RESUMO
BACKGROUND: For myeloid neoplasms with t(7;11)(p15;p15) translocation, the prognosis is quite dismal. Because these tumors are rare, most occurrences are reported as single cases. Clinical results and optimal treatment approaches remain elusive. This study endeavors to elucidate the clinical implications and prognosis of this cytogenetic aberration. METHODS: This study retrospectively analyzed 23 cases of myeloid neoplasm with t(7;11)(p15;p15). Clinicopathological characteristics, genetic alterations, and outcomes were evaluated, and the Kaplan-Meier method was employed to construct survival curves. RESULTS: Of these, nine cases were newly diagnosed acute myeloid leukemia (ND AML), seven presented with relapsed refractory AML (R/R AML), four had myelodysplastic syndrome (MDS), two had secondary AML, and one exhibited a mixed germinoma associated with MDS. Patients with t(7;11)(p15;p15) in AML were primarily younger females who preferred subtype M2. Interestingly, these patients had decreased hemoglobin and red blood cell counts, along with markedly elevated levels of lactic dehydrogenase and interleukin-6, and exhibited the expression of CD117. R/R AML patients exhibited a higher likelihood of additional chromosome abnormalities (ACAs) besides t(7;11). WT1 and FLT3-ITD were the most commonly found mutated genes, and 10 of those instances showed evidence of the NUP98::HOXA9 fusion gene. The composite complete remission rate was 66.7% (12/18), while the cumulative graft survival rate was 100% (4/4). However, the survival outcomes were dismal. Interestingly, the median overall survival for R/R AML patients was 4.0 months (95% CI: 1.7-6.4). Additionally, the type of AML diagnosis or the presence of ACAs or molecular prognostic stratification did not significantly influence clinical outcomes (p = 0.066, p = 0.585, p = 0.570, respectively). CONCLUSION: Myeloid leukemia with t(7;11) exhibits unique clinical features, cytogenetic properties, and molecular genetic characteristics. These survival outcomes were dismal. R/R AML patients have a limited lifespan. For myeloid patients with t(7;11), targeted therapy or transplantation may be an effective course of treatment.
Assuntos
Cromossomos Humanos Par 11 , Translocação Genética , Humanos , Feminino , Masculino , Estudos Retrospectivos , Adulto , Pessoa de Meia-Idade , Prognóstico , Cromossomos Humanos Par 11/genética , Adulto Jovem , Idoso , Adolescente , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/patologia , Cromossomos Humanos Par 7/genética , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/mortalidade , Síndromes Mielodisplásicas/terapiaRESUMO
Neuroblastoma (NB) is a heterogeneous childhood cancer with a slightly higher incidence in boys than girls, with the reason for this gender disparity unknown. Given the growing evidence for the involvement of loss of the Y chromosome (LoY) in male diseases including cancer, we investigated Y chromosome status in NB. Male NB tumor samples from a Swedish cohort, analyzed using Cytoscan HD SNP-microarray, were selected. Seventy NB tumors were analyzed for aneuploidy of the Y chromosome, and these data were correlated with other genetic, biological, and clinical parameters. LoY was found in 21% of the male NB tumors and it was almost exclusively found in those with high-risk genomic profiles. Furthermore, LoY was associated with increased age at diagnosis and enriched in tumors with 11q-deletion and activated telomere maintenance mechanisms. In contrast, tumors with an MYCN-amplified genomic profile retained their Y chromosome. The understanding of LoY in cancer is limited, making it difficult to conclude whether LoY is a driving event in NB or function of increased genomic instability. Gene expression analysis of Y chromosome genes in male NB tumors showed low expression of certain genes correlating with worse overall survival. KDM5D, encoding a histone demethylase stands out as an interesting candidate for further studies. LoY has been shown to impact the epigenomic layer of autosomal loci in nonreproductive tissues, and KDM5D has been reported as downregulated and/or associated with poor survival in different malignancies. Further studies are needed to explore the mechanisms and functional consequences of LoY in NB.
Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 11 , Cromossomos Humanos Y , Neuroblastoma , Humanos , Neuroblastoma/genética , Neuroblastoma/patologia , Masculino , Cromossomos Humanos Y/genética , Cromossomos Humanos Par 11/genética , Lactente , Pré-Escolar , Feminino , Homeostase do Telômero/genética , Criança , Histona Desmetilases/genética , Telômero/genética , Proteína Proto-Oncogênica N-Myc/genética , Suécia/epidemiologiaRESUMO
BACKGROUND: Daratumumab's incorporation in the upfront treatment of light chain (AL) amyloidosis has led to daratumumab (dara) refractoriness early in disease course. Patients who experience relapse or have suboptimal response to dara-based-therapy, have limited options. OBJECTIVE: This study aimed to evaluate the outcomes of venetoclax-based therapy in t(11;14) positive AL patients who previously failed dara. METHODS: Thirty-one patients with AL were included in this bi-institutional retrospective analysis. RESULTS: Dara failure was due to inadequate response in 20 (65%) patients, haematologic relapse in 7 (22%), and both haematologic plus organ relapse in 4 (13%). Overall haematologic response rate to venetoclax-based therapy was 97%, with ≥ VGPR being 91%. Of the 19 evaluable patients with cardiac involvement, 14 (74%) achieved organ response. Of the 13 evaluable patients with renal involvement, 6 (46%) achieved organ response. With a median follow-up of 22 months, median time-to-next-treatment (TTNT) and overall survival (OS) were not reached. The 12- and 24-month TTNT rates were 74% and 56%, respectively. At data-cut-off, four patients had died, all from AL-related organ complications. The 12- and 24-month OS rates were 89% and 85%, respectively. Grade ≥3 adverse events occurred in 26% of patients, with 6% due to infections. CONCLUSION: These findings are encouraging for the use of venetoclax as salvage therapy post-dara failure.
Assuntos
Anticorpos Monoclonais , Compostos Bicíclicos Heterocíclicos com Pontes , Cromossomos Humanos Par 14 , Amiloidose de Cadeia Leve de Imunoglobulina , Sulfonamidas , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Sulfonamidas/uso terapêutico , Sulfonamidas/administração & dosagem , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais/administração & dosagem , Amiloidose de Cadeia Leve de Imunoglobulina/tratamento farmacológico , Amiloidose de Cadeia Leve de Imunoglobulina/genética , Amiloidose de Cadeia Leve de Imunoglobulina/mortalidade , Amiloidose de Cadeia Leve de Imunoglobulina/patologia , Estudos Retrospectivos , Cromossomos Humanos Par 14/genética , Cromossomos Humanos Par 11/genética , Adulto , Idoso de 80 Anos ou mais , Translocação Genética , Resultado do Tratamento , Antineoplásicos/uso terapêuticoRESUMO
The June Hot Topics focuses on the challenges venetoclax regimens have faced in multiple myeloma trials.
Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes , Cromossomos Humanos Par 14 , Mieloma Múltiplo , Sulfonamidas , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genética , Humanos , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Sulfonamidas/uso terapêutico , Sulfonamidas/administração & dosagem , Cromossomos Humanos Par 14/genética , Antineoplásicos/uso terapêutico , Translocação Genética , Cromossomos Humanos Par 11/genética , Ensaios Clínicos como Assunto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
Objective: To study the correlation between the copy number variations of CCND1 gene and chromosome 11 and their associations with clinicopathologic features in acral melanoma. Methods: Thirty-three acral melanoma cases diagnosed at the Department of Pathology of Peking University Third Hospital, Beijing, China from January 2018 to August 2021 were collected. Fluorescence in situ hybridization (FISH) was used to detect the copy number of CCND1 gene and centromere of chromosome 11. The relationship between the copy numbers of CCND1 and chromosome 11 centromere, and the correlation between CCND1 copy number and clinicopathologic characteristics were analyzed. Results: There were 15 male and 18 female patients, with an age ranging from 22-86 years. 63.6% (21/33) of the patients had an increased CCND1 gene copy number. 21.2% (7/33) of patients with increased CCND1 copy number had an accompanying chromosome 11 centromere copy number increase. 27.3% (9/33) of the cases had a low copy number of CCND1 gene, and 4 of them (4/33, 12.1%) were accompanied by chromosome 11 centromere copy number increase. 36.4% (12/33) of the cases had a high copy number of CCND1 gene, and 3 (3/33, 9.1%) of them were accompanied by chromosome 11 centromere copy number increase. No cases with CCND1 low copy number increase showed CCND1/CEP11 ratio greater than 2.00. The 11 cases with CCND1 high copy number increase showed CCND1/CEP11 ratio greater than or equal to 2.00. However, there was no significant correlation between CCND1 copy number increase and any of the examined clinicopathologic features such as age, sex, histological type, Breslow thickness, ulcer and Clark level. Conclusions: CCND1 copy number increase is a significant molecular alteration in acral melanoma. In some cases, CCND1 copy number increase may be accompanied by the copy number increase of chromosome 11. For these cases the copy number increase in CCND1 gene may be a result of the copy number change of chromosome 11.
