-Lisina N-Metiltransferase/antagonistas & inibidores , Histona-Lisina N-Metiltransferase/genética , Proteína de Leucina Linfoide-Mieloide/genética , Proteínas Nucleares/genética , Proteínas de Fusão Oncogênica/genética , Animais , Biomarcadores , Células da Medula Óssea , Linhagem Celular Tumoral , Modelos Animais de Doenças , Humanos , Imunofenotipagem , Hibridização in Situ Fluorescente , Cariotipagem , Leucemia Monocítica Aguda/tratamento farmacológico , Leucemia Monocítica Aguda/genética , Leucemia Monocítica Aguda/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase em Tempo Real , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Cancer Treat Rev ; 81: 101911, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31715421

RESUMO

The RET proto-oncogene has been well-studied. RET is involved in many different physiological and developmental functions. When altered, RET mutations influence disease in a variety of organ systems from Hirschsprung's disease and multiple endocrine neoplasia 2 (MEN2) to papillary thyroid carcinoma (PTC) and non-small cell lung cancer (NSCLC). Changes in RET expression have been discovered in 30-70% of invasive breast cancers and 50-60% of pancreatic ductal adenocarcinomas in addition to colorectal adenocarcinoma, melanoma, small cell lung cancer, neuroblastoma, and small intestine neuroendocrine tumors. RET mutations have been associated with tumor proliferation, invasion, and migration. RET fusions or rearrangements are somatic juxtapositions of 5' sequences from other genes with 3' RET sequences encoding tyrosine kinase. RET rearrangements occur in approximately 2.5-73% of sporadic PTC and 1-3% of NSCLC patients. The most common RET fusions are CDCC6-RET and NCOA4-RET in PTC and KIF5B-RET in NSCLC. Tyrosine kinase inhibitors are drugs that target kinases such as RET in RET-driven (RET-mutation or RET-fusion-positive) disease. Multikinase inhibitors (MKI) target various kinases and other receptors. Several MKIs are FDA-approved for cancer therapy (sunitinib, sorafenib, vandetanib, cabozantinib, regorafenib, ponatinib, lenvatinib, alectinib) and non-oncologic disease (nintedanib). Selective RET inhibitor drugs LOXO-292 (selpercatinib) and BLU-667 (pralsetinib) are also undergoing phase I/II and I clinical trials, respectively, with preliminary results demonstrating partial response and low incidence of serious adverse events. RET fusions provide a viable therapeutic target for oncologic treatment, and further study is warranted into the prevalence and pathogenesis of RET fusions as well as development of current and new tyrosine kinase inhibitors.


Assuntos
Antineoplásicos/uso terapêutico , Proteínas de Fusão Oncogênica/genética , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-ret/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-ret/genética , Antineoplásicos/farmacologia , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Terapia de Alvo Molecular , Proteínas de Fusão Oncogênica/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-ret/metabolismo , Neoplasias da Glândula Tireoide/genética
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