RESUMO
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
Anormalidades Múltiplas/genética , Deleção Cromossômica , Cromossomos Humanos Par 11 , Feminino , Humanos , Lactente , MutaçãoRESUMO
Abstract Background: Rare subgroups of pediatric patients with acute myeloid leukemia (AML), such as t(16:21) (p11;q22), require international cooperation to establish a proper stratification system to assign clinical risk. Case report: Here, we report a 13-year-old female who was admitted for asthenia, fatigue, and intermittent fever. The hematological data showed thrombocytopenia and anemia, and the bone marrow test showed 82.5% blast cells, which were positive for CD13, CD33, CD38, and CD117. Blast cells showed negative myeloperoxidase staining and positive periodic acid-Schiff staining. A diagnosis of AML M6 was made. Cells were positive for the fusion transcript FUS-ERG t(16;21)(p11;q22). The patient achieved morphological remission. However, molecular remission was not achieved, and she died 11 months after diagnosis. Conclusions: It is essential to report this sporadic case of AML to provide clinicians with data for clinical decision-making, such as for risk-group stratification. To the best of our knowledge, this is the first association between this translocation and this morphological subtype.
Resumen Introducción: La leucemia mieloide aguda (LMA) infantil es una enfermedad heterogénea, por lo que existen subgrupos de rara presentación, como aquellos con t(16;21)(p11;q22). Para establecer el riesgo clínico y la estratificación pronóstica adecuada es necesaria la cooperación internacional. Caso clínico: Se reporta el caso de una adolescente de 13 años, admitida por astenia, adinamia y fiebre intermitente. Los datos hematológicos mostraron trombocitopenia y anemia, con un 82.5% de blastos en médula ósea, los cuales fueron positivos para CD13, CD33, CD38 y CD 117. Los blastos fueron negativos para mieloperoxidasa y positivos para ácido peryódico de Schiff. Se realizó el diagnóstico morfológico de LMA M6. Las células fueron positivas para el transcrito FUS-ERG t(16;21)(p11;q22). La paciente alcanzó la remisión morfológica; sin embargo, no fue posible la remisión molecular y falleció 11 meses después del diagnóstico. Conclusiones: Es importante reportar casos en los que se identifique un subtipo muy raro de LMA infantil para incrementar la evidencia clínica y contribuir con elementos que ayuden a tomar decisiones clínicas y lograr la estratificación en grupos de riesgo. Hasta la fecha, este el primer caso reportado en que se asocia el transcrito t(16;21)(p11;q22) con el subtipo morfológico LMA M6.
Assuntos
Adolescente , Feminino , Humanos , Translocação Genética , Leucemia Mieloide Aguda , Cromossomos Humanos Par 11 , Cromossomos Humanos Par 16 , Leucemia Mieloide Aguda/genéticaRESUMO
Background: Background">Rare subgroups of pediatric patients with acute myeloid leukemia (AML), such as t(16:21) (p11;q22), require international cooperation to establish a proper stratification system to assign clinical risk. Case report: Here, we report a 13-year-old female who was admitted for asthenia, fatigue, and intermittent fever. The hematological data showed thrombocytopenia and anemia, and the bone marrow test showed 82.5% blast cells, which were positive for CD13, CD33, CD38, and CD117. Blast cells showed negative myeloperoxidase staining and positive periodic acid-Schiff staining. A diagnosis of AML M6 was made. Cells were positive for the fusion transcript FUS-ERG t(16;21)(p11;q22). The patient achieved morphological remission. However, molecular remission was not achieved, and she died 11 months after diagnosis. Conclusions: It is essential to report this sporadic case of AML to provide clinicians with data for clinical decision-making, such as for risk-group stratification. To the best of our knowledge, this is the first association between this translocation and this morphological subtype.
Introducción: La leucemia mieloide aguda (LMA) infantil es una enfermedad heterogénea, por lo que existen subgrupos de rara presentación, como aquellos con t(16;21)(p11;q22). Para establecer el riesgo clínico y la estratificación pronóstica adecuada es necesaria la cooperación internacional. Caso clínico: Se reporta el caso de una adolescente de 13 años, admitida por astenia, adinamia y fiebre intermitente. Los datos hematológicos mostraron trombocitopenia y anemia, con un 82.5% de blastos en médula ósea, los cuales fueron positivos para CD13, CD33, CD38 y CD 117. Los blastos fueron negativos para mieloperoxidasa y positivos para ácido peryódico de Schiff. Se realizó el diagnóstico morfológico de LMA M6. Las células fueron positivas para el transcrito FUS-ERG t(16;21)(p11;q22). La paciente alcanzó la remisión morfológica; sin embargo, no fue posible la remisión molecular y falleció 11 meses después del diagnóstico. Conclusiones: Es importante reportar casos en los que se identifique un subtipo muy raro de LMA infantil para incrementar la evidencia clínica y contribuir con elementos que ayuden a tomar decisiones clínicas y lograr la estratificación en grupos de riesgo. Hasta la fecha, este el primer caso reportado en que se asocia el transcrito t(16;21)(p11;q22) con el subtipo morfológico LMA M6.
