RESUMO
BACKGROUND: miRNAs are non-coding RNAs participating actively in the post-translational regulation of oncogenes, tumor suppressor, and DNA repair genes implicated in colorectal cancer (CRC). This study aims to examine the association of the variants miR-27a (rs895819 A>G), miR-196a2 (rs11614913 T>G) and miR-146a (rs2910164 C>G) in Mexican CRC patients. METHODS: DNA samples from 183 patients and 186 healthy Mexican subjects were analyzed. Variants were identified by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methodology. Association was calculated by the odds ratio (OR) and adjusted by the Bonferroni test. RESULTS: Patients carrying the G/G genotype of the rs895819 variant in the miR-27a gene showed an increased risk of CRC (19% vs 12%, P=0.013). A similar tendency was noticed for patients younger than 50 years carrying A/G (48% vs 41%, P=0.014). The A/G genotype in TNM stages I+II (55.7% vs 40.8%, P=0.011) and tumor location in the colon (69.5 vs 40.8%, P=0.001) were also increased. For the variant rs11614913 of the miR-196a2 gene, carriers of the C/C genotype showed an increased risk of CRC (32% vs 22%, P=0.009). This genotype was more frequent in TNM stage III+IV (36.8% vs 22.5%, P=0.007) and the tumor had a more recurrent location in the rectum (31.6% vs 22.5%, P=0.013). The rs2910164 variant of the miR-146a gene was found to have no significant risk associations. CONCLUSION: Our results reveal that the rs895819 variant in miR-27a and rs11614913 in miR-196a2 have a substantial impact on the development of CRC.
Assuntos
Neoplasias Colorretais , MicroRNAs , Humanos , MicroRNAs/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Genótipo , Neoplasias Colorretais/genética , Estudos de Casos e ControlesRESUMO
The aim of this review is to present a genetic and molecular overview of colorectal carcinogenesis (sporadic and hereditary origin) as a multistage process, where there are a number of molecular mechanisms associated with the development of colorectal cancer and genomic instability that allows the accumulation of mutations in proto-oncogenes and tumor suppressor genes, chromosomal instability, and methylation and microsatellite instability, and the involvement of altered expression of microRNAs' prognosis factors.
Assuntos
Neoplasias Colorretais/genética , Carcinogênese/genética , Instabilidade Cromossômica/genética , Metilação de DNA , Genes Supressores de Tumor , Humanos , MicroRNAs/metabolismo , Instabilidade de Microssatélites , Mutação , Proto-Oncogenes/genéticaRESUMO
INTRODUCTION: Various disorders affecting the canonical Wnt/ß-catenin signalling pathway have been related to the activation or inactivation of oncogenes and tumour suppressor genes that give rise to a number of well-defined neoplasias, as well as several genes involved in a growing group of complaints, including Alzheimer's disease (AD) and fragile X syndrome (FXS). AIM: To examine the Wnt/ß-catenin signalling pathway as a possible common biological mechanism involved in the origin and development of neurodegenerative conditions and its relationship with cancer. DEVELOPMENT: We review the most recent biomedical literature dealing with the Wnt/ß-catenin signalling pathway and its participation in the genesis of complaints such as AD and FXS. An analysis is also conducted to determine the role that this metabolic pathway might play in explaining the lowered risk of developing cancer displayed by these patients. CONCLUSIONS: The evidence found suggests that the Wnt/ß-catenin pathway could be regulating a set of genes linked with the control of the cell cycle and apoptosis. This would give rise to a metabolic state in which, in conditions such as AD and FXS, the cells would be more likely to undergo apoptosis than initiate mitosis, which would in turn account for the reduced risk of developing cancer.
