RESUMO
Esta revisión tiene como objetivo dar a conocer los aspectos genéticos, clínicos y diagnósticos del síndrome de Lynch, además de brindar la información más relevante acerca de la asesoría genética en estos pacientes y las recomendaciones actuales para su seguimiento.
This review aims to present the genetic, clinical and diagnostic aspects of Lynch syndrome, as well as providing the most relevant information about genetic counseling in these patients and the current recommendations for their surveillance.
Assuntos
História do Século XIX , História do Século XX , Humanos , Neoplasias Colorretais Hereditárias sem Polipose , Algoritmos , Síndromes Neoplásicas Hereditárias/diagnóstico , DNA de Neoplasias/genética , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/história , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Biomarcadores Tumorais , Risco , Endoscopia Gastrointestinal , Medição de Risco , Heterogeneidade Genética , Penetrância , Diagnóstico Diferencial , Genes Neoplásicos , Instabilidade de Microssatélites , Reparo de Erro de Pareamento de DNA/genética , Estudos de Associação Genética , Aconselhamento Genético , Modelos GenéticosRESUMO
Background & objectives: DNA mismatch repair gene (MMR) abnormalities are seen in 95 per cent of hereditary nonpolyposis colorectal cancer (HNPCC) and 10-15 per cent of sporadic colorectal cancers. There are no data on MMR abnormalities in Malaysian colorectal cancer patients. This study was aimed to determine the frequency of abnormal MMR gene protein expression in colorectal carcinoma in Northern Peninsular Malaysia using immunohistochemistry. Methods: Clinicopathological information was obtained from 148 patients’ records who underwent bowel resection for colorectal cancer (CRC) at the three hospitals in Malaysia. Immunohistochemistry for MLH1, MSH2, MSH6 and PMS2 proteins were performed on paraffin embedded tissue containing carcinoma. Results: A total of 148 subjects and 150 colorectal carcinomas of sporadic and hereditary types were assessed. Three patients had synchronous tumours. Twenty eight cancers (18.6%) from 26 subjects (17.6%) had absent immunohistochemical expression of any one of the MMR gene proteins. This comprised absent MLH1 only – 3 cancers, absent MSH2 only – 3, absent MSH6 only – 2, absent PMS2 only – 3, absent MLH1 and PMS2 – 14, absent MSH2 and MSH6 – 2 and absent MLH1, MSH6 and PMS2 – 1. There was significant association between abnormal MMR gene protein expression and proximal colon cancers, mucinous, signet ring and poorly differentiated morphology. Interpretation & conclusions: Cancers with abnormal MMR gene expression were associated with microsatellite instability-high (MSI-H) phenotype. About 15 per cent demonstrated absent MSH2, MSH6 and PMS2 protein expression in isolation or in combination with other MMR genes, which often predicts a germline mutation, synonymous with a diagnosis of HNPCC. This appears to be high frequency compared to reported data.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adenosina Trifosfatases/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Reparo de Erro de Pareamento de DNA/genética , Enzimas Reparadoras do DNA/metabolismo , Proteínas de Ligação a DNA/metabolismo , Feminino , Expressão Gênica/genética , Mutação em Linhagem Germinativa/genética , Imuno-Histoquímica , Malásia , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Proteína MutS de Ligação de DNA com Erro de Pareamento/metabolismo , Proteína 2 Homóloga a MutS/metabolismo , Proteínas Nucleares/metabolismo , Estudos RetrospectivosRESUMO
