Información del artículo
Abstract
Malignant melanoma, a potentially lethal skin neoplasm, is characterized by a complex and heterogeneous etiology. Both incidences and deaths associated with melanoma are increasing in Caucasian populations. While exposure to ultraviolet radiation through sun-exposure is the major risk factor; the host factors including skin type and number of moles are critical in predisposition. The CDKN2A is a high penetrance melanoma susceptibility gene as carriers of the mutations are predisposed to the disease within familial settings. The gene is also somatically altered to varying degrees in sporadic melanoma. The CDK4 gene due to occurrence of activation mutations in a few families worldwide represents another melanoma susceptibility locus. The variants within the melanocortin receptor 1 (MC1R) gene, which encodes a melanocyte specific surface receptor with a key role in pigmentation, are associated with high risk phenotypes and increased risk of melanoma. Melanoma tumors are characterized by activation of the RAS-RAF-MEK-ERK pathway through either autocrine growth factor stimulation or oncogenic mutations in the B-RAF or N-RAS genes. Somatic mutations in the B-RAF gene are complemented by those in the N-RAS gene and represent the major genetic alterations. The mutations in the B-RAF gene in melanoma due to occurrence in melanocytic nevi represent early events that additionally require loss of cell cycle inhibitors like CDKN2A for melanoma progression and development. The sequence of events points to the cooperative collaboration between different genetic pathways in tumor development that can be and are being used as targets for developing specific therapeutic agents.
Key words:
melanoma
genetics
CDKN2A
B-RAF
Resumen
El melanoma maligno, una neoplasia cutánea potencialmente mortal, se caracteriza por una etiología compleja y heterogénea. Tanto la incidencia como las muertes asociadas al melanoma están aumentando en la población caucásica. Aunque la exposición a la radiación ultravioleta a través de la exposición solar es el principal factor de riesgo, los factores que dependen del huésped, como el fototipo y el número de nevus, son críticos en la predisposición. El CDKN2A es un gen de susceptiblidad para el melanoma de alta penetrancia, ya que los portadores de mutaciones están predispuestos a la enfermedad en el entorno familiar. El gen también está alterado somáticamente, en grados variables, en el melanoma esporádico. El gen CDK4, debido a la activación de mutaciones en algunas familias a nivel mundial, representa otro locus de susceptibilidad para el melanoma. Las variaciones dentro del gen del receptor de la melanocortina 1, que codifica un receptor de superficie específico de los melanocitos con un papel clave en la pigmentación, están asociadas con fenotipos de alto riesgo y un riesgo aumentado de melanoma. Los tumores de melanoma se caracterizan por la activación de la vía RAS-RAF-MEK-ERK a través de la estimulación por factor de crecimiento autocrino o por mutaciones oncógenas en los genes B-RAF o N-RAS. Las mutaciones somáticas en el gen B-RAF se complementan por aquellas en el gen N-RAS y representan las principales alteraciones genéticas. Las mutaciones en el gen B-RAF en el melanoma, que tienen lugar en los nevus melanocíticos, representan eventos iniciales que requieren, además, la pérdida de inhibidores del ciclo celular como CDKN2A para la progresión y el desarrollo del mela noma. La secuencia de eventos apunta hacia una colaboración entre las diferentes vías genéticas en el desarrollo tumoral, que pueden y están siendo empleadas como dianas para desarrollar agentes terapéuticos específicos.
Palabras clave:
melanoma
genética
CDKN2A
B-RAF
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