RESUMO
MYC overexpression is considered a driver event in gastric cancer (GC), and is frequently correlated with poor prognosis and metastasis. In this study, we evaluated the prognostic value of genes upregulated by MYC in patients with GC. Metastatic GC cells (AGP01) characterized by MYC amplification, were transfected with siRNAs targeting MYC. RNA-seq was performed in silenced and non-silenced AGP01 cells. Among the differentially expressed genes, CIAPIN1, MTA2, and UXT were validated using qRT-PCR, western blot, and immunohistochemistry in gastric tissues of 213 patients with GC; and their expressions were correlated with clinicopathological and survival data. High mRNA and protein levels of CIAPIN1, MTA2, and UXT were strongly associated with advanced GC stages (P < 0.0001). However, only CIAPIN1 and UXT gene expressions were able to predict distant metastases in patients with early-stage GC (P < 0.0001), with high sensitivity (> 92%) and specificity (> 90%). Overall survival rate of patients with overexpressed CIAPIN1 or UXT was significantly lower (P < 0.0001). In conclusion, CIAPIN1 and UXT may serve as potential molecular markers for GC prognosis.
RESUMO
RESUMO A doença neurodegenerativa mais comum no mundo é a doença de Alzheimer (DA), e 10% dos casos apresentam sintomas antes dos 65 anos, quase todos com associação genética, com hereditariedade autossômica dominante e penetrância entre 92 a 100% dos portadores. Na presente revisão, realizamos uma busca sobre as variantes genéticas associadas à doença de Alzheimer de início precoce (DAIP), enfatizando as características associadas mais importantes e as principais mutações já descritas. Os genes mais comumente relacionados com o surgimento da DAIP são APP, PSEN1, PSEN2 e MAPT, e mutações nestes afetam o metabolismo e a estrutura destas proteínas, resultando em acúmulos de peptídeo Aβ que causam inflamação e toxicidade no cérebro, levando à ativação da micróglia e promovendo a liberação de fatores neurotóxicos e pró-inflamatórios que aceleram a neurodegeneração. O gene PSEN1 é responsável por 70% das mutações conhecidas da DAIP, sendo a L166P associada à idade de ocorrência da doença abaixo dos 30 anos. Mutações em APP levam à agregação da proteína em placas neurodegenerativas. Todas as mutações descritas para MAPT estão associadas a um aumento dos emaranhados neurofibrilares. O polimorfismo E4 da Apolipoproteína E (APOE) influencia o aumento no risco de DAIP elevando as chances em três vezes para portadores heterozigotos e entre oito a dez vezes para os homozigotos. Apenas 5% das mutações associadas à DAIP são conhecidas, e novos estudos apresentam outros genes candidatos, bem como a importância de alterações epigenéticas na gênese desta doença.
SUMMARY The most common neurodegenerative disease in the world is Alzheimer's Disease (AD). Ten percent of Alzheimer patients experience symptoms before the age of 65, and almost all of them present genetic features of autosomal dominant inheritance nature, and penetrance of 92 to 100%. In the present review, we searched for genetic variants associated with early onset Alzheimer's disease (EOAD), emphasizing the most important characteristics and the main mutations. The genes most commonly related to the onset of EOAD are APP, PSEN1, PSEN2 and MAPT, whose mutations affect the metabolism and structure of these proteins. This process results in accumulations of Aβ peptide that leads to activation of the microglia and release of neurotoxic and pro-inflammatory factors that accelerate neurodegeneration. The PSEN1 gene is responsible for 70% of the known mutations in EOAD, while L166P is associated with below 30 years as the starting age of occurrence. APP mutations lead to protein aggregation in neurodegenerative plaques. All of the mutations described for MAPT are associated with an increase in neurofibrillary tangles. The E4 polymorphism of Apolipoprotein E (APOE) influences an increased risk of EOAD increasing up to three times the chances for heterozygous, and between eight and ten times for homozygotes carriers. Only 5% of the mutations associated with EOAD are known; new studies will show other candidate genes, as well as the importance of epigenetic factors changes in the etio-pathogenesis of this disease.