Assuntos
Doença de Alzheimer/fisiopatologia , Síndrome do Cromossomo X Frágil/fisiopatologia , Proteínas Wnt/fisiologia , Via de Sinalização Wnt/fisiologia , beta Catenina/fisiologia , Doença de Alzheimer/epidemiologia , Apoptose/fisiologia , Ataxia/epidemiologia , Ataxia/fisiopatologia , Comorbidade , Resistência à Doença , Feminino , Síndrome do Cromossomo X Frágil/epidemiologia , Humanos , Masculino , Mitose/fisiologia , Modelos Biológicos , Neoplasias/epidemiologia , Degeneração Neural/fisiopatologia , Neurogênese/fisiologia , Risco , Tremor/epidemiologia , Tremor/fisiopatologiaRESUMO
Brachydactyly type C (BDC), a well-recognized autosomal dominant hand malformation, displays brachymesophalangy of the second, third, and fifth fingers, a short first metacarpal, hyperphalangy, and ulnar deviation of the index finger. An "angel-shaped phalanx" is a distinctive radiological sign that can be found in BDC and other skeletal dysplasias, such as angel-shaped phalango-epiphyseal dysplasia (ASPED), an autosomal dominant skeletal abnormality characterized by a typical angel-shaped phalanx, brachydactyly, specific radiological findings, abnormal dentition, hip dysplasia, and delayed bone age. BDC and ASPED result from mutations in the CDMP1 gene. We report here a Mexican patient with BDC and clinical features of ASPED who carries a novel mutation in CDMP1, confirming that BDC and ASPED are part of the CDMP1 mutational spectrum. Based on the large number of clinical features in common, we suggest that both anomalies are part of the same clinical spectrum. Supported by an extensive review of the literature, a possible genotype-phenotype correlation in the mutational spectrum of this gene is proposed.
Assuntos
Doenças do Desenvolvimento Ósseo/genética , Braquidactilia/genética , Fator 5 de Diferenciação de Crescimento/genética , Doenças do Desenvolvimento Ósseo/diagnóstico , Doenças do Desenvolvimento Ósseo/diagnóstico por imagem , Braquidactilia/diagnóstico , Braquidactilia/diagnóstico por imagem , Criança , Epífises/diagnóstico por imagem , Dedos/anormalidades , Mutação da Fase de Leitura , Estudos de Associação Genética , Heterozigoto , Humanos , Masculino , Radiografia , Deleção de SequênciaRESUMO
The Wnt-ß-catenin signalling pathway plays a crucial role in the regulation, differentiation, proliferation and cellular death processes; consequently, alterations in this pathway are involved in numerous abnormalities of development, growth and homeostasis in animal organisms. Wnt proteins include a numerous family of secretion glycoproteins which join to Frizzled receptors and Low Density Lipoprotein Receptor-related Protein, in order to stabilize the critical ß-catenin protein, and to initiate an intricate signaling cascade, which is related to multiple nucleocytoplasmatic processes. Alterations in the canonical Wnt-ß-catenin signaling pathway have been associated with variations in a number of proteins participating in this route, or with activation / inactivation of oncogenes and tumor suppressor genes, which explain different processes of tumorigenesis, in addition to a number of malformations and human diseases. This review describes the relations between the Wnt-ß-catenin signaling pathway with different neoplasic processes, as well as its application in the diagnosis and prognosis of cancer.
Assuntos
Neoplasias/fisiopatologia , Via de Sinalização Wnt , Transformação Celular Neoplásica/genética , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Terapia Genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Leucemia/genética , Leucemia/metabolismo , Leucemia/fisiopatologia , Terapia de Alvo Molecular , Proteínas de Neoplasias/fisiologia , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/terapia , Proteínas Wnt/fisiologia , beta Catenina/fisiologiaRESUMO
Lysosomal storage diseases (LSD) are caused by monogenic mutations in genes coding for multiple aberrant proteins involved in the catabolism of complex lipids, glycosaminoglycans, oligosaccharides, or nucleic acids. The pathophysiology of the LSD is due to abnormal accumulation of non-hydrolyzed substrate in the lysosomes, affecting the architecture and function of cells, tissues and organs. Due to their genic and allelic heterogeneity the LSD present a wide clinical spectrum in severity of symptoms, evolution and age of onset. The therapeutic strategy has two goals: 1) Palliative management of symptoms (splenectomy, surgery to improve or restore joints or bones, drugs for CNS symptoms, etc.), and 2) The correction of activity of the mutant protein, the former has two approaches: A) Replacing deficient protein (bone marrow transplantation, hematopoietic stem cells or umbilical cord blood cells; replacement with recombinant enzyme and gene therapy) and B) Activate or enhanced the functionality of the mutant enzyme with therapeutic small molecules. Neither of the known treatments is able to address all aspects of these multisystemic disorders, nor cure the patients. Currently, the combination of corrective therapy (CT) with paliative therapy (PT) is the most promising strategy to solve most of the multisystem manifestations. The multidisciplinary medical care is fundamental for diagnosis, treatment and control of disease. Nanotechnology opens a promising new era in the treatment of LSD. Finally, the LSD that has CT must be included in newborn screening programs in order to implement timely treatment and prevent irreversible damage.