Assuntos
Centrômero , Cromossomos Humanos Par 11 , Ciclina D1 , Variações do Número de Cópias de DNA , Hibridização in Situ Fluorescente , Melanoma , Neoplasias Cutâneas , Humanos , Ciclina D1/genética , Masculino , Feminino , Melanoma/genética , Melanoma/patologia , Pessoa de Meia-Idade , Centrômero/genética , Idoso , Adulto , Idoso de 80 Anos ou mais , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Cromossomos Humanos Par 11/genética , Adulto JovemRESUMO
Acute myeloid leukemia (AML) shows multiple chromosomal translocations & point mutations which can be used to refine risk-adapted therapy in AML patients. Ecotropic viral integration site-1 (EVI-1) & myocyte enhancer factor 2 C gene (MEF2C) are key regulatory transcription factors in hematopoiesis and leukemogenesis & both drive immune escape. This prospective study involved 80 adult de novo AML patients recruited from Oncology Center, Mansoura University, between March 2019 and July 2021. The MEF2C and EVI1 expression were measured using a Taqman probe-based qPCR assay. The results revealed that EVI1 and MEF2C expression were significantly elevated in AML patients as compared to control subjects (p = 0.001. 0.007 respectively). Aberrant expressions of EVI1 and MEF2C showed a significant negative correlation with hemoglobin levels (p = 0.034, 0.025 respectively), & bone marrow blasts (p = 0.007, 0.002 respectively). 11q23 translocation was significantly associated with EVI1 and MEF2C (p = 0.004 and 0.02 respectively). Also, t (9;22) was significantly associated with EVI1 and MEF2C (p = 0.01 and 0.03 respectively), higher expression of EVI1 and MEF2C were significantly associated with inferior outcome after induction therapy (p = 0.001 and 0.018 respectively) and shorter overall survival (p = 0.001, 0.014 respectively). In conclusion, EVI1 & MEF2C were significantly expressed in AML cases. EVI1 & MEF2C overexpression were significantly associated with 11q23 rearrangements and t (9;22) and were indicators for poor outcome in adult AML patients; These results could be a step towards personalized therapy in those patients.
Assuntos
Leucemia Mieloide Aguda , Proteína do Locus do Complexo MDS1 e EVI1 , Fatores de Transcrição MEF2 , Translocação Genética , Humanos , Fatores de Transcrição MEF2/genética , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Masculino , Proteína do Locus do Complexo MDS1 e EVI1/genética , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Cromossomos Humanos Par 11/genética , Estudos Prospectivos , Adulto Jovem , Rearranjo Gênico , AdolescenteRESUMO
The WHO classifications of hematolymphoid malignancies have recognized several distinct entities within the large B cell lymphomas, including the more recently described high-grade B cell lymphoma with 11q aberration (HGBCL-11q). We utilized genomic array to assess for chromosome 11q abnormalities in a broad set of aggressive B cell lymphomas from 27 patients with a focus on younger adults. The findings suggest more frequent alterations of 11q in diffuse large B cell lymphoma (DLBCL)/HGBCL-GC BCL2-, in comparison to cases of Burkitt lymphoma (BL) or DLBCL-GC BCL2+, and confirm a low genomic complexity score of BL. Variability identified in patterns of 11q alterations suggests genomic array studies may afford value over FISH testing as we continue to understand HGBCL-11q as a distinct entity, and interrogate cases of DLBCL/HGBCL-GC BCL2-.
