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1.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(11): 1077-1080, 2019 Nov 10.
Artigo em Chinês | MEDLINE | ID: mdl-31703129

RESUMO

OBJECTIVE: To assess the value of detecting multiple rearrangements of MLL gene in children with acute mononuclear leukemia (AML). METHODS: Eighty six children with AML were analyzed by fluorescence in situ hybridization (FISH), chromosomal karyotyping and multiplex reverse transcription-PCR (RT-PCR). RESULTS: Cross signals were detected by FISH in 26 cases, and 30.2% were detected with MLL gene rearrangements. R-band karyotyping analysis revealed 14 translocations with breakages involving 11q23 and 5 other aberrations, which yielded an overall detection rate of 22.1%. Multiple RT-PCR has detected 12 fusion genes produced by the MLL translocation, which yielded a detection rate of 14.0%. A significant difference was found in the detection rate of the three methods (P< 0.05). CONCLUSION: Combined use of FISH, chromosomal karyotyping and multiplex RT-PCR can improve the detection of MLL gene rearrangements and provide important clues for clinical diagnosis, treatment and prognosis of AML.


Assuntos
Histona-Lisina N-Metiltransferase/genética , Leucemia Mieloide Aguda/genética , Proteína de Leucina Linfoide-Mieloide/genética , Criança , Cromossomos Humanos Par 11 , Rearranjo Gênico , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Translocação Genética
2.
Rinsho Ketsueki ; 60(10): 1425-1430, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31695002

RESUMO

A 70-year-old man was admitted to our hospital due to fever, lymphadenopathy, and leukocytosis. White blood cell count was 22,700/µl with 92% blastoid cells. Bone marrow examination revealed abnormal lymphoid cell expansion. Abnormal cells expressed surface CD5 (dim), CD10, CD19, CD20, CD23 (dim) antigens, and kappa immunoglobulin light chains. Cytogenetic analysis of bone marrow cells at the time of diagnosis showed t (11:14) (q13;q32), t (14;18) (q32;q21), and t (8;14;18) (q24;q32;q21). Fluorescence in situ hybridization analyses of bone marrow identified translocations of IGH/MYC, IGH/BCL2, and IGH/CCND1. The patient was diagnosed with aggressive B-cell lymphoma with IGH/MYC, IGH/BCL2, and IGH/CCND1 translocation and was treated with various chemotherapies including R-CHOP, R-ESHAP, DA-EPOCH-R, R-hyper-CVAD, and radiotherapy. However, the lymphoma recurred after every chemotherapy session. Finally, he died after 6 months after first admission. Double-hit lymphoma/triple-hit lymphoma has previously been reported to present with an aggressive clinical course. In the present case, co-existence of IGH/CCND1, IGH/MYC, and IGH/BCL2 is very rare. Further clinical and biological investigations are necessary to establish an optimal treatment strategy.


Assuntos
Linfoma de Células B/genética , Translocação Genética , Idoso , Ciclina D1/genética , Evolução Fatal , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Hibridização in Situ Fluorescente , Linfoma de Células B/tratamento farmacológico , Masculino , Recidiva Local de Neoplasia , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-myc/genética
3.
Pathologe ; 40(6): 649-661, 2019 Nov.
Artigo em Alemão | MEDLINE | ID: mdl-31602505

RESUMO

Traditionally, tissue-based histopathological approaches play an outstanding role in the diagnostics of lung cancer. The importance of these methods has become even more important with the introduction of individualized treatment options. Lung cancer is basically classified following the World Health Organization (WHO) guidelines using conventional histology and immunohistochemistry. For individual entities in certain clinical stages, the evaluation of the tumor biological profile serves as the basis for the so-called individualized treatment or precision medicine where changes in the intracellular signal transduction mechanisms are the target of therapeutic efforts or the therapy tries to re-initiate immunogenic reactions of the autologous immune system against the tumor cells. The histopathologic overexpression of receptors as well as various genetic and epigenetic changes (e.g. inversion, translocation and methylation) are the key players for predictive approaches to uncover the individual tumor biology and to make treatment decisions.


