RESUMO
A patient with extensive multisystem overgrowth caused by a somatic gain of function PIK3CA-mutation is described. This case is an example of the clinical diversity of the PIK3CA-Related Overgrowth Spectrum (PROS) as the patient had overlapping features of Congenital Lipomatous Overgrowth Vascular malformations Epidermal nevi and Skeletal abnormalities (CLOVES) syndrome and Megalencephaly-Capillary malformation Polymicrogyria (MCAP) syndrome and underlines the utility of this umbrella term.
Assuntos
Anormalidades Múltiplas/diagnóstico , Classe I de Fosfatidilinositol 3-Quinases/genética , Lipoma/diagnóstico , Megalencefalia/diagnóstico , Anormalidades Musculoesqueléticas/diagnóstico , Nevo/diagnóstico , Dermatopatias Vasculares/diagnóstico , Telangiectasia/congênito , Malformações Vasculares/diagnóstico , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/terapia , Sequência de Bases , Broncodilatadores/uso terapêutico , Diagnóstico Diferencial , Nutrição Enteral , Humanos , Imunossupressores/uso terapêutico , Recém-Nascido , Lipoma/genética , Lipoma/terapia , Masculino , Megalencefalia/genética , Megalencefalia/terapia , Anormalidades Musculoesqueléticas/genética , Anormalidades Musculoesqueléticas/terapia , Mutação , Nevo/genética , Nevo/terapia , Fenótipo , Respiração Artificial/métodos , Sirolimo/uso terapêutico , Dermatopatias Vasculares/genética , Dermatopatias Vasculares/terapia , Telangiectasia/diagnóstico , Telangiectasia/genética , Telangiectasia/terapia , Malformações Vasculares/genética , Malformações Vasculares/terapiaRESUMO
BACKGROUND: Keratinocytic epidermal nevus syndrome (KENS) is a complex disorder not only characterized by the presence of epidermal nevi but also by abnormalities in the internal organ systems. A small number of cases with KENS are molecularly characterized and reported in the literature with somatic activating RAS, FGFR3 and PIK3CA mutations. CASE PRESENTATION: In this study we present a patient with hyper- and hypopigmented regions, verrucous pigmented skin lesions and a paravertebral conglomerate tumour at the level of the cervical and thoracic spine. A large lipomatous dumbbell tumour caused atrophy of the spinal cord with progressive paraparesis. We identified a mosaic c.35G > A (p.Gly12Asp) KRAS mutation in the pigmented verrucous epidermal nevus tissue, the intraneural schwann cells and the lipoma. The c.35G > A (p.Gly12Asp) KRAS mutation was absent in the peripheral blood leukocytes. CONCLUSION: We conclude that KENS, the intraneural Schwann cell proliferation and the lipoma in this individual were caused by a postzygotic and mosaic activating c.35G > A (p.Gly12Asp) KRAS mutation.
Assuntos
Lipoma/complicações , Mutação , Proteínas Proto-Oncogênicas/genética , Células de Schwann/patologia , Proteínas ras/genética , Adolescente , Proliferação de Células , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Nevo/complicações , Nevo/genética , Nevo/patologia , Proteínas Proto-Oncogênicas p21(ras) , Dermatopatias/complicações , Dermatopatias/genética , Dermatopatias/patologia , Adulto JovemRESUMO
3'EPCAM (Epithelial Cell Adhesion Molecule) genomic rearrangements can be a cause of mismatch repair deficiency in rare Lynch syndrome families. 3'EPCAM deletions include the polyadenylation signal and might result in promoter hypermethylation of the centromeric MSH2 gene in cis. A somatic rearrangement in trans affecting MSH2 is responsible for the final mismatch repair deficiency in the corresponding tumors but the mechanisms are not well documented. In this report two germline 3'EPCAM deletions are described together with the corresponding somatic mutations in the patient's colorectal tumors. Mutation and breakpoint analysis resulted in the identification of one novel (c.556-531_*872del) and one known EPCAM deletion (c.859-689_*14697del). Both deletions resulted from Alu mediated homologous recombination causing aberrant EPCAM-MSH2 fusion transcripts. The colorectal tumors of the deletion carriers were MSI-high. Strong hypermethylation of the MSH2 promoter was measured. Analysis of somatic genomic rearrangements showed a 4 Mb deletion including the EPCAM, MSH2 and MSH6 genes in one tumor and copy neutral loss of heterozygosity in the EPCAM-MSH2 region in the other tumor. This indicates that hemi- and homozygous hypermethylation of the MSH2 promoter and hence complete silencing of MSH2 expression was responsible for the mismatch repair deficiency in both colorectal tumors.