Assuntos
Aberrações Cromossômicas , Cromossomos Humanos Par 11 , Centro Germinativo , Linfoma Difuso de Grandes Células B , Fenótipo , Proteínas Proto-Oncogênicas c-bcl-2 , Humanos , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Cromossomos Humanos Par 11/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Centro Germinativo/patologia , Adulto , Pessoa de Meia-Idade , Feminino , Masculino , Idoso , Adulto Jovem , Idoso de 80 Anos ou mais , Hibridização in Situ Fluorescente , AdolescenteRESUMO
Primary mucinous ovarian carcinoma (PMOC) is a rare tumor, accounting for approximately 3% of all epithelial ovarian cancers (EOCs), with clinical risk factors and biologic features distinct from that of EOC. The prognosis for women with recurrent and high-grade PMOC remains poor, likely related to a poor response to conventional chemotherapy for EOC. A 27-year-old Chinese woman sought medical attention in January 2021 for abdominal distention from a large pelvic mass. After extensive investigations and workup, she was diagnosed with PMOC of the right ovary. Following multidisciplinary team (MDT) discussions, the patient underwent fertility-sparing surgery (FSS) (abdominal left adnexectomy, right partial oophorectomy, pelvic lymph node dissection, para-aortic lymph node dissection, omentectomy) as she yearned to preserve her fertility and the contralateral ovary appeared normal. Deep genetic analyses revealed ERBB2 co-amplification with CDK12 and chromosome 11q13.3 amplicon. Treatment with fertility-sparing surgery and adjuvant chemotherapy with trastuzumab results in complete remission. This novel strategy utilizing precise diagnostics and characterization of the histo-type of rare tumors allowed personalized targeting with optimum drug response for women who yearn fertility preservation and remission from the disease, especially when there is very limited clinical experience on management of such rare ovarian tumors.
Assuntos
Preservação da Fertilidade , Neoplasias Ovarianas , Receptor ErbB-2 , Trastuzumab , Humanos , Feminino , Adulto , Quimioterapia Adjuvante , Trastuzumab/uso terapêutico , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/cirurgia , Preservação da Fertilidade/métodos , Adenocarcinoma Mucinoso/genética , Adenocarcinoma Mucinoso/tratamento farmacológico , Adenocarcinoma Mucinoso/cirurgia , Cromossomos Humanos Par 11/genética , Antineoplásicos Imunológicos/uso terapêutico , Resposta Patológica Completa , Quinases Ciclina-DependentesRESUMO
BACKGROUND: The plasma cell malignancy, multiple myeloma (MM), remains incurable despite advanced treatment protocols. Overexpression of Bcl-2 (an anti-apoptotic protein), in MM harboring the translocation (11;14), contributes to resistance to prior therapy. Venetoclax, a selective oral inhibitor of BCL-2 is a novel agent that shows promise as a therapeutic agent. AIMS: The objective of this systematic review is to address how the use of venetoclax, alone or as a combination regimen, contributed to the treatment of patients with t(11:14) positive relapsed/refractory multiple myeloma (RRMM). DATA SOURCES: This systematic review was conducted in accordance to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and was done on 5th June 2022. A literature search was conducted on PubMed and Scopus, 145 articles were screened and 10 studies were included. Risk of bias assessment was performed using the Methodological Index for Non-Randomized Studies (MINORS) criteria. DATA SUMMARY: Across the studies reviewed, a total of 311 patients were identified with t(11;14) positive RRMM. The overall response rate achieved ranged between 33% and 95.5%. Furthermore, the use of venetoclax has exhibited a favorable adverse effect profile. Side effects included hematological side effects, nausea, vomiting, and diarrhea. CONCLUSION: Venetoclax demonstrates promising results. When given with drugs like dexamethasone, daratumumab and carfilzomib, a synergistic effect is seen in treating translocation (11:14) positive relapsed/refractory MM. The use of venetoclax in clinical practice can potentially improve outcomes and quality of life in RRMM patients, and future research should continue to explore this promising treatment option.
Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes , Mieloma Múltiplo , Sulfonamidas , Humanos , Antineoplásicos/uso terapêutico , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 14/genética , Resistencia a Medicamentos Antineoplásicos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genética , Recidiva Local de Neoplasia/tratamento farmacológico , Sulfonamidas/uso terapêutico , Sulfonamidas/administração & dosagem , Translocação GenéticaRESUMO
Three years ago, our patient, at that time a 16-month-old boy, was discovered to have bilateral kidney lesions with a giant tumor in the right kidney. Chemotherapy and bilateral nephron-sparing surgery (NSS) for Wilms tumor with nephroblastomatosis was carried out. The patient also had eye affection, including glaucoma, eye enlargement, megalocornea, severe corneal swelling and opacity, complete aniridia, and nystagmus. The diagnosis of WAGR syndrome was suspected. De novo complex chromosomal rearrangement with balanced translocation t(10,11)(p15;p13) and a pericentric inversion inv(11)(p13q12), accompanied by two adjacent 11p14.1p13 and 11p13p12 deletions, were identified. Deletions are raised through the complex molecular mechanism of two subsequent rearrangements affecting chromosomes 11 and 10. WAGR syndrome diagnosis was clinically and molecularly confirmed, highlighting the necessity of comprehensive genetic testing in patients with congenital aniridia and/or WAGR syndrome.
Assuntos
Aniridia , Neoplasias Renais , Síndrome WAGR , Tumor de Wilms , Masculino , Humanos , Lactente , Síndrome WAGR/diagnóstico , Síndrome WAGR/genética , Síndrome WAGR/patologia , Deleção Cromossômica , Aniridia/diagnóstico , Aniridia/genética , Tumor de Wilms/genética , Neoplasias Renais/genética , Cromossomos Humanos Par 11/genética , Inversão CromossômicaRESUMO
Epstein-Barr virus (EBV) is an oncogenic herpesvirus associated with several cancers of lymphocytic and epithelial origin1-3. EBV encodes EBNA1, which binds to a cluster of 20 copies of an 18-base-pair palindromic sequence in the EBV genome4-6. EBNA1 also associates with host chromosomes at non-sequence-specific sites7, thereby enabling viral persistence. Here we show that the sequence-specific DNA-binding domain of EBNA1 binds to a cluster of tandemly repeated copies of an EBV-like, 18-base-pair imperfect palindromic sequence encompassing a region of about 21 kilobases at human chromosome 11q23. In situ visualization of the repetitive EBNA1-binding site reveals aberrant structures on mitotic chromosomes characteristic of inherently fragile DNA. We demonstrate that increasing levels of EBNA1 binding trigger dose-dependent breakage at 11q23, producing a fusogenic centromere-containing fragment and an acentric distal fragment, with both mis-segregated into micronuclei in the next cell cycles. In cells latently infected with EBV, elevating EBNA1 abundance by as little as twofold was sufficient to trigger breakage at 11q23. Examination of whole-genome sequencing of EBV-associated nasopharyngeal carcinomas revealed that structural variants are highly enriched on chromosome 11. Presence of EBV is also shown to be associated with an enrichment of chromosome 11 rearrangements across 2,439 tumours from 38 cancer types. Our results identify a previously unappreciated link between EBV and genomic instability, wherein EBNA1-induced breakage at 11q23 triggers acquisition of structural variations in chromosome 11.