Assuntos
Neoplasias Pulmonares , Patologia Molecular , Biomarcadores Tumorais , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/patologia , Técnicas de Diagnóstico Molecular , Medicina de Precisão , Translocação Genética
4.
Rinsho Ketsueki ; 60(9): 1236-1242, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31597849

RESUMO

Recent technology advances in genomic analysis have unraveled the genomic complexity and evolutionary process of multiple myeloma (MM). Hyperdiploidy or IgH translocations t (4;14), t (11;14), t (6;14), t (14;16), and t (14;20), leading to ectopic overexpression of MMSET/FGFR3, CCND1, CCND3, MAF, and MAFB, respectively, are initiating events. Subsequent secondary events, such as gene copy number alterations, and gene somatic mutations, participate in tumor progression in a branching pattern consistent with Darwin's evolutionary model. Copy number alterations, such as 1q21 amplification and del (17p), have been associated with adverse outcomes. N/KRAS mutations are most commonly found in around 20% of patients, but numerous gene mutations are infrequent. Pathological and clinical relevance of gene mutations combined with cytogenetic abnormalities are currently under investigation. Additionally, detailed genomic analysis of individual patients using targeted-sequencing panels has been facilitated, and efforts toward personalized therapy based on molecular features have begun. This paper outlines MM molecular pathology and its clinical application in Japanese patients.


Assuntos
Mieloma Múltiplo/genética , Aberrações Cromossômicas , Dosagem de Genes , Humanos , Japão , Translocação Genética
5.
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
6.
Zhonghua Bing Li Xue Za Zhi ; 48(10): 791-795, 2019 Oct 08.
Artigo em Chinês | MEDLINE | ID: mdl-31594044

RESUMO

Objective: To correlate chromosomal translocations of DUSP22 or TP63 with clinical significance in ALK-negative anaplastic large cell lymphoma (ALK(-)ALCL). Methods: Thirty-two patients with ALK(-)ALCL were selected from January 2004 to January 2014 at Fujian Provincial Hospital for the detection of chromosomal translocations of DUSP22 and TP63 by fluorescence in situ hybridization (FISH). The relationship between DUSP22 and TP63 chromosomal translocations and the clinicopathological parameters of ALK(-)ALCL was analyzed. Results: Among the 32 ALK(-)ALCL patients, 7(21.8%) had DUSP22 gene rearrangement (DUSP22(+)ALK(-)ALCL). Three patients (9.4%) had TP63 gene rearrangement (TP63(+) ALK(-)ALCL). There were 22 patients (68.8%) without rearrangement of either DUSP22 or TP63 (DUSP22(-)TP63(-)ALK(-)ALCL). The patients with DUSP22(+) ALK(-)ALCL were among the younger, and the patients with TP63(+) ALK(-)ALCL were among the elder. The mean age of patients with DUSP22(-)TP63(-)ALK(-) ALCL was between those of DUSP22(+)ALK(-)ALCL and TP63(+) ALK(-)ALCL (P<0.05). Based on Ann Arbor staging, incidence of DUSP22 gene rearrangement decreased as the clinical stage of ALK(-)ALCL increased (P<0.05). Incidence of TP63 gene rearrangement cases increases in patients at more advanced clinical stage(P<0.05). The five-year survival rate and prognosis of patients with DUSP22(+)ALK(-)ALCL were the highest. Patients with TP63(+) ALK(-)ALCL had the lower five-year survival and the worse prognosis (P<0.05). Conclusion: Presences of DUSP22 and TP63 chromosomal translocations correlate with the clinical stages and prognosis of ALK(-)ALCL and may be used for the differential diagnosis, determination of tumor aggressiveness and prognostication of ALK(-)ALCL.


