Merlina y nuevos tratamientos de schwannomas vestibulares en pacientes con neurofibromatosis tipo 2 / Merlin and new treatments for vestibular schwannomas in patients with Neurofibromatosis type 2

Los schwannomas vestibulares son tumores benignos que habitualmente se presentan en forma esporádica y unilateral, pero pueden aparecer de manera bilateral en el contexto de una neurofibromatosis tipo 2 (NF2). En aquellos asociados a NF2 se han identificado mutaciones del gen NF2 que codifica para merlina, una proteína citoplasmática que se localiza primariamente en protrusiones celulares ricas en actina, y en sitios de contacto entre células y matriz extracelular. La evidencia sugiere que merlina ejerce un rol como proteína supresora de tumores ya que regula la cascada de activación de diversos tipos de receptores de factores de crecimiento celular De esta manera, el déficit de merlina provoca un patrón de proliferación celular aumentado, alteraciones del citoesqueleto, apoptosis disminuida, y un incremento de la adhesión a la matriz extracelular. Se han desarrollado terapias clínicas para la NF2 con anticuerpos monoclonales e inhibidores dirigidos contra distintas moléculas involucradas en las cascadas de señalización celular moduladas por merlina. En este artículo se revisan y discuten los mecanismos celulares dependientes de merlina y los diversos estudios clínicos y experimentales que se han probado en pacientes con NF2.

Vestibular schwannomas are benign tumors that may occur bilaterally in the context of neurofibromatosis type 2 (NF2). A mutation in the NF2 gene coding for merlin protein has been identified in those cases associated with NF2. Merlin is a cytoplasmic protein localized in actin rich cell protrusions, and near contact sites between cells and extracellular matrix. The evidence suggests that merlin plays a role as tumor suppressor protein, regulating the activation cascade of different types of receptors for cell growth factors. Thus, merlin deficiency causes a pattern of increased cell proliferation, cytoskeletal alterations, decreased apoptosis and increased cell adhesion to the extracellular matrix. Several clinical therapies have been developed for NF2 patients including monoclonal antibodies and inhibitors directed against different molecules involved in cell signaling cascades modulated by merlin. In this article we review and discuss cellular mechanisms dependent of merlin and some clinical and experimental studies that have been studied in patients with NF2.

NF2 tumor suppressor gene: a comprehensive and efficient detection of somatic mutations by denaturing HPLC and microarray-CGH.

The NF2 tumor suppressor gene, located in chromosome 22q12, is involved in the development of multiple tumors of the nervous system, either associated with neurofibromatosis 2 or sporadic ones, mainly schwannomas and meningiomas. In order to evaluate the role of the NF2 gene in sporadic central nervous system (CNS) tumors, we analyzed NF2 mutations in 26 specimens: 14 meningiomas, 4 schwannomas, 4 metastases, and 4 other histopathological types of neoplasms. Denaturing high performance liquid chromatography (denaturing HPLC) and comparative genomic hybridization on a DNA microarray (microarray- CGH) were used as scanning methods for small mutations and gross rearrangements respectively. Small mutations were identified in six out of seventeen meningiomas and schwannomas, one mutation was novel. Large deletions were detected in six meningiomas. All mutations were predicted to result in truncated protein or in the absence of a large protein domain. No NF2 mutations were found in other histopathological types of CNS tumors. These results provide additional evidence that mutations in the NF2 gene play an important role in the development of sporadic meningiomas and schwannomas. Denaturing HPLC analysis of small mutations and microarray-CGH of large deletions are complementary, fast, and efficient methods for the detection of mutations in tumor tissues.