Assuntos
Leucemia Mieloide Aguda , Translocação Genética , Adolescente , Cromossomos Humanos Par 11 , Cromossomos Humanos Par 16 , Feminino , Humanos , Leucemia Mieloide Aguda/genéticaRESUMO
Mucosa-associated lymphoid tissue (MALT) lymphomas are B-cell neoplasms that commonly affect the gastrointestinal (GI) tract, usually the stomach. In most cases, extranodal marginal zone lymphoma (ENMZL) is an indolent disease. Bone marrow involvement is common with MALT lymphoma accompanied by paraproteinemia; such involvement impels disease progression. Here, we present the case of an 82-year-old Hispanic patient with long-standing ENMZL in whom the gastric site responded to antibiotic treatment and Helicobacter pylori eradication, but the disease progressed over the years, with a biclonal gammopathy and bone marrow involvement with marked plasmacytic differentiation. In view of this, we suggest the routine evaluation of paraprotein in patients with ENMZL.
Assuntos
Cromossomos Humanos Par 11 , Linfoma de Zona Marginal Tipo Células B , Paraproteinemias/diagnóstico , Neoplasias Gástricas , Idoso de 80 Anos ou mais , Medula Óssea/patologia , Doenças da Medula Óssea/patologia , Cromossomos Humanos Par 11/genética , Fadiga/diagnóstico , Infecções por Helicobacter/tratamento farmacológico , Helicobacter pylori , Humanos , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Cadeias lambda de Imunoglobulina/sangue , Neoplasias Pulmonares/diagnóstico por imagem , Linfoma de Zona Marginal Tipo Células B/sangue , Linfoma de Zona Marginal Tipo Células B/tratamento farmacológico , Linfoma de Zona Marginal Tipo Células B/genética , Linfoma de Zona Marginal Tipo Células B/patologia , Masculino , Mieloma Múltiplo/diagnóstico , Proteínas de Fusão Oncogênica/genética , Neoplasias Gástricas/sangue , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Trissomia/genéticaRESUMO
Genetic analysis of admixed populations raises special concerns with regard to study design and data processing, particularly to avoid population stratification biases. The point mutation responsible for sickle cell anaemia codes for a variant hemoglobin, sickle hemoglobin or HbS, whose presence drives the pathophysiology of disease. Here we propose to explore ancestry and population structure in a genome-wide study with particular emphasis on chromosome 11 in two SCA admixed cohorts obtained from urban populations of Brazil (Pernambuco and São Paulo) and the United States (Pennsylvania). Ancestry inference showed different proportions of European, African and American backgrounds in the composition of our samples. Brazilians were more admixed, had a lower African background (43% vs. 78% on the genomic level and 44% vs. 76% on chromosome 11) and presented a signature of positive selection and Iberian introgression in the HbS region, driving a high differentiation of this locus between the two cohorts. The genetic structures of the SCA cohorts from Brazil and US differ considerably on the genome-wide, chromosome 11 and HbS mutation locus levels.
Assuntos
Anemia Falciforme/genética , Cromossomos Humanos Par 11/genética , Genética Populacional/métodos , Genótipo , Hemoglobina Falciforme/genética , Grupos Populacionais , Grupos Raciais/genética , Brasil , Estudos de Coortes , Frequência do Gene , Genoma , Estudo de Associação Genômica Ampla , Haplótipos , Humanos , Estados UnidosRESUMO
ABSTRACT Aniridia is a congenital eye disorder with a variable degree of hypoplasia or absence of iris tissue. It is caused by loss of function of the PAX6 gene and may be an isolated ocular abnormality or part of a syndrome. WAGRO refers to a rare genetic condition leading to Wilms tumor, aniridia, genitourinary anomalies, mental retardation, and obesity and is caused by a deletion of the short arm of chromosome 11 (11p), where the PAX6 gene is located. Here, we report on an 8-year-old boy with aniridia, polar cataract, and lens subluxation along with neuropsychomotor and speech delays. Karyotype evaluation showed an interstitial deletion including region 11p13-p14, confirming the diagnosis of WAGRO syndrome. In cases of aniridia, a diagnosis of WAGRO syndrome should be considered.