Assuntos
Quinase do Linfoma Anaplásico/genética , Fosfatases de Especificidade Dupla/genética , Linfoma Anaplásico de Células Grandes/genética , Fosfatases da Proteína Quinase Ativada por Mitógeno/genética , Fatores de Transcrição/genética , Translocação Genética , Proteínas Supressoras de Tumor/genética , Humanos , Hibridização in Situ Fluorescente
7.
Nat Cell Biol ; 21(10): 1273-1285, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31548606

RESUMO

Chromosome translocation is a major cause of the onset and progression of diverse types of cancers. However, the mechanisms underlying this process remain poorly understood. Here, we identified a non-homologous end-joining protein, IFFO1, which structurally forms a heterotetramer with XRCC4. IFFO1 is recruited to the sites of DNA damage by XRCC4 and promotes the repair of DNA double-strand breaks in a parallel pathway with XLF. Interestingly, IFFO1 interacts with lamin A/C, forming an interior nucleoskeleton. Inactivating IFFO1 or its interaction with XRCC4 or lamin A/C leads to increases in both the mobility of broken ends and the frequency of chromosome translocation. Importantly, the destruction of this nucleoskeleton accounts for the elevated frequency of chromosome translocation in many types of cancer cells. Our results reveal that the lamin A/C-IFFO1-constituted nucleoskeleton prevents chromosome translocation by immobilizing broken DNA ends during tumorigenesis.


Assuntos
Carcinogênese/genética , Quebras de DNA de Cadeia Dupla , Reparo do DNA por Junção de Extremidades , Proteínas de Ligação a DNA/metabolismo , Lamina Tipo A/metabolismo , Translocação Genética , Animais , Carcinoma/genética , Cromossomos Humanos , Enzimas Reparadoras do DNA/genética , Enzimas Reparadoras do DNA/metabolismo , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/genética , Células HEK293 , Humanos , Proteínas de Filamentos Intermediários/genética , Camundongos , Matriz Nuclear/metabolismo , Proteínas Associadas à Matriz Nuclear/química , Proteínas Associadas à Matriz Nuclear/metabolismo , Proteínas Associadas à Matriz Nuclear/fisiologia
8.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(8): 777-780, 2019 Aug 10.
Artigo em Chinês | MEDLINE | ID: mdl-31400126

RESUMO

OBJECTIVE: To assess the value of detecting the rearrangement of mixed lineage leukemia (MLL) gene in children with acute mononuclear leukemia (AML). METHODS: Dual-color fluorescence in situ hybridization (FISH) probe was used to detect MLL gene rearrangement in 68 children with AML by interphase FISH. The results were compared with that of conventional G banding chromosomal analysis. RESULTS: Among the 68 children, 28 were detected by FISH with positive hybridization signals, with a detection rate for MLL gene rearrangement being 41.2%. Twelve (17.6%) reciprocal translocations and interruption of 11q23 were detected by G banding analysis. The difference in the detection rates between the two methods was statistically significant (P< 0.05). CONCLUSION: The sensitivity of FISH assay for MLL gene rearrangement was significantly higher than that of G banding chromosomal karyotyping. Combined use of both methods for children with AML can improve the detection rate of MLL gene rearrangements and provide crucial clues for clinical diagnosis, treatment and prognosis.


Assuntos
Histona-Lisina N-Metiltransferase/genética , Leucemia Monocítica Aguda/genética , Proteína de Leucina Linfoide-Mieloide/genética , Criança , Cromossomos Humanos Par 11 , Rearranjo Gênico , Humanos , Hibridização in Situ Fluorescente , Translocação Genética
9.
Chem Biol Interact ; 312: 108797, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31422076

