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1.
Blood ; 144(16): 1722-1731, 2024 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-39074355

RESUMO

ABSTRACT: Mutations in the TP53 gene, particularly multihit alterations, have been associated with unfavorable clinical features and prognosis in patients diagnosed with myelodysplastic syndrome (MDS). Despite this, the role of TP53 gene aberrations in MDS with isolated deletion of chromosome 5 [MDS-del(5q)] remains unclear. This study aimed to assess the impact of TP53 gene mutations and their allelic state in patients with MDS-del(5q). To that end, a comprehensive analysis of TP53 abnormalities, examining both TP53 mutations and allelic imbalances, in 682 patients diagnosed with MDS-del(5q) was conducted. Twenty-four percent of TP53-mutated patients exhibited multihit alterations, whereas the remaining patients displayed monoallelic mutations. TP53-multihit alterations were predictive of an increased risk of leukemic transformation. The impact of monoallelic alterations was dependent on the variant allele frequency (VAF); patients with TP53-monoallelic mutations and VAF <20% exhibited behavior similar to TP53 wild type, and those with TP53-monoallelic mutations and VAF ≥20% presented outcomes equivalent to TP53-multihit patients. This study underscores the importance of considering TP53 allelic state and VAF in the risk stratification and treatment decision-making process for patients with MDS-del(5q).


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 5 , Síndromes Mielodisplásicas , Proteína Supressora de Tumor p53 , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Alelos , Cromossomos Humanos Par 5/genética , Frequência do Gene , Mutação , Síndromes Mielodisplásicas/genética , Prognóstico , Proteína Supressora de Tumor p53/genética
2.
Mol Cell ; 67(1): 55-70.e4, 2017 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-28673543

RESUMO

Ribosomal protein (RP) expression in higher eukaryotes is regulated translationally through the 5'TOP sequence. This mechanism evolved to more rapidly produce RPs on demand in different tissues. Here we show that 40S ribosomes, in a complex with the mRNA binding protein LARP1, selectively stabilize 5'TOP mRNAs, with disruption of this complex leading to induction of the impaired ribosome biogenesis checkpoint (IRBC) and p53 stabilization. The importance of this mechanism is underscored in 5q− syndrome, a macrocytic anemia caused by a large monoallelic deletion, which we found to also encompass the LARP1 gene. Critically, depletion of LARP1 alone in human adult CD34+ bone marrow precursor cells leads to a reduction in 5'TOP mRNAs and the induction of p53. These studies identify a 40S ribosome function independent of those in translation that, with LARP1, mediates the autogenous control of 5'TOP mRNA stability, whose disruption is implicated in the pathophysiology of 5q− syndrome.


Assuntos
Autoantígenos/metabolismo , Biossíntese de Proteínas , Sequência de Oligopirimidina na Região 5' Terminal do RNA , Estabilidade de RNA , RNA Mensageiro/metabolismo , Ribonucleoproteínas/metabolismo , Proteínas Ribossômicas/metabolismo , Ribossomos/metabolismo , Anemia Macrocítica/genética , Anemia Macrocítica/metabolismo , Autoantígenos/genética , Células da Medula Óssea/metabolismo , Deleção Cromossômica , Cromossomos Humanos Par 5/genética , Cromossomos Humanos Par 5/metabolismo , Células HCT116 , Humanos , Complexos Multiproteicos , Ligação Proteica , Interferência de RNA , RNA Mensageiro/genética , Ribonucleoproteínas/genética , Proteínas Ribossômicas/genética , Ribossomos/genética , Fatores de Tempo , Transfecção , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Antígeno SS-B
3.
Br J Haematol ; 204(4): 1243-1248, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38083865

RESUMO

Among 210 patients with myelodysplastic syndromes (MDSs) with del(5q), molecular information was available at diagnosis or at least 3 months before leukaemic transformation in 146 cases. Multivariate analysis identified therapy-related setting (p = 0.02; HR 2.3) and TP53 variant allele frequency (VAF) ≥22% (p < 0.01; HR 2.8), but not SF3B1 mutation (p = 0.65), as independent risk factors for survival. Median survival was 11.7 versus 4 years (5/10-year survival 73%/52% vs. 42%/14%) in the absence (N = 112) versus presence (N = 34) of ≥1 risk factors; leukaemia-free survival was affected by TP53 VAF ≥22% (p < 0.01). Such information might inform treatment decision-making in MDS-del(5q) regarding allogeneic stem cell transplant.