Assuntos
Quebra Cromossômica , DNA , Herpesvirus Humano 4 , Proteínas Virais , Humanos , Sítios de Ligação , DNA/química , DNA/metabolismo , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/metabolismo , Herpesvirus Humano 4/patogenicidade , Proteínas Virais/genética , Proteínas Virais/metabolismo , Quebras de DNA de Cadeia Dupla , Cromossomos Humanos Par 11/química , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 11/metabolismo , Instabilidade Genômica , MitoseRESUMO
OBJECTIVES: To evaluate clinicopathologic characteristics of biclonal chronic lymphocytic leukemia (CLL). METHODS: Retrospectively analyze clinical data and pathologic features. RESULTS: Ten cases were identified in which flow cytometry demonstrated an abnormal B-cell population with a CLL-like immunophenotype but showed no definitive light chain restriction. All had cytogenetic abnormalities detected, including seven with two CLL-related abnormalities. Four of these showed features suggestive of clonal evolution, all having del(13q) as a "stem-line" abnormality and three showing del(11q) as a "side-line" abnormality. Five (50%) cases demonstrated deleterious NOTCH1 mutations, in contrast to 11.8% in a control group of monoclonal CLL (Pâ <â .05). Of the 10 patients, 5 received treatment, with good/partial response in three cases and therapeutic resistance in one case. The median treatment-free survival was estimated at 68 months. CONCLUSIONS: Despite a polytypic pattern of light chain expression, the neoplastic nature of biclonal CLL is suggested by a characteristic CLL phenotype and can be confirmed by cytogenetic and genomic analyses. The two clones with discordant light chain isotypes may share a "stem-line" cytogenetic abnormality, suggesting possible clonal evolution. Biclonal CLL is associated with NOTCH1 mutations, which may occur in a small subclone and gradually evolve in clonal size. Genomic analysis on light chain-sorted and/or chronologically collected samples may provide insight into clonal evolution in CLL.
Assuntos
Linfócitos B , Evolução Clonal , Switching de Imunoglobulina , Cadeias Leves de Imunoglobulina , Leucemia Linfocítica Crônica de Células B , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/patologia , Linfócitos B/patologia , Cadeias Leves de Imunoglobulina/genética , Switching de Imunoglobulina/genética , Aberrações Cromossômicas , Receptor Notch1/genética , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 13RESUMO
Neurodevelopmental disorders (NDDs) are considered synaptopathies, as they are due to anomalies in neuronal connectivity during development. DLG2 is a gene involved insynaptic function; the phenotypic effect of itsalterations in NDDs has been underestimated since few cases have been thoroughly described.We report on eight patients with 11q14.1 imbalances involving DLG2, underlining its potential effects on clinical presentation and its contribution to NDD comorbidity by accurate neuropsychiatric data collection. DLG2 is a very large gene in 11q14.1, extending over 2.172 Mb, with alternative splicing that gives rise to numerous isoforms differentially expressed in brain tissues. A thorough bioinformatic analysis of the altered transcripts was conducted for each patient. The different expression profiles of the isoforms of this gene and their influence on the excitatory-inhibitory balance in crucial brain structures could contribute to the phenotypic variability related to DLG2 alterations. Further studies on patients would be helpful to enrich clinical and neurodevelopmental findings and elucidate the molecular mechanisms subtended to NDDs.
