Análise imunoistoquímica do CD133, c-MYC e AXL no adenocarcinoma e pólipos colorretais e sua associação prognóstica e clínico-patológica
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Rutz, Leticia Elizabeth Augustin Czeczko
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Introdução: O câncer colorretal (CCR) tem sido extensivamente caracterizado molecularmente nos últimos anos para fornecer ferramentas que possam permitir a diferenciação de subgrupos com implicações prognósticas e terapêuticas diferentes. O CD133, é uma glicoproteína transmembrana atualmente considerada como o marcador de superfície mais robusto das células tronco tumorais do câncer colorretal. O c-MYC é um dos principais genes responsáveis pela regulação do crescimento e metabolismo celular e sua superexpressão o transforma em um potente oncogene. O AXL é um receptor tirosina quinase, que no contexto da malignidade, impulsiona processos abrangentes, incluindo transição epitelial para mesênquima. Objetivos: O objetivo deste estudo foi avaliar o prognóstico e características clínico-patológicas do CD133, c-MYC e AXL nos adenocarcinomas colorretais e associar sua positividade com a displasia e morfologia nos pólipos. Material e Método: No grupo adenocarcinoma foram incluídos 122 pacientes de ambos os gêneros, os quais tiveram diagnóstico entre os anos de 2010 e 2015. No grupo pólipos foram estudados 39 pólipos colorretais resultantes de polipectomias realizadas em colonoscopias entre os anos de 2009 e 2012. Foi realizada imunoistoquímica para os biomarcadores CD133, c-MYC e AXL em todas as amostras. Dados clínicos retrospectivos foram coletados e plotados em duas tabelas de dados. Através da técnica TMA (tissue microarray) os tecidos foram submetidos a imunoistoquímica pela técnica de peroxidase. As informações clínico-epidemiológicas foram cruzadas com o resultado obtido pela imunomarcação e sua análise estatística. Resultados: No grupo adenocarcinoma a amostra era de 63 homens (51,6%) com idade média de 61,9 anos. Houve uma distribuição de 40 casos em cólon direito (34,4%) e 75 em cólon esquerdo e reto (61,4%). A maioria dos pacientes apresentou uma classificação UICC avançada III e IV (n=74). Do total, 68 (55,7%) morreram e observou-se que são fatores de risco independentes para o óbito (p<0,05) adenocarcinomas histologicamente pouco diferenciados e a presença de progressão de doença. O tempo mediano de sobrevida geral estimado foi de 30 meses. O CD133+ (tumores CD133 positivos) apresentou relação de proteção contra o óbito na análise univariada, porém essa relevância não ocorreu na análise multivariada. Houve associação entre os tumores c-MYC+ (tumores c-MYC positivos) e a presença de metástase para outros locais (não hepática, pulmonar e peritoneal). O AXL teve quatro casos positivos, impossibilitando análises adicionais. Não houve associação significante entre as demais características analisadas. No grupo pólipo havia 31 adenomas (79,5%) e 15 (38,5%) presentaram displasia de alto grau. Dos 39 pólipos, marcaram positivamente para CD133: 35,9% (n=14); para c-MYC: 15,4% (n=6) e para AXL: 15,4% (n=6). Não foi encontrada associação estatisticamente significante entre os tumores positivos e o tamanho dos pólipos, localização, tipo, diagnóstico histológico e displasia de alto grau. Foi encontrada uma concordância moderada entre os biomarcadores c-MYC e AXL por apresentarem 28 (71,8%) casos concordantes e 11 (28,2%) discordantes. Conclusão: o CD133 não é um fator independente de proteção contra o óbito no adenocarcinoma colorretal, enquanto o c-MYC possui associação com metástase a distância. Os pólipos não apresentaram associação entre o CD133, c-MYC, AXL e variáveis clinico-patológicas Há uma tendência do c-MYC e do AXL serem superexpressos no mesmo perfil de tumores.