RESUMO A aniridia é uma doença ocular congênita com grau variável de hipoplasia ou ausência do tecido da íris. É causada pela perda de função do gene PAX6 e pode ser uma anormalidade ocular isolada ou parte de uma síndrome. WAGRO refere-se a uma condição genética rara que leva ao tumor de Wilms, aniridia, anomalias geniturinárias, déficit intelectual e obesidade e é causada por uma deleção do braço curto do cromossomo 11 (11p), onde o gene PAX6 está localizado. Aqui, nós relatamos um menino de 8 anos de idade com aniridia, catarata polar e subluxação do cristalino, além de retardo neuropsicomotor e de fala. A avaliação cariotípica revelou uma deleção intersticial envolvendo a região 11p13-p14, confirmando o diagnóstico da síndrome WAGRO. Em casos de aniridia, um diagnóstico de síndrome de WAGRO deve ser considerado.
Assuntos
Humanos , Masculino , Criança , Catarata/diagnóstico , Aniridia/diagnóstico , Subluxação do Cristalino/diagnóstico , Síndrome WAGR/diagnóstico , Obesidade/diagnóstico , Catarata/genética , Cromossomos Humanos Par 11/genética , Aniridia/genética , Subluxação do Cristalino/genética , Deleção Cromossômica , Síndrome WAGR/genética , Cariótipo , Obesidade/genéticaRESUMO
Aniridia is a congenital eye disorder with a variable degree of hypoplasia or absence of iris tissue. It is caused by loss of function of the PAX6 gene and may be an isolated ocular abnormality or part of a syndrome. WAGRO refers to a rare genetic condition leading to Wilms tumor, aniridia, genitourinary anomalies, mental retardation, and obesity and is caused by a deletion of the short arm of chromosome 11 (11p), where the PAX6 gene is located. Here, we report on an 8-year-old boy with aniridia, polar cataract, and lens subluxation along with neuropsychomotor and speech delays. Karyotype evaluation showed an interstitial deletion including region 11p13-p14, confirming the diagnosis of WAGRO syndrome. In cases of aniridia, a diagnosis of WAGRO syndrome should be considered.
Assuntos
Aniridia/diagnóstico , Catarata/diagnóstico , Subluxação do Cristalino/diagnóstico , Obesidade/diagnóstico , Síndrome WAGR/diagnóstico , Aniridia/genética , Catarata/genética , Criança , Deleção Cromossômica , Cromossomos Humanos Par 11/genética , Humanos , Cariótipo , Subluxação do Cristalino/genética , Masculino , Obesidade/genética , Síndrome WAGR/genéticaRESUMO
AIM: To investigate the presence/absence of the Chr-11 tRNA-Lys-CUU gene as a marker for genetic predisposition to Type 2 diabetes mellitus (T2DM). METHODS: We enrolled 122 patients diagnosed with T2DM and 77 non-diabetic individuals. We evaluated clinical and biochemical parameters (body mass index, hypertension, cholesterol levels, glycosylated hemoglobin, triglycerides, etc.), and performed a genotypic profiling of Chr-11 tRNA-Lys-CUU by polymerase chain reaction analyses. RESULTS: Approximately one third of the population lacked Chr-11 tRNA-Lys-CUU. We did not observe a statistically significant association between the presence/absence of Chr-11 tRNA-Lys-CUU and T2DM. CONCLUSION: The genotypic distribution of Chr-11 tRNA-Lys-CUU in our population was consistent to that reported by others. This gene failed as a marker for T2DM predisposition.