RESUMO

Epidemiological studies of 1,3-butadiene (BD) exposures have reported a possible association with chronic myelogenous leukemia (CML), which is defined by the presence of the t(9;22) translocation (Philadelphia chromosome) creating an oncogenic BCR-ABL fusion gene. Butadiene diepoxide (DEB), the most mutagenic of three epoxides resulting from BD, forms DNA-DNA crosslink adducts that can lead to DNA double-strand breaks (DSBs). Thus, a study was designed to determine if (±)-DEB exposure of HL60 cells, a promyelocytic leukemia cell line lacking the Philadelphia chromosome, can produce t(9;22) translocations. In HL60 cells exposed for 3 h to 0-10 µM DEB, overlapping dose-response curves suggested a direct relationship between 1,4-bis-(guan-7-yl)-2,3-butanediol crosslink adduct formation (R = 0.977, P = 0.03) and cytotoxicity (R = 0.961, P = 0.002). Experiments to define the relationships between cytotoxicity and the induction of micronuclei (MN), a dosimeter of DNA DSBs, showed that 24 h exposures of HL60 cells to 0-5.0 µM DEB caused significant positive correlations between the concentration and (i) the degree of cytotoxicity (R = 0.998, p = 0.002) and (ii) the frequency of MN (R = 0.984, p = 0.016) at 48 h post exposure. To determine the relative induction of MN and t(9;22) translocations following exposures to DEB, or x-rays as a positive control for formation of t(9;22) translocations, HL60 cells were exposed for 24 h to 0, 1, 2.5, or 5 µM DEB or to 0, 2.0, 3.5, or 5.0 Gy x-rays, or treatments demonstrated to yield 0, 20%, 50%, or 80% cytotoxicity. Treatments between 0 and 3.5 Gy x-rays caused significant dose-related increases in both MN (p < 0.001) and t(9;22) translocations (p = 0.01), whereas DEB exposures causing similar cytotoxicity levels did not increase translocations over background. These data indicate that, while DEB induces DNA DSBs required for formation of MN and translocations, acute DEB exposures of HL60 cells did not produce the Philadelphia chromosome obligatory for CML.


Assuntos
Adutos de DNA/metabolismo , Compostos de Epóxi/toxicidade , Translocação Genética/efeitos dos fármacos , Butadienos/metabolismo , Adutos de DNA/análise , Compostos de Epóxi/química , Células HL-60 , Humanos , Radiação Ionizante , Translocação Genética/efeitos da radiação
10.
Cancer Sci ; 110(10): 3382-3390, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31444835

RESUMO

Anaplastic lymphoma kinase (ALK) fusions have been recognized as a therapeutic target in non-small cell lung cancer (NSCLC). However, molecular signatures and clinical characteristics of the Chinese population with ALK-rearranged NSCLC are not well elucidated. In the present study, we carried out targeted next-generation sequencing on tissue and plasma ctDNA samples in 1688 patients with NSCLC. Overall, ALK fusions were detected in 70 patients (4.1%), and the frequencies of ALK fusions detected in tissue and plasma samples were 5.1% and 3.3%, respectively. Additionally, the prevalence of breakpoint locations for EML4-ALK fusions in ctDNA was significantly correlated with that in tumor tissues (R2  = .91, P = .045). According to age, the incidence rates of ALK fusions among young (age <45 years), middle-aged (between 45 and 70 years) and elderly (>70 years) patients were significantly different (P < .001). In 70 ALK-rearranged cases, coexistence of epidermal growth factor receptor (EGFR) alterations and ALK fusions was detected in 12 cases (17.1%) and EGFR mutations tended to coexist with non-EML4-ALK rearrangements. Notably, novel ALK fusion partners, including TRIM66, SWAP70, WNK3, ERC1, TCF12 and FBN1 were identified in the present study. Among EML4-ALK fusion variants, patients with variant V1 were younger than patients with variant V3 (P = .023), and TP53 mutations were more frequently concurrent with variant V3 compared with variant V1 (P = .009). In conclusion, these findings provide new insights into the molecular-clinical profiles of patients with ALK-rearranged NSCLC that may improve the treatment strategy of this population.


Assuntos
Quinase do Linfoma Anaplásico/genética , Grupo com Ancestrais do Continente Asiático/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Rearranjo Gênico , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Neoplasias Pulmonares/genética , Adulto , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Feminino , Frequência do Gene , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Fusão Oncogênica/genética , Estudos Prospectivos , Análise de Sequência de DNA , Translocação Genética
11.
Hematol Oncol ; 37(4): 375-382, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31408531