Assuntos
Síndromes Mielodisplásicas , Humanos , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/terapia , Síndromes Mielodisplásicas/diagnóstico , Frequência do Gene , Mutação , Prognóstico , Deleção Cromossômica , Cromossomos Humanos Par 5/genética , Proteína Supressora de Tumor p53/genética
4.
Clin Genet ; 106(4): 386-393, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-38923490

RESUMO

PURA is mapped to chromosome 5q31 and plays a vital role in neuronal development and synapse formation. Here, we aim to explore PURA's impact on cognitive development and epilepsy phenotype by comparing patients with single nucleotide variants (SNPs) in the PURA gene (PURA-SNP patients) to those with 5q31 microdeletions including PURA (5q31del + PURA) and those with 5q31 microdeletions not including the PURA gene (5q31del-PURA). A systematic literature search was conducted in PubMed. Two separate searches were performed in order to find patients with PURA SNPs and 5q31 microdeletions. This review includes data from 191 patients collected from a total of 18 articles; 174 of the patients had PURA SNPs, 13 had 5q31 microdeletions involving the PURA gene, and 4 had 5q31 microdeletions without PURA gene implication. All patients exhibited hypotonia, feeding difficulties and dysmorphic features, however epilepsy was primarily present in patients with PURA syndrome, that is, groups PURA-SNP and 5q31del + PURA. Regarding the developmental milestones the 5q31del + PURA group stood out as being the most severe, while the 5q31del-PURA group showed a relatively mild phenotype. Our findings support the hypothesis of PURA being the key contributor of developmental delay and epilepsy among patients with PURA syndrome.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 5 , Deficiências do Desenvolvimento , Epilepsia , Humanos , Cromossomos Humanos Par 5/genética , Deficiências do Desenvolvimento/genética , Epilepsia/genética , Polimorfismo de Nucleotídeo Único , Fenótipo , Proteínas de Ligação a DNA/genética , Masculino , Feminino , Fatores de Transcrição/genética , Síndrome , Pré-Escolar
5.
Eur J Haematol ; 112(6): 860-869, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38294126

RESUMO

Myelodysplastic syndromes (MDS) encompass a heterogeneous set of acquired bone marrow neoplastic disorders characterized by ineffective hematopoiesis within one or more bone marrow lineages. Nearly half of MDS patients carry cytogenetic alterations, with del(5q) being the most prevalent. Since its first description, del(5q) was consistently correlated with a typical clinical phenotype marked by anemia, thrombocytosis, and a low risk of evolving into acute leukemia. Presently, the World Health Organization (WHO) classification of myeloid neoplasms recognizes a specific subtype of MDS known as "myelodysplastic neoplasm with low blast and isolated del(5q)" identified by the sole presence of 5q deletion or in combination with one other abnormality excluding -7/del(7q). Several studies have sought to unravel the biological processes triggered by del(5q) in the development of MDS, revealing the involvement of various genes localized in specific regions of chromosome 5 referred to as common deleted regions (CDR). This intricate biological landscape makes the MDS cells with del(5q) exceptionally sensitive to lenalidomide. Several studies have confirmed the efficacy of lenalidomide in this context. Regrettably, the response to lenalidomide is not conclusive, prompting ongoing research into biological mechanisms that drive patients toward leukemia and strategies to circumvent lenalidomide resistance and disease progression.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 5 , Síndromes Mielodisplásicas , Humanos , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/terapia , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/etiologia , Cromossomos Humanos Par 5/genética , Lenalidomida/uso terapêutico , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia
6.
Future Oncol ; 20(27): 1993-2004, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39140298

RESUMO

Aim: To assess treatment patterns and outcomes in patients with non-del(5q) lower-risk myelodysplastic syndromes.Methods: Patient medical records were reviewed in the USA, Canada (CAN), UK and the EU.Results: Analysis included 119 patients in the USA/CAN (median age, 61.5 years) and 245 patients in the UK/EU (median age, 67.3 years). Most patients received erythropoiesis-stimulating agents (ESAs) as first-line (1L) therapy (USA/CAN: 89.0%; UK/EU: 90.2%). A substantial proportion of 1L erythropoiesis-stimulating agent-treated patients were transfusion dependent before 1L (USA/CAN: 37.1%; UK/EU: 51.2%); a small percentage of these patients achieved transfusion independence during 1L therapy (USA/CAN: 2.8%; UK/EU: 14.4%).Conclusion: These findings highlight an unmet need for more effective treatments among patients with non-del(5q) lower-risk myelodysplastic syndromes.