Assuntos
Biomarcadores/análise , Cromossomos Humanos Par 11/genética , Diabetes Mellitus Tipo 2/genética , Deleção de Genes , Predisposição Genética para Doença , RNA de Transferência de Lisina/genética , Idoso , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Espanha/epidemiologiaRESUMO
OBJECTIVES: To identify potential molecular drivers associated with prognosis and response to treatment in advanced oropharyngeal squamous cell carcinomas (OPSCC). MATERIALS AND METHODS: Thirty-three OPSCC biopsies from untreated Brazilian patients were evaluated for human papilloma virus genotyping, genome wide copy number alterations and gene expression profiling. Data were integrated using CONEXIC algorithm. Validation with TCGA dataset and confirmation by RT-qPCR of candidate genes were performed. RESULTS: High-risk HPV positive cases, detected in 55% of advanced OPSCC, were associated with better outcome. Losses of 8p11.23-p11.22, 14q11.1-q11.2 and 15q11.2, and gains of 11q13.2 and 11q13.2-q13.3 were detected as recurrent alterations. Gains of 3q26.31 and 11q13.2 and losses of 9p21.3 were exclusively detected in HPV-negative tumors. Two clusters of expression profiles were observed, being one composed mostly by HPV positive cases (83%). HPV-positive enriched cluster showed predominantly immune response-related pathways. Integrative analysis identified 10 modulators mapped in 11q13, which were frequently cancer-related. These 10 genes showed copy number gains, overexpression and an association with worse survival, further validated by TCGA database analyses. Overexpression of four genes (ORAOV1, CPT1A, SHANK2 and PPFIA1) evaluated by RT-qPCR confirmed their association with poor survival. Multivariate analysis showed that PPFIA1 overexpression and HPV status are independent prognostic markers. Moreover, SHANK2 overexpression was significantly associated with incomplete response to treatment. CONCLUSION: The integrative genomic and transcriptomic data revealed potential driver genes mapped in 11q13 associated with worse prognosis and response to treatment, giving fundamentals for the identification of novel therapeutic targets in OPSCC.
Assuntos
Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/terapia , Cromossomos Humanos Par 11 , Oncogenes , Neoplasias Orofaríngeas/genética , Neoplasias Orofaríngeas/terapia , Resultado do Tratamento , Proteínas Adaptadoras de Transdução de Sinal/genética , Alphapapillomavirus/isolamento & purificação , Carcinoma de Células Escamosas/virologia , Mapeamento Cromossômico , Feminino , Genômica , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/genética , Neoplasias Orofaríngeas/virologia , Prognóstico , TranscriptomaAssuntos
Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 22/genética , Linfoma de Célula do Manto/genética , Translocação Genética , Doenças Assintomáticas , Contagem de Células Sanguíneas , Medula Óssea/patologia , Feminino , Humanos , Linfoma de Célula do Manto/sangue , Linfoma de Célula do Manto/diagnóstico por imagem , Linfoma de Célula do Manto/patologia , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons combinada à Tomografia ComputadorizadaAssuntos
Anemia Falciforme , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 2/genética , Hemoglobina Fetal , Hidroxiureia/administração & dosagem , Adolescente , Adulto , Anemia Falciforme/sangue , Anemia Falciforme/tratamento farmacológico , Anemia Falciforme/genética , Criança , Pré-Escolar , Feminino , Hemoglobina Fetal/genética , Hemoglobina Fetal/metabolismo , Estudo de Associação Genômica Ampla , Humanos , MasculinoRESUMO
Obesity is a major public health concern in Mexico and worldwide. Although the estimated heritability is high, common variants identified by genome-wide association studies explain only a small proportion of this heritability. A combination of linkage and association strategies could be a more robust and powerful approach to identify other obesity-susceptibility variants. We thus sought to identify novel genetic variants associated with obesity-related traits in the Mexican population by combining these methods. We performed a genome-wide linkage scan for body mass index (BMI) and other obesity-related phenotypes in 16 Mexican families using the Sequential Oligogenic Linkage Analysis Routines Program. Associated single-nucleotide polymorphisms (SNPs) were tested for associations in an independent cohort. Two suggestive BMI-linkage peaks (logarithm of odds ⩾1.5) were observed at chromosomal regions 11q13 and 13q22. Only rs614080 in the 11q13 region was significantly associated with BMI and related traits in these families. This association was also significant in an independent cohort of Mexican adults. Moreover, this variant was significantly associated with GSTP1 gene expression levels in adipose tissue. In conclusion, the rs614080 SNP near the GSTP1 gene was significantly associated with BMI and GSTP1 expression levels in the Mexican population.