RESUMO

In large B-cell lymphoma (LBCL), MYC translocation and MYC/BCL2 or MYC/BCL6 double hit (DH) are associated with poor prognosis, and there is an unmet need for novel treatment targets in this patient group. Treatments targeting the PD-L1/PD-1 pathway are still poorly elucidated in LBCL. PD-L1 expression might predict response to treatment targeting the PD-L1/PD-1 pathway. We therefore investigated the relationship between PD-L1 protein and mRNA expression levels and MYC and DH translocation in LBCL. We detected MYC, BCL2, and BCL6 translocation by fluorescent in situ hybridization in tissue samples from 130 patients randomly selected from two cohorts of patients with LBCL: 49 patients with MYC translocation of whom 36 had DH and 81 without MYC translocation. PD-L1 protein expression was detected by immunohistochemistry (IHC) in tissue samples from 77 patients and PD-L1 mRNA expression by next-generation RNA sequencing (NGS) in another 77 patients. Twenty-four patients overlapped, ie, were analysed with both IHC and NGS. Nonparametric tests were performed to evaluate intergroup differences. PD-L1 protein expression level was significantly lower in patients with MYC (n = 42, median = 3.3%, interquartile range [IQR] 0.0-10.8) or DH translocations (n = 31, median = 3.3%, IQR 0.0-10.0) compared with patients with no MYC (n = 35, median = 16.7%, IQR 3.3-30.0) or no DH translocations (n = 46, 13.3%, IQR 2.5-30.0), P = .004 and P ≤ .001, respectively. PD-L1 mRNA expression was also significantly lower in patients with MYC or DH translocations, P = .001 and P = .006, respectively. Higher PD-L1 protein and mRNA expression levels were associated with non-germinal centre (GC) type compared with germinal centre B-cell (GCB)-type diffuse LBCL (DLBCL), P = .004 and P = .002, respectively. In conclusion, we report an association between low PD-L1 expression and MYC and DH translocation in patients with LBCL. Our findings may indicate that patients with MYC or DH translocation may benefit less from treatment with PD-L1/PD-1-inhibitors compared with patients without these translocations. This should be evaluated in larger, prospective, consecutive trials.


Assuntos
Antígeno B7-H1/biossíntese , Regulação Neoplásica da Expressão Gênica , Genes myc , Linfoma Difuso de Grandes Células B/metabolismo , Proteínas de Neoplasias/biossíntese , RNA Mensageiro/biossíntese , RNA Neoplásico/biossíntese , Translocação Genética , Adulto , Idoso , Subpopulações de Linfócitos B/metabolismo , Subpopulações de Linfócitos B/patologia , Antígeno B7-H1/genética , Feminino , Perfilação da Expressão Gênica , Genes bcl-2 , Centro Germinativo/patologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Linfoma Difuso de Grandes Células B/mortalidade , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Proteínas Proto-Oncogênicas c-bcl-6/genética , RNA Mensageiro/genética , RNA Neoplásico/genética , Estudos Retrospectivos
12.
Cytogenet Genome Res ; 158(4): 192-198, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31394532

RESUMO

Prader-Willi syndrome (PWS) and recurrent 15q13.3 microdeletion syndrome can be caused by genomic rearrangements in the complex 15q11q13 chromosomal region. Here, we describe the first female child with PWS and 15q13.3 microdeletion syndrome resulting from an unusual 10.7-Mb deletion from 15pter to 15q13.3 due to an unbalanced de novo 15;19 translocation. The patient presents with hypotonia, microcephaly, developmental delay with lack of speech, intellectual disability, happy demeanor, clinodactyly of the 4th and 5th fingers, and dysmorphic facial features discordant for PWS and consistent with an atypical phenotype.


Assuntos
Transtornos Cromossômicos/complicações , Transtornos Cromossômicos/genética , Deficiência Intelectual/complicações , Deficiência Intelectual/genética , Síndrome de Prader-Willi/complicações , Síndrome de Prader-Willi/genética , Convulsões/complicações , Convulsões/genética , Translocação Genética/genética , Pré-Escolar , Deleção Cromossômica , Cromossomos Humanos Par 15/genética , Feminino , Humanos , Recém-Nascido
13.
Anticancer Res ; 39(8): 4329-4332, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366525