[Box: see text].


Assuntos
Síndromes Mielodisplásicas , Humanos , Síndromes Mielodisplásicas/terapia , Síndromes Mielodisplásicas/genética , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Canadá/epidemiologia , Estados Unidos/epidemiologia , Europa (Continente) , Resultado do Tratamento , Cromossomos Humanos Par 5/genética , Hematínicos/uso terapêutico , Idoso de 80 Anos ou mais , Prontuários Médicos , Adulto
7.
Clin Lab ; 70(10)2024 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-39382936

RESUMO

BACKGROUND: The aim of the study was to improve the clinical cognition of nonaccelerating myelodysplastic/myeloproliferative neoplasms-unclassifiable (MDS/MPN-U) with 5q- karyotype and to avoid misdiagnosis or delayed diagnosis. METHODS: The clinical manifestations and laboratory results of a patient with nonaccelerating MDS/MPN-U with 5q- karyotype were analyzed, and related literature was reviewed. RESULTS: The patient was admitted to hospital mainly due to chest tightness and shortness of breath, aggravated for 4 days. After admission, combined with clinical manifestations, bone marrow cell morphology, immunology, multiparameter flow cytometry, cytogenetics and molecular biology, etc., the final diagnosis was MDS-MPN-U. CONCLUSIONS: Research on the correlation between MPN-U and MDS with 5q deletion is still needed. Clinically, MPN-U combined with MDS is prone to misdiagnosis. In diagnosing MPN-U patients, it is essential to not only complete routine and immunological tests but also consider clinical manifestations and laboratory results. It is crucial to be vigilant about the possibility of concurrent diseases, especially cancer, and to choose targeted examinations in a timely manner to avoid missed or incorrect diagnoses.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 5 , Humanos , Cromossomos Humanos Par 5/genética , Masculino , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/genética , Doenças Mieloproliferativas-Mielodisplásicas/diagnóstico , Doenças Mieloproliferativas-Mielodisplásicas/genética , Cariótipo , Transtornos Mieloproliferativos/diagnóstico , Transtornos Mieloproliferativos/genética , Cariotipagem , Idoso
8.
Int J Mol Sci ; 25(16)2024 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-39201328

RESUMO

Non-small cell lung cancer (NSCLC) leads as a primary cause of cancer-related premature mortality in Western populations. This study leverages cutting-edge gene-expression-profiling technologies to perform an in-depth molecular characterization of NSCLC specimens, with the objective of uncovering tumor-specific genomic alterations. By employing DNA microarray analysis, our research aims to refine the classification of NSCLC for early detection, guide molecular-targeted treatment approaches, enhance prognostication, and broaden the scientific understanding of the disease's biology. We identified widespread genomic abnormalities in our samples, including the recurrent loss of chromosomal regions 3p, 5q, 13q, and 21q and the gain of 12p. Furthermore, utilizing Metascape for bioinformatic analysis revealed critical biological pathways disrupted in NSCLC, offering promising leads for novel therapeutic interventions.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Feminino , Pessoa de Meia-Idade , Deleção Cromossômica , Cromossomos Humanos Par 3/genética , Idoso , Cromossomos Humanos Par 5/genética , Gradação de Tumores , Cromossomos Humanos Par 13/genética , Perfilação da Expressão Gênica/métodos
9.
Blood ; 137(4): 493-499, 2021 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-32905580

RESUMO

Agammaglobulinemia is the most profound primary antibody deficiency that can occur due to an early termination of B-cell development. We here investigated 3 novel patients, including the first known adult, from unrelated families with agammaglobulinemia, recurrent infections, and hypertrophic cardiomyopathy (HCM). Two of them also presented with intermittent or severe chronic neutropenia. We identified homozygous or compound-heterozygous variants in the gene for folliculin interacting protein 1 (FNIP1), leading to loss of the FNIP1 protein. B-cell metabolism, including mitochondrial numbers and activity and phosphatidylinositol 3-kinase/AKT pathway, was impaired. These defects recapitulated the Fnip1-/- animal model. Moreover, we identified either uniparental disomy or copy-number variants (CNVs) in 2 patients, expanding the variant spectrum of this novel inborn error of immunity. The results indicate that FNIP1 deficiency can be caused by complex genetic mechanisms and support the clinical utility of exome sequencing and CNV analysis in patients with broad phenotypes, including agammaglobulinemia and HCM. FNIP1 deficiency is a novel inborn error of immunity characterized by early and severe B-cell development defect, agammaglobulinemia, variable neutropenia, and HCM. Our findings elucidate a functional and relevant role of FNIP1 in B-cell development and metabolism and potentially neutrophil activity.