Assuntos
Predisposição Genética para Doença , Glutationa S-Transferase pi/genética , Obesidade/genética , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Característica Quantitativa Herdável , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Adolescente , Adulto , Idoso , Índice de Massa Corporal , Cromossomos Humanos Par 11/química , Família , Feminino , Ligação Genética , Estudo de Associação Genômica Ampla , Humanos , Padrões de Herança , Masculino , México/epidemiologia , Pessoa de Meia-Idade , Obesidade/epidemiologia , Obesidade/patologiaRESUMO
Beckwith-Wiedemann Syndrome (BWS) is an overgrowth disorder with various congenital anomalies. Although the most classic constellation includes macrosomia, macroglossia, and omphalocele, nephrourological findings are commonly associated with BWS. Clinical presentation is highly variable because of its complex molecular heterogeneity, which involves changes in DNA methylation and disruption of growth regulatory genes. We report 3 pediatric patients, ages 13 months to 3 years old, who presented with clinical features consistent with BWS. A variety of nephrourological abnormalities were also noted, including posterior urethral valves, hydroureteronephrosis, and undescended testes. Genetic testing for all 3 patients revealed duplication of the region chromosome 11p15.5.
Assuntos
Síndrome de Beckwith-Wiedemann/diagnóstico , Síndrome de Beckwith-Wiedemann/genética , Duplicação Cromossômica , Cromossomos Humanos Par 11 , Síndrome de Beckwith-Wiedemann/diagnóstico por imagem , Pré-Escolar , Humanos , Lactente , MasculinoRESUMO
BACKGROUND: Genome-wide profiling of rare tumors is crucial for improvement of diagnosis, treatment, and, consequently, achieving better outcomes. Desmoplastic small round cell tumor (DSRCT) is a rare type of sarcoma arising from mesenchymal cells of abdominal peritoneum that usually develops in male adolescents and young adults. A specific translocation, t(11;22)(p13;q12), resulting in EWS and WT1 gene fusion is the only recurrent molecular hallmark and no other genetic factor has been associated to this aggressive tumor. Here, we present a comprehensive genomic profiling of one DSRCT affecting a 26-year-old male, who achieved an excellent outcome. METHODS: We investigated somatic and germline variants through whole-exome sequencing using a family based approach and, by array CGH, we explored the occurrence of genomic imbalances. Additionally, we performed mate-paired whole-genome sequencing for defining the specific breakpoint of the EWS-WT1 translocation, allowing us to develop a personalized tumor marker for monitoring the patient by liquid biopsy. RESULTS: We identified genetic variants leading to protein alterations including 12 somatic and 14 germline events (11 germline compound heterozygous mutations and 3 rare homozygous polymorphisms) affecting genes predominantly involved in mesenchymal cell differentiation pathways. Regarding copy number alterations (CNA) few events were detected, mainly restricted to gains in chromosomes 5 and 18 and losses at 11p, 13q, and 22q. The deletions at 11p and 22q indicated the presence of the classic translocation, t(11;22)(p13;q12). In addition, the mapping of the specific genomic breakpoint of the EWS-WT1 gene fusion allowed the design of a personalized biomarker for assessing circulating tumor DNA (ctDNA) in plasma during patient follow-up. This biomarker has been used in four post-treatment blood samples, 3 years after surgery, and no trace of EWS-WT1 gene fusion was detected, in accordance with imaging tests showing no evidence of disease and with the good general health status of the patient. CONCLUSIONS: Overall, our findings revealed genes with potential to be associated with risk assessment and tumorigenesis of this rare type of sarcoma. Additionally, we established a liquid biopsy approach for monitoring patient follow-up based on genomic information that can be similarly adopted for patients diagnosed with a rare tumor.
Assuntos
Neoplasias Abdominais/diagnóstico por imagem , Tumor Desmoplásico de Pequenas Células Redondas/diagnóstico por imagem , Neoplasias Abdominais/genética , Neoplasias Abdominais/terapia , Adulto , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Cromossomos Humanos Par 11/genética , DNA de Neoplasias/sangue , DNA de Neoplasias/genética , Tumor Desmoplásico de Pequenas Células Redondas/genética , Tumor Desmoplásico de Pequenas Células Redondas/terapia , Humanos , Masculino , Técnicas de Diagnóstico Molecular , Polimorfismo Genético , Translocação GenéticaRESUMO
Cells that are deficient in homologous recombination, such as those that have mutations in any of the Fanconi Anemia (FA)/BRCA genes, are hypersensitive to inhibition of poly(ADP-ribose) polymerase (PARP). However, FA/BRCA-deficient tumors represent a small fraction of breast cancers, which might restrict the therapeutic utility of PARP inhibitor monotherapy. The gene encoding the serine-threonine protein kinase p21-activated kinase 1 (PAK1) is amplified and/or overexpressed in several human cancer types including 25-30% of breast tumors. This enzyme controls many cellular processes by phosphorylating both cytoplasmic and nuclear substrates. Here, we show that depletion or pharmacological inhibition of PAK1 down-regulated the expression of genes involved in the FA/BRCA pathway and compromised the ability of cells to repair DNA by Homologous Recombination (HR), promoting apoptosis and reducing colony formation. Combined inhibition of PAK1 and PARP in PAK1 overexpressing breast cancer cells had a synergistic effect, enhancing apoptosis, suppressing colony formation, and delaying tumor growth in a xenograft setting. Because reduced PAK1 activity impaired FA/BRCA function, inhibition of this kinase in PAK1 amplified and/or overexpressing breast cancer cells represents a plausible strategy for expanding the utility of PARP inhibitors to FA/BRCA-proficient cancers.
Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Resistencia a Medicamentos Antineoplásicos , Proteínas de Grupos de Complementação da Anemia de Fanconi/genética , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Quinases Ativadas por p21/metabolismo , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Cromossomos Humanos Par 11/genética , Dano ao DNA/efeitos dos fármacos , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/genética , Sinergismo Farmacológico , Proteínas de Grupos de Complementação da Anemia de Fanconi/deficiência , Feminino , Amplificação de Genes , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Recombinação Homóloga , Humanos , Camundongos , Ensaios Antitumorais Modelo de Xenoenxerto , Quinases Ativadas por p21/genéticaRESUMO
The 11q terminal deletion disorder is a rare genetic disorder associated with numerous clinical features. A few case reports have been made about de novo interstitial deletion of chromosome 11q. However, due to the heterogeneity in size and position of the deletions, a clear genotype-phenotype correlation is not easily made. Here we report a case interstitial 20.5-Mb deletion at chromosome 11q13.4q21, as confirmed by array comparative genomic hybridization. Dysmorphic features such as coarse facial features, congenital laryngomalacia, oblique inguinal hernia, high-arched palate, and camptodactyly were observed in the subject. The present case broadens the spectrum of clinical findings observed in individuals with 11q interstitial deletion.
Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 11 , Síndrome da Deleção Distal 11q de Jacobsen/genética , Cariótipo Anormal , Anormalidades Múltiplas/genética , Hibridização Genômica Comparativa , Humanos , Recém-Nascido , Síndrome da Deleção Distal 11q de Jacobsen/diagnóstico , Masculino , FenótipoRESUMO
Partial duplication of the long arm of chromosome 11 and the partial trisomy of 22q are uncommon karyotypic abnormalities. Here, we report the case of a 6-year-old girl who showed partial trisomy of 11q and 22q, as a result of a maternal balanced reciprocal translocation (11;22), and exhibited dysmorphic features, severe intellectual disability, brain malformations, and speech delay related to this unique chromosomal abnormality. Array comparative genomic hybridization (array CGH) revealed a gain in copy number on the long arm of chromosome 11, spanning at least 18.22 Mb. Additionally, there was a gain in copy number on the long arm of chromosome 22, spanning at least 3.46 Mb. FISH analysis using a chromosome 11 short arm telomere probe (11p14.2), a chromosome 11 long arm telomere probe (11q24.3), and a chromosome 22 long arm telomere probe (22q13.33) confirmed the origin of the marker chromosome. It has been confirmed by the State Key Laboratory of Medical Genetics of China that this is the first reported instance of the karyotype 47,XX, +der(22)t(11;22)(q23.3;q11.1)mat in the world. Our study reports an additional case that can be used to further characterize and delineate the clinical ramifications of partial trisomy of 11q and 22q.
Assuntos
Anormalidades Múltiplas/genética , Deficiência Intelectual/genética , Trissomia/genética , Criança , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 22/genética , Hibridização Genômica Comparativa/métodos , Feminino , Humanos , CariótipoRESUMO
Translocation t(4;11)(q21;p15) is a rare recurrent change associated to T-cell acute leukemia. In most cases, this alteration appears as the only abnormality or as part of a simple karyotype. In this report, we present the first case of T acute lymphoblastic leukemia/lymphoma (T-ALL/LBL) with the unbalanced translocation der(11)t(4;11)(q21;p15) as part of a very complex karyotype with multiple chromosome abnormalities, most of them not previously described in the literature. FISH (fluorescence in situ hybridization) and spectral karyotype (HiSKY) analysis confirmed the presence of complex alterations. The patient, a 16-year-old male, showed poor response to treatment and short survival (11 months). A detailed review of previously reported cases with t(4;11)(q21;p15) is also provided. The description of this type of alterations may contribute to the identification of new molecular mechanism associated to neoplastic development.