RESUMO

BACKGROUND/AIM: Acute myeloid leukemia is well characterized by chromosomal aberrations that correspond to various subtypes of acute leukemias. The t(8;21)(q22;q22) is a frequent chromosomal abnormality strongly associated with acute myeloblastic leukemia with maturation (AML-M2), but is rarely associated with other subtypes. Translocation involving a third chromosome could produce new genetic rearrangements that lead to leukemogenesis. PATIENTS AND METHODS: Conventional cytogenetic analysis and fluorescence in situ hybridization (FISH) were performed to identify the karyotype. Reverse transcriptase polymerase chain reaction (RT-PCR) was used to detect the AML1/ETO transcript. RESULTS/CONCLUSION: We herein report a novel rearrangement with a three-way translocation involving chromosomes 8, 21 and another unknown chromosome, in an 83-year-old female patient diagnosed as AML-M4, with an ALM1/ETO negative transcript. This is an uncommon case of AML-M4 with three-way translocation in a new variant of t(8;21) acute myeloid leukaemia. The detailed mechanism of different phenotype expression is unclear. Further study is needed to identify the leukemogenetic transformation resulting from t(8;21) translocation.


Assuntos
Análise Citogenética , Cariótipo , Leucemia Mielomonocítica Aguda/genética , Translocação Genética/genética , Idoso de 80 Anos ou mais , Cromossomos Humanos Par 21/genética , Cromossomos Humanos Par 8/genética , Feminino , Humanos , Hibridização in Situ Fluorescente/métodos , Cariotipagem/métodos , Leucemia Mielomonocítica Aguda/diagnóstico , Leucemia Mielomonocítica Aguda/patologia
14.
Hematol Oncol ; 37(4): 368-374, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31325190

RESUMO

In 2009, the four laboratories of the Fondazione Italiana Linfomi (FIL) minimal residual disease (MRD) Network started a collaborative effort to harmonize and standardize their methodologies at the national level, performing quality control (QC) rounds for follicular lymphoma (FL) and mantle cell lymphoma (MCL) MRD assessment. In 16 QC rounds between 2010 and 2017, the four laboratories received 208 bone marrow (BM) samples (126 FL; 82 MCL); 187 were analyzed, according to the EuroMRD Consortium guidelines, by both nested (NEST) polymerase chain reaction (PCR) and real-time quantitative (RQ) PCR for BCL2/IGH MBR or IGHV rearrangements. Here, we aimed at analyzing the samples that challenged the interlaboratory reproducibility and data interpretation. Overall, 156/187 BM samples (83%) were concordantly classified as NEST+/RQ+ or NEST-/RQ- by all the four laboratories. The remaining 31 samples (17%) resulted alternatively positive and negative in the interlaboratory evaluations, independently of the method and the type of rearrangement, and were defined "borderline" (brd) samples: 12 proved NEST brd/RQ brd, 7 NEST-/RQ brd, 10 NEST brd/RQ positive not quantifiable (PNQ), and 2 NEST brd/RQ-. Results did not change even increasing the number of replicates/sample. In 6/31 brd samples, droplet digital PCR (ddPCR) was tested and showed no interlaboratory discordance. Despite the high interlaboratory reproducibility in the MRD analysis obtained and maintained by the QC round strategy, samples with the lowest MRD levels can still represent a challenge: 17% (31/187) of our samples showed discordant results in interlaboratory assessments, with 6.4% (12/187) remained brd even applying the two methods. Thus, although representing a minority, brd samples are still problematic, especially when a clinically oriented interpretation of MRD results is required. Alternative, novel methods such as ddPCR and next-generation sequencing have the potential to overcome the current limitations.