Assuntos
Cromossomos Humanos Par 11 , Guanilato Quinases , Transtornos do Neurodesenvolvimento , Proteínas Supressoras de Tumor , Processamento Alternativo , Estruturas Cromossômicas , Cromossomos Humanos Par 11/genética , Guanilato Quinases/genética , Humanos , Transtornos do Neurodesenvolvimento/genética , Isoformas de Proteínas/genética , Proteínas Supressoras de Tumor/genéticaRESUMO
Carotid plaque is a subclinical measure of atherosclerosis. We have previously shown measures of carotid plaque to be heritable in a sample of 100 Dominican families and found evidence for linkage and association of common variants (CVs) on 7q36, 11p15, 14q32 and 15q23 with plaque presence. Our current study aimed to refine these regions further and identify rare variants (RVs) influencing plaque presence. Therefore, we performed targeted sequencing of the one LOD unit down region on 7q36, 11p15, 14q32 and 15q23 in 12 Dominican families with evidence for linkage to plaque presence. Gene-based RV analyses were performed using the Sequence Association Test for familial data (F-SKAT) under two filtering algorithms; 1. all exonic RVs and 2. non-synonymous RVs. Replication analyses were performed using a sample of 22 Dominican families and 556 unrelated Dominicans with Exome Array data. To identify additional non-synonymous RVs influencing plaque, we looked for co-segregation of RVs with plaque in each of the sequenced families. Our most strongly associated gene with evidence for replication was AMPD3 which showed suggestive association with plaque presence in the sequenced families (exonic RV p = 0.003, nonsynonymous RV p = 0.005) and replication families (exonic RV p = 0.04, nonsynonymous RV p = 0.02). Examination of the sequenced family pedigrees revealed two missense variants on chromosome 11 which co-segregated with plaque presence in one of our families; rs61751342 (located in DENND2B), and rs61760882 (located in RNF141). The rs61751342 missense variant is an eQTL for SCUBE2 in the atrial appendage. Notably, SCUBE2 encodes a protein which interacts with vascular endothelial growth factor (VEGF) receptor 2 to regulate VEGF-induced angiogenesis, thus providing biologic plausibility for this gene in atherosclerosis. In conclusion, using targeted sequencing of previously-identified linkage regions, we have identified suggestive evidence for the role of RVs in carotid plaque pathogenesis.
Assuntos
Ligação Genética , Placa Aterosclerótica/genética , AMP Desaminase/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Adulto , Idoso , Proteínas de Ligação ao Cálcio/genética , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 14/genética , Cromossomos Humanos Par 15/genética , Cromossomos Humanos Par 7/genética , Proteínas de Ligação a DNA/genética , República Dominicana , Genótipo , Humanos , Pessoa de Meia-Idade , Linhagem , Placa Aterosclerótica/patologia , Polimorfismo Genético , Locos de Características Quantitativas , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genéticaAssuntos
Histona-Lisina N-Metiltransferase/genética , Cinesinas/genética , Leucemia Mieloide/genética , Proteína de Leucina Linfoide-Mieloide/genética , Miosinas/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Translocação Genética , Doença Aguda , Adolescente , Linhagem da Célula/genética , Coloração Cromossômica/métodos , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 6/genética , Feminino , Rearranjo Gênico , Humanos , Quimioterapia de Indução/métodos , Leucemia Mieloide/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologiaAssuntos
Aberrações Cromossômicas , Cromossomos Humanos Par 11/genética , Histona-Lisina N-Metiltransferase , Leucemia Mieloide Aguda , Proteína de Leucina Linfoide-Mieloide , Proteínas de Neoplasias , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adulto , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Leucemia Mieloide Aguda/enzimologia , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Masculino , Proteína de Leucina Linfoide-Mieloide/genética , Proteína de Leucina Linfoide-Mieloide/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/enzimologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologiaRESUMO
BACKGROUND: Tinnitus is an auditory phantom sensation in the absence of an acoustic stimulus, which affects nearly 15% of the population. Excessive noise exposure is one of the main causes of tinnitus. To now, the knowledge of the genetic determinants of susceptibility to tinnitus remains limited. RESULTS: We performed a two-stage genome-wide association study (GWAS) and identified that two single nucleotide polymorphisms (SNPs), rs2846071 located in the intergenic region at 11q13.5 (odds ratio [OR] = 2.14, 95% confidence interval [CI] = 1.96-3.40, combined P = 4.89 × 10- 6) and rs4149577 located in the intron of TNFRSF1A gene at 12p13.31 (OR = 2.05, 95% CI = 1.89-2.51, combined P = 6.88 × 10- 6), are significantly associated with the susceptibility to noise-induced tinnitus. Furthermore, the expression quantitative trait loci (eQTL) analyses revealed that rs2846071 is significantly correlated with the expression of WNT11 gene, and rs4149577 with the expression of TNFRSF1A gene in multiple brain tissues (all P < 0.05). The newly identified candidate gene WNT11 is involved in Wnt pathway, and TNFRSF1A in the tumor necrosis factor pathway, respectively. Pathway enrichment analyses also showed that these two pathways are closely relevant to tinnitus. CONCLUSIONS: Our findings highlight two novel loci at 11q13.5 and 12p13.31 conferring susceptibility to noise-induced tinnitus. and suggest that the WNT11 and TNFRSF1A genes might be the candidate causal targets of 11q13.5 and 12p13.31 loci, respectively.
