Publication: Análisis de las vías de carcinogénesis del cáncer colorrectal sincrónico no hereditario
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2017-09-19
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Universidad Complutense de Madrid
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Abstract
El cáncer colorrectal (CCR), es la tercera neoplasia más común y la segunda causa de mortalidad por cáncer en los países desarrollados. Desde una perspectiva molecular, la formación de un tumor es consecuencia de la acumulación de múltiples alteraciones tanto a nivel genético como epigenético. La mayoría de los CCR son esporádicos y aparecen como consecuencia de mutaciones a nivel somático. Sin embargo, pueden existir mutaciones a nivel germinal que transmiten la susceptibilidad para el CCR a las generaciones posteriores, produciendo los diferentes síndromes de CCR hereditario. Se han identificado tres grandes vías de carcinogénesis en el desarrollo del CCR: vía supresora o de inestabilidad cromosómica (INC), vía mutadora o de inestabilidad de microsatélites (IMS) vía metiladora o del fenotipo metilador de islas de CpG (CIMP). La vía supresora o de INC es la alteración más frecuente. No sólo se encuentra en la mayor parte de los casos de CCR esporádicos, sino también en síndromes hereditarios como la poliposis adenomatosa familiar (PAF). Este tipo de tumores se caracterizan por el desequilibrio cromosómico (aneuploidía), con deleciones, amplificaciones y una alta frecuencia de pérdida de heterocigosidad (LOH, Loss of Heterozygosity). Existen dos tipos de alteraciones: 1. la activación de oncogenes, como K-RAS y c-MYC 2. la inactivación de genes supresores del crecimiento tumoral, APC, DCC, p53, TGFBR o PIK3CA...
Colorectal Cancer (CRC) is the third most common malignant neoplasm worldwide and the second leading cause of cancer deaths in developed countries. From a molecular perspective, the formation of a tumor is the consequence of combined genetic and epigenetic changes to the DNA sequence. The majority of CRC cases are sporadic and appear as a consequence of somatic mutation. However, there may exist germline mutations in pivotal genes underlying the inherited forms of CRC and producing the different CRC hereditary syndromes. Three main carcinogenic pathways have been implicated in the development of CRC: Chromosomal instability (CIN) Microsatellite instability (MSI) CpG island methylator phenotype (CIMP) CIN is the most common pathway in sporadic CRC (80-85%) including in CRC hereditary syndromes such as Familial Adenomatous Polyposis (FAP). CIN tumors are characterized by chromosome abnormalities (aneuploidy), with deletions, amplifications, loss of heterozygosity (LOH), homozygous deletions, translocations, and inversions. These tumors are associated to two types of abnormalities: Transcriptional activation of oncogenes such as K-ras and c-MYC. The inactivation of tumor suppressor genes such as APC, DCC, p53, TGFBR and PIK3CA. A defective DNA mismatch repair (MMR) system is the cause of microsatellite instability (MSI) pathway. The genes (MSH2, MLH1, PSM1 Y PSM2, MSH6 o MLH3) regulate the repair of DNA replication errors such as base mismatches, insertions and deletions. Mutations in these genes can induce errors in DNA replication that lead to Lynch syndrome (LS), but are also produced in 15-30% of sporadic CRC...
Colorectal Cancer (CRC) is the third most common malignant neoplasm worldwide and the second leading cause of cancer deaths in developed countries. From a molecular perspective, the formation of a tumor is the consequence of combined genetic and epigenetic changes to the DNA sequence. The majority of CRC cases are sporadic and appear as a consequence of somatic mutation. However, there may exist germline mutations in pivotal genes underlying the inherited forms of CRC and producing the different CRC hereditary syndromes. Three main carcinogenic pathways have been implicated in the development of CRC: Chromosomal instability (CIN) Microsatellite instability (MSI) CpG island methylator phenotype (CIMP) CIN is the most common pathway in sporadic CRC (80-85%) including in CRC hereditary syndromes such as Familial Adenomatous Polyposis (FAP). CIN tumors are characterized by chromosome abnormalities (aneuploidy), with deletions, amplifications, loss of heterozygosity (LOH), homozygous deletions, translocations, and inversions. These tumors are associated to two types of abnormalities: Transcriptional activation of oncogenes such as K-ras and c-MYC. The inactivation of tumor suppressor genes such as APC, DCC, p53, TGFBR and PIK3CA. A defective DNA mismatch repair (MMR) system is the cause of microsatellite instability (MSI) pathway. The genes (MSH2, MLH1, PSM1 Y PSM2, MSH6 o MLH3) regulate the repair of DNA replication errors such as base mismatches, insertions and deletions. Mutations in these genes can induce errors in DNA replication that lead to Lynch syndrome (LS), but are also produced in 15-30% of sporadic CRC...
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Tesis inédita de la Universidad Complutense de Madrid, Facultad de Medicina, Departamento de Medicina, leída el 04-02-2016