Assuntos
Exame de Medula Óssea , Medula Óssea/patologia , Ensaio de Proficiência Laboratorial , Linfoma não Hodgkin/patologia , Reação em Cadeia da Polimerase , Exame de Medula Óssea/normas , Células Clonais , Rearranjo Gênico de Cadeia Pesada de Linfócito B , Genes de Imunoglobulinas , Genes bcl-2 , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Região Variável de Imunoglobulina/genética , Itália/epidemiologia , Linfoma não Hodgkin/genética , Neoplasia Residual , Proteínas de Fusão Oncogênica/análise , Reação em Cadeia da Polimerase/métodos , Reação em Cadeia da Polimerase/normas , Proteínas Proto-Oncogênicas c-bcl-2/genética , Garantia da Qualidade dos Cuidados de Saúde , Reprodutibilidade dos Testes , Translocação Genética
15.
Anticancer Res ; 39(7): 3893-3899, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262918

RESUMO

BACKGROUND/AIM: Chronic myelogenous leukemia (CML) is characterized by the presence of the Philadelphia chromosome, resulting from the reciprocal translocation involving chromosomes 9 and 22. About 5-10% of newly diagnosed patients in chronic-phase (CP) CML show complex additional chromosomal aberrations (ACA), that may involve one or more chromosomes in addition to 9 and 22. Data concerning the prognostic significance of ACA in CP-CML subjects at diagnosis are controversial. Furthermore, there is no evidence showing that selection of imatinib (IM) or second-generation tyrosine kinase inhibitors (2G-TKI) would be of benefit for these patients. CASE REPORT: We report the three-way complex variant translocation t(2;9;22) in a CP-CML patient. Conventional cytogenetic analysis was employed to identify the ACA. Multiplex reverse transcription-PCR was used to identify the BCR-ABL1 transcript and its levels were measured using quantitative real-time-PCR. This rare ACA t(2;9;22) in our young patient displayed primary resistance to IM, but was responsive to second-line treatment with nilotinib. CONCLUSION: CP-CML patients exhibiting this rare aberration at diagnosis may benefit from a 2G-TKI therapy compared to IM.


Assuntos
Antineoplásicos/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Adulto , Proteínas de Fusão bcr-abl/genética , Humanos , Masculino , Translocação Genética , Resultado do Tratamento , Adulto Jovem
16.
Anticancer Res ; 39(7): 3949-3954, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262926

RESUMO

We report the case of an 89-year-old male diagnosed with chronic-phase CML and expressing a rare e13a3 BCR-ABL1 fusion transcript. His cytogenetic analysis showed the t(9;22) translocation generating the Philadelphia chromosome (Ph), with a multiplex RT-PCR detecting an atypical fragment. Using two primers complementary to exon 10 of BCR and exon 4 of ABL1, a larger PCR product was observed, where after Sanger sequencing, an e13a3 BCR-ABL1 transcript was revealed. Given the diagnosis, the patient received 100 mg of dasatinib every other day and was then monitored by measuring both hematological and cytogenetic parameters, while his BCR-ABL1 transcripts were examined by PCR and semi-nested-PCR. According to the 2013 European Leukemia Network criteria, after six months of dasatinib the patient's response was classified as warning as he displayed 20% of Philadelphia-positive metaphases. Sequencing of the ABL1 catalytic domain did not detect point mutations. A complete cytogenetic response was achieved after one year of dasatinib. However, semi-nested-PCR confirmed the presence of the e13a3 BCR-ABL1 fusion transcript that has persisted up to the latest follow-up visit.


Assuntos
Antineoplásicos/uso terapêutico , Dasatinibe/uso terapêutico , Proteínas de Fusão bcr-abl/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Inibidores de Proteínas Quinases/uso terapêutico , Idoso de 80 Anos ou mais , Humanos , Masculino , Translocação Genética , Resultado do Tratamento
17.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(7): 682-685, 2019 Jul 10.
Artigo em Chinês | MEDLINE | ID: mdl-31302910

RESUMO

OBJECTIVE: To make molecular diagnosis of an infant affected with severe developmental delay and multiple birth defects, assisting prenatal diagnosis for the second pregnancy. METHODS: Standard G-banded karyotyping was performed for the fetus and his parents. Single nucleotide polymorphism array (SNP array) was used to detect submicroscopic chromosomal aberration. Fluorescence in situ hybridization (FISH) was employed to determine the parental origin of the aberration. RESULTS: Both the proband and the fetus harbored a 5.4 Mb distal 4p deletion and a 6.9 Mb distal 6q duplication. FISH confirmed that the mother has carried a balanced translocation involving 4p and 6q. CONCLUSION: The unbalanced chromosomal aberration in the proband and the fetus were both derived from the mother. Both patients showed a Wolf-Hirschhorn syndrom phenotype and partial phenotype of 6q trisomy. SNP array combined with FISH are essential for the detection of cryptic chromosomal aberrations which may be missed by coventional karyotyping analysis.