Assuntos
Agamaglobulinemia/genética , Linfócitos B/patologia , Cardiomiopatia Hipertrófica/genética , Proteínas de Transporte/genética , Síndromes de Imunodeficiência/genética , Linfopenia/genética , Adulto , Animais , Linfócitos B/metabolismo , Criança , Pré-Escolar , Cromossomos Humanos Par 5/genética , Códon sem Sentido , Consanguinidade , Doença de Crohn/genética , Variações do Número de Cópias de DNA , Deficiências do Desenvolvimento/genética , Modelos Animais de Doenças , Suscetibilidade a Doenças , Feminino , Cardiopatias Congênitas/genética , Humanos , Infecções/etiologia , Mutação com Perda de Função , Masculino , Camundongos , Neutropenia/genética , Linhagem , Dissomia Uniparental , Sequenciamento do Exoma
10.
Haematologica ; 108(10): 2715-2729, 2023 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-37102608

RESUMO

Inflammation is associated with the pathogenesis of myelodysplastic syndromes (MDS) and emerging evidence suggests that MDS hematopoietic stem and progenitor cells (HSPC) exhibit an altered response to inflammation. Deletion of chromosome 5 (del(5q)) is the most common chromosomal abnormality in MDS. Although this MDS subtype contains several haploinsufficient genes that impact innate immune signaling, the effects of inflammation on del(5q) MDS HSPC remains undefined. Utilizing a model of del(5q)-like MDS, inhibiting the IRAK1/4-TRAF6 axis improved cytopenias, suggesting that activation of innate immune pathways contributes to certain clinical features underlying the pathogenesis of low-risk MDS. However, low-grade inflammation in the del(5q)-like MDS model did not contribute to more severe disease but instead impaired the del(5q)-like HSPC as indicated by their diminished numbers, premature attrition and increased p53 expression. Del(5q)-like HSPC exposed to inflammation became less quiescent, but without affecting cell viability. Unexpectedly, the reduced cellular quiescence of del(5q) HSPC exposed to inflammation was restored by p53 deletion. These findings uncovered that inflammation confers a competitive advantage of functionally defective del(5q) HSPC upon loss of p53. Since TP53 mutations are enriched in del(5q) AML following an MDS diagnosis, increased p53 activation in del(5q) MDS HSPC due to inflammation may create a selective pressure for genetic inactivation of p53 or expansion of a pre-existing TP53-mutant clone.


Assuntos
Síndromes Mielodisplásicas , Proteína Supressora de Tumor p53 , Humanos , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Deleção Cromossômica , Síndromes Mielodisplásicas/patologia , Células-Tronco Hematopoéticas/metabolismo , Transdução de Sinais , Cromossomos Humanos Par 5/genética , Cromossomos Humanos Par 5/metabolismo
11.
Br J Haematol ; 198(1): 114-130, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35362549

RESUMO

Evolution of erythrocyte transfusion-dependent (RBC-TD) anaemia associated with haploinsufficiency of the ribosomal protein subunit S14 gene (RPS14) is a characteristic complication of myelodysplastic syndromes (MDS) with del(5q) [MDS.del(5q)]. Evaluating 39 patients with MDS.del(5q), <5% of anaemia progression was attributable to RPS14-dependent alterations of normoblasts, pro-erythroblasts, or CD34+ CD71+ precursors. Ninety-three percent of anaemia progression and 70% of the absolute decline in peripheral blood Hb value were attributable to disappearance of erythroblastic islands (Ery-Is). Ery-Is loss occurred independently of blast excess, TP53 mutation, additional chromosome aberrations and RPS14-dependent alterations of normoblasts and pro-erythroblasts. It was associated with RPS14-dependent intrinsic (S100A8+ ) and extrinsic [tumour necrosis factor α (TNF-α)-overproduction] alterations of (CD169+ ) marrow macrophages (p < 0.00005). In a mouse model of RPS14 haploinsufficiency, Ery-Is disappeared to a similar degree: approximately 70% of Ery-Is loss was related to RPS14-dependent S100A8 overexpression of marrow macrophages, less than 20% to that of CD71high Ter119- immature precursors, and less than 5% to S100A8/p53 overexpression of normoblasts or pro-erythroblasts. Marked Ery-Is loss predicted reduced efficacy (erythrocyte transfusion independence) of lenalidomide therapy (p = 0.0006). Thus, erythroid hypoplasia, a characteristic complication of MDS.del(5q), seems to result primarily from a macrophage-associated failure of the erythropoietic niche markedly reducing the productive capacity of erythropoiesis as the leading factor in anaemia progression and evolution of RBC-TD in MDS.del(5q).