Introduction: Colorectal cancer (RCC) has been extensively molecularly characterized in recent years to provide tools that can allow differentiation of subgroups with different prognostic and therapeutic implications. CD133 is a transmembrane glycoprotein currently considered to be the most robust surface marker of colorectal cancer tumor stem cells. C-MYC is one of the major genes responsible for regulating cell growth and metabolism and its overexpression makes it a potent oncogene. AXL is a receptor tyrosine kinase that in the context of malignancy drives comprehensive processes including epithelial transition to mesenchyme. Objectives: The purpose of this study was to evaluate the prognosis and clinical and pathological characteristics of CD133, c-MYC and AXL in colorectal adenocarcinomas and to associate its positivity with dysplasia and morphology in polyps. Material and Method: The adenocarcinoma group included 122 patients of both genders, who were diagnosed between 2010 and 2015. In the polyp group, 39 colorectal polyps resulting from polypectomies performed in colonoscopies between 2009 and 2012 were studied. Immunohistochemistry was performed for CD133, c-MYC and AXL biomarkers in all samples. Retrospective clinical data was collected and plotted in two data tables. Through TMA (tissue microarray) technique, the tissues were subjected to immunohistochemistry by the peroxidase technique. Clinical-epidemiological information was crossed with the result obtained by immunostaining and its statistical analysis. Results: The adenocarcinoma group had 63 men (51.6%) with a mean age of 61.9 years. There was a distribution of 40 cases in the right colon (34.4%) and 75 in left colon and rectum (61.4%). Most patients had an advanced UICC classification (III and IV) (n = 74). From the total number of patients, 68 (55.7%) died and poorly differentiated tumors and disease progression were found to be independent risk factors for death (p <0.05). The median estimated overall survival time was 30 months. CD133+ (CD133 positive tumors) showed a protective relationship against death in univariate analysis but this relevance did not occur in multivariate analysis. There was an association between c-MYC+ (c-MYC positive tumors) and metastasis to other sites (non-hepatic, pulmonary and peritoneal). AXL had four positive cases, precluding further analysis. There was no significant association between the other characteristics analyzed. In the polyp group there were 31 adenomas (79.5%) and 15 (38.5%) presented high-grade dysplasia. Of the 39 polyps, 35.9% (n=14) scored positive for CD133: 15.4% (n = 6) for c-MYC and 15.4% (n = 6) for AXL. There was no statistically significant association between positive tumors and polyp size, location, type, histological diagnosis and high-grade dysplasia. Moderate agreement was found between the c-MYC and AXL biomarkers due to 28 (71.8%) cases in agreement and 11 (28.2%) cases in disagreement. Conclusion: CD133 is not an independent protective factor against death in colorectal adenocarcinoma, whereas c-MYC is associated with distant metastasis. Polyps showed no association between CD133, c-MYC, AXL and clinico-pathological variables. There is a tendency for c-MYC and AXL to be overexpressed in the same tumor profile.
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Introduction: Colorectal cancer (RCC) has been extensively molecularly characterized in recent years to provide tools that can allow differentiation of subgroups with different prognostic and therapeutic implications. CD133 is a transmembrane glycoprotein currently considered to be the most robust surface marker of colorectal cancer tumor stem cells. C-MYC is one of the major genes responsible for regulating cell growth and metabolism and its overexpression makes it a potent oncogene. AXL is a receptor tyrosine kinase that in the context of malignancy drives comprehensive processes including epithelial transition to mesenchyme. Objectives: The purpose of this study was to evaluate the prognosis and clinical and pathological characteristics of CD133, c-MYC and AXL in colorectal adenocarcinomas and to associate its positivity with dysplasia and morphology in polyps. Material and Method: The adenocarcinoma group included 122 patients of both genders, who were diagnosed between 2010 and 2015. In the polyp group, 39 colorectal polyps resulting from polypectomies performed in colonoscopies between 2009 and 2012 were studied. Immunohistochemistry was performed for CD133, c-MYC and AXL biomarkers in all samples. Retrospective clinical data was collected and plotted in two data tables. Through TMA (tissue microarray) technique, the tissues were subjected to immunohistochemistry by the peroxidase technique. Clinical-epidemiological information was crossed with the result obtained by immunostaining and its statistical analysis. Results: The adenocarcinoma group had 63 men (51.6%) with a mean age of 61.9 years. There was a distribution of 40 cases in the right colon (34.4%) and 75 in left colon and rectum (61.4%). Most patients had an advanced UICC classification (III and IV) (n = 74). From the total number of patients, 68 (55.7%) died and poorly differentiated tumors and disease progression were found to be independent risk factors for death (p <0.05). The median estimated overall survival time was 30 months. CD133+ (CD133 positive tumors) showed a protective relationship against death in univariate analysis but this relevance did not occur in multivariate analysis. There was an association between c-MYC+ (c-MYC positive tumors) and metastasis to other sites (non-hepatic, pulmonary and peritoneal). AXL had four positive cases, precluding further analysis. There was no significant association between the other characteristics analyzed. In the polyp group there were 31 adenomas (79.5%) and 15 (38.5%) presented high-grade dysplasia. Of the 39 polyps, 35.9% (n=14) scored positive for CD133: 15.4% (n = 6) for c-MYC and 15.4% (n = 6) for AXL. There was no statistically significant association between positive tumors and polyp size, location, type, histological diagnosis and high-grade dysplasia. Moderate agreement was found between the c-MYC and AXL biomarkers due to 28 (71.8%) cases in agreement and 11 (28.2%) cases in disagreement. Conclusion: CD133 is not an independent protective factor against death in colorectal adenocarcinoma, whereas c-MYC is associated with distant metastasis. Polyps showed no association between CD133, c-MYC, AXL and clinico-pathological variables. There is a tendency for c-MYC and AXL to be overexpressed in the same tumor profile.
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Palavras-chave
genes myc , câncer colorretal , pólipos do cólon , biomarcadores tumorais , prognóstico , CNPQ::CIENCIAS DA SAUDE