Assuntos
Diagnóstico Pré-Natal , Translocação Genética , Síndrome de Wolf-Hirschhorn/genética , Cromossomos Humanos Par 4/genética , Cromossomos Humanos Par 6/genética , Feminino , Humanos , Hibridização in Situ Fluorescente , Lactente , Cariotipagem , Masculino , Linhagem , Gravidez
18.
Rinsho Ketsueki ; 60(6): 584-593, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31281149

RESUMO

Genetic abnormalities of acute myeloid leukemia (AML) include chromosomal translocations and gene mutations. Commonly observed chromosomal abnormalities in AML are t (8;21), t (15;17), inv (16), and 11q23-related translocations. These aberrations produce RUNX1-RUNX1T1, PML-RARA, CBF-MYH11, and MLL-fusion genes, respectively, which promote leukemic stem cell formation by interfering with hematopoietic differentiation and enhancing the self-renewal capacity of hematopoietic cells. Gene mutations recurrently occur in transcription factors, signaling molecules, tumor suppressor genes, epigenetic regulators, RNA splicing factors, and cohesion complexes, with FLT3, NPM1, and DNMT3A being the most frequently mutated genes in AML. Recent studies disclosed the biological function of mutated genes and their correlation with prognosis. Based on these findings, development of novel therapeutic drugs targeting mutated genes or dysregulated genetic pathways is underway.


Assuntos
Leucemia Mieloide Aguda/genética , Mutação , Translocação Genética , Aberrações Cromossômicas , Humanos , Prognóstico
19.
Cytogenet Genome Res ; 158(3): 115-120, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31266029

RESUMO

Unbalanced translocations of Y-chromosomal fragments harboring the sex-determining region Y gene (SRY) to the X chromosome or an autosome result in 46,XX and 45,X testicular disorders of sex development (DSD), respectively. Of these, Y;autosome translocation is an extremely rare condition. Here, we identified a 20-year-old man with a 45,X,t(Y;7)(q11.21;q35) karyotype, who exhibited unilateral cryptorchidism, small testis, intellectual disability, and various congenital anomalies. The fusion junction of the translocation was blunt, and the breakpoint-flanking regions shared only 50% similarity. These results indicate that Y;autosome translocations can occur between 2 low-similarity sequences, probably via nonhomologous end joining. Furthermore, translocations of a Ypterq11.21 fragment to 7q35 likely result in normal or only mildly impaired male-type sexual development, along with various clinical features of 7q deletion syndrome, although their effects on adult testicular function remain to be studied.


Assuntos
Cromossomos Humanos Par 7/genética , Cromossomos Humanos Y/genética , Transtornos do Desenvolvimento Sexual/genética , Genes sry/genética , Doenças Testiculares/genética , Translocação Genética/genética , Adulto , Pontos de Quebra do Cromossomo , Feminino , Humanos , Hibridização in Situ Fluorescente , Recém-Nascido , Cariótipo , Masculino , Adulto Jovem
20.
Cytogenet Genome Res ; 158(2): 83-87, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31195399

RESUMO

The case presented here describes a female patient with recurrent miscarriages and a normal microarray analysis result. However, the coexistence of a robertsonian (21;21) translocation and complementary mosaic ring chromosome 21 was detected by karyotyping and FISH analysis. Partial trisomy 21 was found with QF-PCR and microarray analysis in one of the fetuses. The aim of this report was to emphasize the diagnostic importance of conventional cytogenetics.


Assuntos
Aborto Espontâneo/epidemiologia , Cromossomos Humanos Par 21/genética , Aborto Espontâneo/genética , Adolescente , Feminino , Humanos , Mosaicismo , Linhagem , Cromossomos em Anel , Translocação Genética
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