Assuntos
Anemia , Síndromes Mielodisplásicas , Anemia/complicações , Animais , Aberrações Cromossômicas , Deleção Cromossômica , Cromossomos Humanos Par 5/genética , Humanos , Lenalidomida , Macrófagos/metabolismo , Camundongos , Síndromes Mielodisplásicas/patologia , Talidomida
12.
Nature ; 534(7605): 55-62, 2016 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-27251275

RESUMO

Somatic mutations have been extensively characterized in breast cancer, but the effects of these genetic alterations on the proteomic landscape remain poorly understood. Here we describe quantitative mass-spectrometry-based proteomic and phosphoproteomic analyses of 105 genomically annotated breast cancers, of which 77 provided high-quality data. Integrated analyses provided insights into the somatic cancer genome including the consequences of chromosomal loss, such as the 5q deletion characteristic of basal-like breast cancer. Interrogation of the 5q trans-effects against the Library of Integrated Network-based Cellular Signatures, connected loss of CETN3 and SKP1 to elevated expression of epidermal growth factor receptor (EGFR), and SKP1 loss also to increased SRC tyrosine kinase. Global proteomic data confirmed a stromal-enriched group of proteins in addition to basal and luminal clusters, and pathway analysis of the phosphoproteome identified a G-protein-coupled receptor cluster that was not readily identified at the mRNA level. In addition to ERBB2, other amplicon-associated highly phosphorylated kinases were identified, including CDK12, PAK1, PTK2, RIPK2 and TLK2. We demonstrate that proteogenomic analysis of breast cancer elucidates the functional consequences of somatic mutations, narrows candidate nominations for driver genes within large deletions and amplified regions, and identifies therapeutic targets.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Genômica , Mutação/genética , Proteômica , Transdução de Sinais , Neoplasias da Mama/classificação , Neoplasias da Mama/enzimologia , Proteínas de Ligação ao Cálcio/deficiência , Proteínas de Ligação ao Cálcio/genética , Deleção Cromossômica , Cromossomos Humanos Par 5/genética , Classe I de Fosfatidilinositol 3-Quinases , Quinases Ciclina-Dependentes/genética , Quinases Ciclina-Dependentes/metabolismo , Receptores ErbB/genética , Receptores ErbB/metabolismo , Feminino , Quinase 1 de Adesão Focal/genética , Quinase 1 de Adesão Focal/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Espectrometria de Massas , Anotação de Sequência Molecular , Fosfatidilinositol 3-Quinases/genética , Fosfoproteínas/análise , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/genética , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Proteínas Quinases Associadas a Fase S/genética , Proteínas Quinases Associadas a Fase S/metabolismo , Proteína Supressora de Tumor p53/genética , Quinases Ativadas por p21/genética , Quinases Ativadas por p21/metabolismo , Quinases da Família src/genética , Quinases da Família src/metabolismo
13.
J Pediatr Hematol Oncol ; 44(1): e109-e113, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33625084

RESUMO

Therapy-related myeloid neoplasm (t-MN) in the pediatric population is not well characterized. We studied 12 pediatric patients diagnosed with t-MN in our institution since 2006. The median age at the t-MN diagnoses was 14.8 years (range, 9 to 20 y). The primary malignancies included 9 solid tumors and 3 hematopoietic malignancies. Rhabdomyosarcoma (n=4) was the most common primary malignancy. Five of the 9 patients with solid tumors and all 3 patients with hematopoietic malignancies had primary neoplasms involving bone marrow. The median latency period was 5.2 years (range, 1.8 to 13.8 y). Thrombocytopenia was present in all patients at the t-MN diagnoses. Complete or partial monosomy of chromosome 5 or 7 were the 2 most common cytogenetic abnormalities. A quarter of patients demonstrated a genetic predisposition to t-MN: 1 with Li-Fraumeni syndrome with a germline TP53 R248Q mutation, 1 with Noonan syndrome with a somatic mutation (PTPN11 S502T), and 1 with a constitutive chromosomal translocation [t(X;9)(p22;q34)] and a germline TP53 L130V mutation. Outcomes remain poor. Two patients survived 3 and 5.1 years after hematopoietic stem cell transplantation.