Assuntos
Antígenos de Neoplasias/genética , Moléculas de Adesão Celular/genética , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais/genética , Mutação em Linhagem Germinativa , Deleção de Sequência , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais Hereditárias sem Polipose/metabolismo , Variações do Número de Cópias de DNA , Metilação de DNA , Reparo de Erro de Pareamento de DNA/genética , Molécula de Adesão da Célula Epitelial , Humanos , Instabilidade de Microssatélites , Proteína 2 Homóloga a MutS/genética , Regiões Promotoras GenéticasRESUMO
Triggered by the existing confusion in the field, the current paper aimed to review the current knowledge of both microsatellite instability (MSI) and loss of heterozygosity (LOH) detected by microsatellite markers in head and neck squamous cell carcinoma (HNSCC), and to provide the reader with an assessment of their prognostic and predictive value in this tumor type. For both MSI and LOH, various detection methods were included such as mono- and polynucleotidemarkers and gel- as well as automated analyses. Only studies based on PCR techniques with microsatellite markers were considered. Taking the methodological problems occurring in investigations with microsatellite markers into account, LOH seems to be more common than MSI in HNSCC. Although both types of microsatellite alterations have been correlated with clinicopathological features of this tumor type, only LOH seems to have a clear prognostic value. The predictive value of both MSI and LOH is debatable. More research has to be performed to clearly establish LOH detection as a translational application in the HNSCC field, aiming to predict response to treatments or outcome, and eventually to use as a therapeutic target.
Assuntos
Carcinoma de Células Escamosas/genética , Neoplasias de Cabeça e Pescoço/genética , Perda de Heterozigosidade/genética , Instabilidade de Microssatélites , Repetições de Microssatélites/genética , Reparo de Erro de Pareamento de DNA , Humanos , Valor Preditivo dos Testes , PrognósticoRESUMO
BACKGROUND AND PURPOSE: Because the locoregional control for HNSCC is still disappointing, research efforts focus on the exploration of new molecular markers located in both tumour and microenvironment, which could help stratify patients. The aim of the present work was therefore first to assess microsatellite alterations and hypoxia in HNSCC as possible molecular markers. Second, a relation between both was investigated, as hypoxia is known to select for genetic alterations. MATERIAL AND METHODS: Forty-eight patients with advanced HNSCC treated by surgery+/-radiotherapy were included. MSI and LOH were investigated with microsatellite markers using automatic fragment analysis. The presence of hypoxia was assessed by immunohistochemistry for pimonidazole, CA IX and GLUT-1. The mutual relationship between MSI/LOH and hypoxia was evaluated. RESULTS: No MSI was detected in this patient group. LOH occurred mostly on chromosomal arms 3p, 5q, 9p, 17p and 17q. Patients with LOH at D17S799, located in the near environment of p53, showed a higher CA IX expression (p=0.01). CONCLUSIONS: LOH is a possible molecular marker in HNSCC. The positive correlation between LOH at D17S799 and CA IX is in full concordance with previous publications linking hypoxia to selective pressure on the p53 gene.
Assuntos
Antígenos de Neoplasias/biossíntese , Anidrases Carbônicas/biossíntese , Carcinoma de Células Escamosas/genética , Transportador 2 de Aminoácido Excitatório/biossíntese , Neoplasias de Cabeça e Pescoço/genética , Instabilidade de Microssatélites , Nitroimidazóis/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Sequência de Bases/genética , Anidrase Carbônica IX , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/radioterapia , Carcinoma de Células Escamosas/cirurgia , Hipóxia Celular/fisiologia , Feminino , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/radioterapia , Neoplasias de Cabeça e Pescoço/cirurgia , Humanos , Imuno-Histoquímica , Perda de Heterozigosidade , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Nitroimidazóis/administração & dosagemRESUMO
Giant cell granuloma (GCG) of the jaw is a rare, well-known feature of neurofibromatosis type 1 (NF1), an inborn multisystem disorder. Recently, the development of GCG in NF1 was attributed to second hit mutations in the NF1 gene. The treatment of GCG is pragmatic with a preference for local curettage of lytic osseous areas. This report describes the surgical therapy of an NF1-affected female with multilocular mandibular GCG and hypodontia who additionally suffered from a brain tumour and Hashimoto's thyroiditis. Although local recurrence of GCG was noted, augmentation of the curetted cavities with a bone substitute in successive interventions successfully restored the extensive periradicular local defects and stabilised the teeth. A meticulous in vitro study of the GCG specimen revealed a second hit mutation in the NF1 gene in the GCG spindle-cells. This study contributes to the increasing knowledge of the molecular basis for GCG in the jaw of NF1 patients, indicating that it is a neoplasm.