Assuntos
Povo Asiático/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Zumbido/genética , China/etnologia , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 12/genética , Humanos , Masculino , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Leukemia patients bearing the t(4;11)(q21;q23) translocations can be divided into two subgroups: those expressing both reciprocal fusion genes, and those that have only the MLL-AF4 fusion gene. Moreover, a recent study has demonstrated that patients expressing both fusion genes have a better outcome than patients that are expressing the MLL-AF4 fusion protein alone. All this may point to a clonal process where the reciprocal fusion gene AF4-MLL could be lost during disease progression, as this loss may select for a more aggressive type of leukemia. Therefore, we were interested in unraveling the decisive role of the AF4-MLL fusion protein at an early timepoint of disease development. We designed an experimental model system where the MLL-AF4 fusion protein was constitutively expressed, while an inducible AF4-MLL fusion gene was induced for only 48 h. Subsequently, we investigated genome-wide changes by RNA- and ATAC-Seq experiments at distinct timepoints. These analyses revealed that the expression of AF4-MLL for only 48 h was sufficient to significantly change the genomic landscape (transcription and chromatin) even on a longer time scale. Thus, we have to conclude that the AF4-MLL fusion protein works through a hit-and-run mechanism, probably necessary to set up pre-leukemic conditions, but being dispensable for later disease progression.
Assuntos
Sequenciamento de Cromatina por Imunoprecipitação/métodos , Leucemia Mieloide Aguda/genética , Proteína de Leucina Linfoide-Mieloide/genética , Proteínas de Fusão Oncogênica/genética , Análise de Sequência de RNA/métodos , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 4/genética , Progressão da Doença , Células HEK293 , Humanos , Translocação GenéticaRESUMO
AIM: To detect the frequency, diagnostic and prognostic significance of 11q23/MLL rearrangements and to determine the chromosomes that are most frequently involved in 11q23/MLL abnormalities in adult acute leukemia (AL). MATERIALS AND METHODS: Cytogenetic investigations of bone marrow and/or peripheral blood cells from 140 patients with acute myeloid leukemia (AML) and 57 patients with acute lymphoblastic leukemia (ALL) were performed. The methods of conventional cytogenetics (GTG-banding) and fluorescence in situ hybridization were used. RESULTS: Chromosomal abnormalities in leukemia cells were found by conventional cytogenetic methods in 80 (57%) and 37 (65%) adult patients with AML and ALL, respectively. 11q23/MLL rearrangements were found in 7 (5%) and 8 (14%) patients with AML and ALL, respectively. Among them, 8 (53.4%) patients had translocations, 2 (13.3%) - had deletions and 5 (33.3%) patients had trisomies or tetrasomies of chromosome 11. With respect to the distribution of partner chromosomes involved in 11q23/MLL translocations chromosome 4 was found to participate in 3 (37.5%) cases of 11q23/MLL translocations, 9 - in 2 (25%) cases and chromosomes 10, 14 and non-identified chromosome were involved in 1 (12.5%) case each. Nine patients (60%), besides abnormal ones, had 9-86% normal metaphases in their karyotypes. Of 15 patients with 11q23/MLL rearrangements, 5 (33%) patients had only 11q23/MLL rearrangements, whereas other 10 (67%) - had additional cytogenetic abnormalities, besides 11q23/MLL rearrangements. CONCLUSIONS: Chromosomal abnormalities of various kinds were found in 57% and 65% adult patients with AML and ALL, respectively. The frequency of 11q23/MLL rearrangements in patients with AML and ALL was 5% and 14%, respectively. Since AL patients with 11q23/MLL rearrangements are attributed to cytogenetic categories of AL with a poor or intermediate risk prognosis, cytogenetic methods should be included in the standard examination of AL patients for diagnosis, prognosis and selection of the optimal treatment strategy.