Assuntos
Cromossomos Humanos Par 5/genética , Predisposição Genética para Doença , Neoplasias Hematológicas , Transplante de Células-Tronco Hematopoéticas , Síndrome de Li-Fraumeni , Transtornos Mieloproliferativos , Segunda Neoplasia Primária , Síndrome de Noonan , Rabdomiossarcoma , Adolescente , Adulto , Aloenxertos , Criança , Pré-Escolar , Deleção Cromossômica , Cromossomos Humanos Par 7/genética , Feminino , Neoplasias Hematológicas/epidemiologia , Neoplasias Hematológicas/genética , Humanos , Lactente , Síndrome de Li-Fraumeni/epidemiologia , Síndrome de Li-Fraumeni/genética , Síndrome de Li-Fraumeni/terapia , Masculino , Transtornos Mieloproliferativos/epidemiologia , Transtornos Mieloproliferativos/genética , Segunda Neoplasia Primária/epidemiologia , Segunda Neoplasia Primária/genética , Síndrome de Noonan/epidemiologia , Síndrome de Noonan/genética , Síndrome de Noonan/terapia , Rabdomiossarcoma/epidemiologia , Rabdomiossarcoma/genética , Rabdomiossarcoma/terapia , Adulto Jovem
14.
Genes Chromosomes Cancer ; 60(6): 452-457, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33486841

RESUMO

A complex karyotype, detected in myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML), is associated with a reduced median survival. The most frequent chromosomal aberrations in complex karyotypes are deletions of 5q and 17p harboring the tumor suppressor gene TP53. The unbalanced translocation der(5;17) involving chromosome 5q and 17p is a recurrent aberration in MDS/AML, resulting in TP53 loss. We analyzed the karyotypes of 178 patients with an unbalanced translocation der(5;17) using fluorescence R-/G-banding analysis. Whenever possible, fluorescence in situ hybridization (FISH) (n = 138/141), multicolor FISH (n = 8), telomere length measurement (n = 9), targeted DNA sequencing (n = 13), array-CGH (n = 7) and targeted RNA sequencing (n = 2) were conducted. The der(5;17) aberration was accompanied with loss of genetic material in 7q (53%), -7 (27%), gain of 21q (29%), +8 (17%) and - 18 (16%) and all analyzed patients (n = 13) showed a (likely) pathogenic variant inTP53. The der(5;17) cohort showed significantly shortened telomeres in comparison to the healthy age-matched controls (P < .05), but there was no significant telomere shortening in comparison to MDS/AML patients with a complex karyotype without der(5;17). No fusion genes resulted from the unbalanced translocation. This study demonstrates that the unbalanced translocation der(5;17) is associated with a biallelic inactivation of TP53 due to a deletion of TP53 in one allele and a pathogenic variant of the second TP53 allele. Since the breakpoints are located within (near-) heterochromatic regions, alterations of DNA methylation or histone modifications may be involved in the generation of der(5;17).


Assuntos
Cromossomos Humanos Par 17/genética , Cromossomos Humanos Par 5/genética , Leucemia Mieloide Aguda/genética , Síndromes Mielodisplásicas/genética , Translocação Genética , Proteína Supressora de Tumor p53/genética , Cariótipo Anormal , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Feminino , Humanos , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/patologia
15.
Int J Cancer ; 148(3): 748-758, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33045100

RESUMO

Deletion of chromosome 5q is common in prostate cancer and is linked to aggressive disease. Most previous studies focused on 5q21 where CHD1 is located, but deletion of mapping studies has identified a second deletion hotspot at 5q13. To clarify the prevalence and clinical relevance of 5q13 deletions and to determine the relative importance of 5q13 and 5q21 abnormalities, a tissue microarray containing samples from 12 427 prostate cancers was analyzed by fluorescence in situ hybridization. Deletion of 5q13 and 5q21 was found in 13.5% and 10%, respectively, of 7932 successfully analyzed cancers. Deletion was restricted to 5q13 in 49.4% and to 5q21 in 32.0% of cancers with a 5q deletion. Only 18.6% of 5q-deleted cancers had deletions of both loci. Both 5q13 and 5q21 deletions were significantly linked to advanced tumor stage, high Gleason grade, nodal metastasis and early biochemical recurrence (P < .005 each). Cancers with co-deletion of 5q13 and 5q21 had a worse prognosis than cancers with isolated 5q13 or 5q21 deletion (P = .0080). Comparison with TMPRSS2:ERG fusion status revealed that 5q21 deletions were tightly linked to ERG negativity (P < .0001) while 5q13 deletions were unrelated to the ERG status. In summary, 5q13 deletion and 5q21 deletion are common, but independent genomic alterations with different functional effects lead to aggressive prostate cancer.


