Caracterización de la poliposis adenomatosa familiar en población española: estudio de familias APC/MUTYH negativas

• Autores: Bárbara Rivera Polo
• Directores de la Tesis: Miguel Urioste Azcorra (dir. tes.)
• Lectura: En la Universidad Autónoma de Madrid ( España ) en 2012
• Idioma: español
• Tribunal Calificador de la Tesis: José Fernández Piqueras (presid.), María Belén Pérez González (secret.), Angel Miguel Alonso Sanchez (voc.), Mercedes Robledo Batanero (voc.), Gabriel Capellà Munar (voc.)
• Materias:
  • Ciencias de la vida
    • Biología molecular
• Enlaces
  • Tesis en acceso abierto en: Biblos-e Archivo
• Resumen

  • Colorectal cancer is the second most frequent form of cancer in the developed world, accounting for around 600.000 deaths in 2008. Hereditary colorectal cancer represents up to 5% of all CRC; and in particular, Familial Adenomatous Polyposis (FAP) is the second most common form of hereditary colorectal cancer amounting to 1% of all CRC cases. FAP is a truly hereditary condition that confers almost 100% CRC susceptibility and inherits in an autosomal dominant manner with near 100% of penetrance. There are two different forms of FAP: the classical one, diagnosed when the patient develops more than 100 polyps along the colorectum during the second or third decade of life, and the attenuated version that is characterized by the development of 10-99 polyps with a 10 year later onset.

    Mutations in the adenomatous polyposis coli (APC) gene are responsible for the great majority of the cases (50-80 %) depending on the phenotype of the patient. In 2002, the implication of MUTYH gene, a base excision repair gene was discovered in a small percentage of FAP cases (up to 30% of the APC negative cases), mainly attenuated forms. Still, in around 15-20% of the classical forms of FAP and in up to 50% of the attenuated phenotypes no mutation is found. This apparent negativity is partially due to a failure in the screening technique, but also it might be possible that other genes are underlying the genetic cause of these negative FAP patients.

    In the present study we collected a Spanish series of FAP to fully clinically and molecularly characterize it and further study the previously described genotype ¿phenotype correlation. As a result of the characterization of the series we were able to identify a group of patients where no mutation was found and which showed clinical differences to the APC positives group. These negative cases represent a problem facing genetic counseling, but also it constitutes an interesting group of research. Therefore we hypothesized about the genetic origin of the syndrome in these families and focused our effort on the thorough investigation of these cases.

    The fact that a genetic test results negative does not rule out the possibility of an aberration in APC or MUTYH existence. There are mutations and other mechanisms of inactivation of those genes that escape the available techniques in routine screening. Through an in depth study of those genes we were able to identify mutations in APC in around 40% of the patients. In order to test the possible implication of other genes in the syndrome, we selected two Wnt genes (AXIN2 and GSK3B) and BUB1B, a SAC gene that interact with APC in chromosomal segregation and we were able to confirm the presence of variants in AXIN2 and GSK3B that are likely related to the syndrome in two families.

    As a final step, we have characterized a series of adenomatous polyps from APC/MUTYH negative patients and compared their expression profiles for a battery of proteins with APC and MUTYH positive polyps, oligopoliposis and sporadic adenomas to discard whether a specific profile in IHC expression is associated with the negative cases.