Assuntos
Genes da Neurofibromatose 1 , Granuloma de Células Gigantes/genética , Doenças Mandibulares/genética , Mutação , Adolescente , Substitutos Ósseos , Neoplasias Encefálicas/complicações , Tomografia Computadorizada de Feixe Cônico , Feminino , Granuloma de Células Gigantes/diagnóstico por imagem , Granuloma de Células Gigantes/cirurgia , Humanos , Processamento de Imagem Assistida por Computador , Doenças Mandibulares/diagnóstico por imagem , Doenças Mandibulares/cirurgia , Neurofibromatose 1/complicações , Neurofibromatose 1/genética , Radiografia Panorâmica , RecidivaRESUMO
In Helicobacter pylori gastritis, constant antigenic stimulation triggers a sustained B-cell proliferation. Errors made during this continuous DNA replication are supposed to be corrected by the DNA mismatch repair mechanism. Failure of this mismatch repair mechanism has been described in hereditary non-polyposis colorectal cancer (HNPCC) and results in a replication error phenotype. Inherent to their instability during replication, microsatellites are the best markers of this replication error phenotype. We aimed to evaluate the role of defects in the DNA mismatch repair (MMR) mechanism and microsatellite instability (MSI) in relation to the most frequent genetic anomaly, translocation t(11;18)(q21;q21), in gastric mucosa-associated lymphoid tissue (MALT) lymphoma. Therefore, we examined 10 microsatellite loci (BAT25, BAT26, D5S346, D17S250, D2S123, TGFB, BAT40, D18S58, D17S787 and D18S69) for instability in 28 patients with MALT lymphomas. In addition, these tumors were also immunostained for MLH1, MSH2, MSH6 and PMS2, as well as screened for the presence of t(11;18)(q21;q21) by real-time polymerase chain reaction (RT-PCR). We found MSI in 5/28 (18%) lymphomas, with MSI occurring in both t(11;18)(q21;q21)-positive and -negative tumors. One tumor displayed high levels of instability, and, remarkably, this was the only case displaying features of a diffuse large B-cell lymphoma. All microsatellite unstable lymphomas showed a loss of MSH6 expression. In conclusion, our data suggest that a MMR-defect may be involved in the development of gastric MALT lymphomas, and that a defect of MSH6 might be associated with those MSI-driven gastric lymphomas.
Assuntos
Linfoma de Zona Marginal Tipo Células B/genética , Instabilidade de Microssatélites , Neoplasias Gástricas/genética , Adulto , Idoso , Transformação Celular Neoplásica/genética , Cromossomos Humanos Par 11 , Cromossomos Humanos Par 18 , Reparo de Erro de Pareamento de DNA , Proteínas de Ligação a DNA/metabolismo , Feminino , Humanos , Linfoma de Zona Marginal Tipo Células B/metabolismo , Masculino , Pessoa de Meia-Idade , Proteína 2 Homóloga a MutS/metabolismo , Neoplasias Gástricas/metabolismo , Translocação GenéticaRESUMO
PURPOSE: The present study aimed to use the most definitive available techniques to resolve controversy in the literature as to the prevalence of microsatellite instability (MSI) in head and neck squamous cell carcinoma (HNSCC). METHODS: Eighty patients with advanced HNSCC were enrolled in the study that examined 20 microsatellite markers with automatic fragment analysis. These markers included ones derived from the NCI reference panel and ones previously reported to detect MSI in HNSCC (HNSCC panel). RESULTS: Only one of 80 tumors could be considered positive for MSI. For this case, both panels showed MSI-High (8/10 positive markers for the NCI reference panel and 6/10 positive markers for the HNSCC panel). Qualitatively, the observed MSI could be classified as Type B MSI. CONCLUSIONS: The present results indicate that MSI has a low prevalence in HNSCC.