Assuntos
Cromossomos Humanos Par 5/genética , Hibridização in Situ Fluorescente/métodos , Neoplasias da Próstata/patologia , Deleção de Sequência , Humanos , Metástase Linfática , Masculino , Estadiamento de Neoplasias , Prognóstico , Neoplasias da Próstata/genética , Análise Serial de Tecidos
16.
Br J Haematol ; 193(4): 798-803, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33765355

RESUMO

Splicing factor 3B subunit 1 (SF3B1) mutations define a distinct myelodysplastic syndromes (MDS) patient group with a relatively favourable disease course and high response rates to luspatercept. Few data are available on bone marrow phenotype beyond ring sideroblasts in this subgroup of patients with MDS. In the present study, we identified immunophenotypic erythroid, myelomonocyte and progenitor features associated with SF3B1 mutations. In addition, we illustrate that SF3B1-mutation type is associated with distinct immunophenotypic features, and show the impact of co-occurrence of a SF3B1 mutation and a deletion of chromosome 5q on bone marrow immunophenotype. These genotype-phenotype associations and phenotypic subtypes within SF3B1-MDS provide leads that may further refine prognostication and therapeutic strategies for this particular MDS subgroup.


Assuntos
Células da Medula Óssea/imunologia , Cromossomos Humanos Par 5 , Deleção de Genes , Imunofenotipagem , Síndromes Mielodisplásicas , Fosfoproteínas , Fatores de Processamento de RNA , Cromossomos Humanos Par 5/genética , Cromossomos Humanos Par 5/imunologia , Feminino , Humanos , Masculino , Síndromes Mielodisplásicas/classificação , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/imunologia , Fosfoproteínas/genética , Fosfoproteínas/imunologia , Fatores de Processamento de RNA/genética , Fatores de Processamento de RNA/imunologia
17.
Cytogenet Genome Res ; 161(12): 556-563, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-35021179

RESUMO

5q14.3 deletion syndrome (MIM#613443) is an uncommon but well-known syndrome characterized by intellectual disability, epilepsy, hypotonia, brain malformations, and facial dysmorphism. Most patients with this syndrome have lost one copy of the MEF2C gene (MIM*600662), whose haploinsufficiency is considered to be responsible for the distinctive phenotype. To date, nearly 40 cases have been reported; the deletion size and clinical spectrum are variable, and at least 6 cases without MEF2C involvement have been documented. We herein report the clinical and cytogenomic findings of an 11-year-old girl who has a 5q14.3q21.1 de novo deletion that does not involve MEF2C but shares the clinical features described in other reported patients. Moreover, she additionally presents with bilateral cleft-lip palate (CLP), which has not been previously reported as a feature of the syndrome. The most frequent syndromic forms of CLP were ruled out in our patient mainly by clinical examination, and Sanger sequencing was performed to discard the presence of a TBX22 gene (MIM*300307) defect. Our report suggests CLP as a possible unreported feature and redefines the critical phenotypic regions of 5q14.3 deletion syndrome.


Assuntos
Anormalidades Múltiplas/genética , Deleção Cromossômica , Cromossomos Humanos Par 5/genética , Fenda Labial/genética , Fissura Palatina/genética , Criança , Epilepsia/congênito , Epilepsia/genética , Feminino , Humanos , Deficiência Intelectual/genética , Fatores de Transcrição MEF2 , Síndrome
18.
Am J Med Genet A ; 185(2): 549-554, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33191647

RESUMO

Silver-Russell syndrome (SRS) is characterized by pre- and postnatal growth deficiency. It is most often caused by hypomethylation of the paternal imprinting center 1 of chromosome 11p15.5. In contrast, Sotos syndrome is an overgrowth syndrome that results either from pathogenic NSD1 gene variants or copy number variations affecting the NSD1 gene. Here, we report on a 6 month-old boy with severe short stature, relative macrocephaly, severe feeding difficulties with underweight, muscular hypotonia, motor delay, medullary nephrocalcinosis, bilateral sensorineural hearing impairment and facial dysmorphisms. SNP array revealed a 2.1 Mb de novo interstitial deletion of 5q35.2q35.3 encompassing the NSD1 gene. As Sotos syndrome could not satisfactorily explain his symptoms, diagnostic testing for SRS was initiated. It demonstrated hypomethylation of the imprinting center 1 of chromosome 11p15.5 confirming the clinically suspected SRS. We compared the symptoms of our patient with the typical clinical features of individuals with SRS and Sotos syndrome, respectively. To our knowledge, this is the first study reporting the very unusual coincidence of both Sotos syndrome and SRS in the same patient.