Las mutaciones de los genes MLH1 y MSH2 son frecuentemente implicadas en el síndrome de Lynch. La expresión inmunohistoquímica (IHQ) es una forma simple de selección para pruebas moleculares. Se analizó la IHQ de MLH1 y MSH2 en pacientes con síndrome de Lynch (16 casos) y pacientes menores de 50 años sin antecedentes familiares (25 casos). Se estudiaron 41 tumores de un grupo de pacientes (64% mujeres) de edad promedio 40.7 años (rango: 16-75). Se obtuvieron resultados concluyentes en 40 casos (97.6%). Dieciocho casos (45%) presentaron falta de expresión (MLH1 negativa: 11 casos; MSH2 negativa: 6 casos; MLH1 negativa y MSH2 negativa: 1 caso), con una incidencia significativamente mayor en pacientes con síndrome de Lynch (68.7% vs. 28%, p=0.01). Entre los casos esporádicos, 5 casos (20%) mostraron falta de expresión MLH1 y 2 casos (8%) con falta de expresión MSH2. La falta de expresión IHQ presentó una fuerte asociación con inestabilidad microsatelital alta (IMS): expresión normal: 5.9%, expresión negativa: 92.3%, P<0.0001. Los índices de sensibilidad y especificidad de la IHQ para detectar IMS fueron de 92.3% y 94.1% respectivamente. Los patrones de IHQ y de IMS no se relacionaron a ninguna característica histopatológica. En conclusión, el análisis inmunohistoquímico de las proteínas MLH1 y MSH2 fue altamente sensible y específico para detectar IMS y permitió identificar en un 45% de los casos la proteína alterada. El índice de falta de expresión IHQ entre los casos esporádicos diagnosticados antes de los 50 años justifica su implementación sistemática en este grupo de pacientes.
Mutation of the mismatch repair genes MLH1 and MSH2 account for the majority of the genetic abnormalities in Lynch syndrome. Immunohistochemical detection of their protein products is becoming an increasingly common method to detect these mutations. The aim of this study was to compare the expression of MLH1 and MSH2 by immunohistochemistry and its relationship with a group of clinical and histological variables in patients with known Lynch syndrome (n=16) and in cohort of young patients (less than 50 years) who did not meet Amsterdam criteria (n=25). The mean age was 40.7 and 64% were women. Conclusive results were obtained in 40 cases (97.6%). Eighteen cases (45%) showed abnormal expression of either MLH1 (11 cases) or MSH2 (6 cases) and both stains (1 case). Alteration of the normal staining pattern was seen more commonly in patients with Lynch syndrome than in the sporadic group (68.7% vs 28%, p=0.01). A significant correlation was obtained between abnormal protein expression and microsatellite instability (MSI): normal expression: 5.9%, lack of expression: 92.3%, p<0.0001. The sensitivity and specificity of the immunohistochemical to predict MSI were 92.3% and 94.1% respectively. Immunohistochemistry and MSI results did not correlate with any histopathological parameter. In conclusion, in our experience abnormal staining of MLH and MSH correlates strongly with the presence of MSI. In addition it appears that in our population a significant proportion of young patients (< 50 years old) demonstrate alterations in the mismatch repair gene products suggesting an important role of these molecules in tumorigenesis.
Assuntos
Humanos , Masculino , Feminino , Adolescente , Adulto , Pessoa de Meia-Idade , Proteínas Adaptadoras de Transdução de Sinal/genética , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais/genética , Reparo de Erro de Pareamento de DNA , Instabilidade de Microssatélites , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Neoplasias Colorretais/patologia , Proteínas de Neoplasias/metabolismo , Proteínas Nucleares/metabolismo , Reação em Cadeia da PolimeraseRESUMO
El CCRHNP es la forma más común de cáncer hereditario y representa aproximadamente el 15 % de todos los cánceres colorectales. En este artículo se destaca, a partir de un caso probable de presentación atípica, la importancia de los antecedentes familiares, la histología típica del tumor, la reacción inflamatoria peritumoral simil enfermedad de Crohn, la investigación de la inestabilidad microsatelital, el defecto genético de los genes MMR y la recomendación de um screening apropiado para el estudio de estos pacientes. Finalmente se destaca la posibilidad de lograr mayor difusión a nivel nacional sobre los centros donde se pueda realizar los estudios genéticos que permitan detectar portadores de esta enfermedad: asimismo al formación de grupos de estudio nos van a permitir obtener estadísticas propias, proyectar trabajos conjuntos y elaborar campañas de prevención.