Assuntos
Histona-Lisina N-Metiltransferase/genética , Síndrome de Silver-Russell/genética , Síndrome de Sotos/genética , Deleção Cromossômica , Cromossomos Humanos Par 5/genética , Variações do Número de Cópias de DNA/genética , Metilação de DNA/genética , Impressão Genômica/genética , Humanos , Lactente , Recém-Nascido , Masculino , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Síndrome de Silver-Russell/complicações , Síndrome de Silver-Russell/diagnóstico , Síndrome de Silver-Russell/patologia , Síndrome de Sotos/complicações , Síndrome de Sotos/diagnóstico , Síndrome de Sotos/patologia
19.
Am J Med Genet A ; 185(12): 3844-3850, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34322994

RESUMO

Microdeletions at 5q11.2 are rare. Subjects show a phenotypic spectrum that overlaps CHARGE syndrome and 22q11.2 deletion syndrome. A growing number of subjects present with learning difficulty and/or intellectual disability, immune deficiency, congenital heart malformation, and dysmorphism. DHX29 and IL6ST have been proposed as candidate genes for the development of the major clinical manifestations. We present a new case and narrow down the shortest region of overlap to evaluate possible candidate genes. Our case does not present developmental delay or immune deficiency indicating a reduced penetrance for some of the main clinical manifestations. The shortest region of overlap between subjects with deletions at 5q11.2 is approximately 450 kb (position 54.3-54.7 Mb). The narrowed region comprises 10 protein coding genes, including DHX29. DHX29 is a strong candidate gene for the main features of 5q11.2-microdeletion syndrome; however, our findings suggest a joined impact of several genes as the cause of the syndrome.


Assuntos
Anormalidades Múltiplas/genética , Anemia Macrocítica/genética , Cardiopatias Congênitas/genética , Deficiência Intelectual/genética , RNA Helicases/genética , Anormalidades Múltiplas/fisiopatologia , Anemia Macrocítica/fisiopatologia , Pré-Escolar , Deleção Cromossômica , Cromossomos Humanos Par 5/genética , Hibridização Genômica Comparativa , Receptor gp130 de Citocina/genética , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/fisiopatologia , Fácies , Cardiopatias Congênitas/fisiopatologia , Humanos , Lactente , Recém-Nascido , Deficiência Intelectual/fisiopatologia , Deficiências da Aprendizagem/genética , Deficiências da Aprendizagem/fisiopatologia , Masculino , Fenótipo
20.
Ann Hematol ; 100(6): 1463-1471, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33903952

RESUMO

Myelodysplastic syndrome (MDS) with isolated deletion of chromosome 5q (MDS del5q) is a distinct subtype of MDS with quite favorable prognosis and excellent response to treatment with lenalidomide. Still, a relevant percentage of patients do not respond to lenalidomide and even experience progression to acute myeloid leukemia (AML). In this study, we aimed to investigate whether global DNA methylation patterns could predict response to lenalidomide. Genome-wide DNA methylation analysis using Illumina 450k methylation arrays was performed on n=51 patients with MDS del5q who were uniformly treated with lenalidomide in a prospective multicenter trial of the German MDS study group. To study potential direct effects of lenalidomide on DNA methylation, 17 paired samples pre- and post-treatment were analyzed. Our results revealed no relevant effect of lenalidomide on methylation status. Furthermore, methylation patterns prior to therapy could not predict lenalidomide response. However, methylation clustering identified a group of patients with a trend towards inferior overall survival. These patients showed hypermethylation of several interesting target genes, including genes of relevant signaling pathways, potentially indicating the evaluation of novel therapeutic targets.


Assuntos
Antineoplásicos/uso terapêutico , Metilação de DNA/efeitos dos fármacos , Lenalidomida/uso terapêutico , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/farmacologia , Deleção Cromossômica , Cromossomos Humanos Par 5/genética , Feminino , Humanos , Lenalidomida/farmacologia , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
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