The genetics of skin cancer

Abstract

Recent advances in molecular genetics have led to a better understanding of the biological underpinnings of skin cancer formation. As with most cancers, the RB, p53, and RAS pathways appear to play prominent roles in the pathogenesis of several skin cancer types. Although various components of these pathways may be differentially altered in squamous cell carcinoma (SCC), basal cell carcinoma (BCC), and cutaneous melanoma, the final biochemical expression of these defects may be the same. With the unraveling of these genetic mechanisms, a more targeted approach to diagnosis and treatment may be possible in the near future.

Mutant p53 subverts p63 control over KLF4 expression in keratinocytes

“…The two most widespread non-melanoma cancers of epithelial origin in the skin are basal cell carcinomas (BCCs) and SCCs: the former is locally destructive, but it rarely metastasizes, while SCC cells have high metastatic potential (Tsai and Tsao, 2004). The risk of developing SCC is directly related to UV exposure and susceptibility to sunburn.…”

Nuevos modelos experimentales para el estudio de la homeostasis y la enfermedad cutánea

“…Así, en el modelo de la carcinogénesis química de piel de ratón, la fuerza conductora de la carcinogénesis son las mutaciones en el oncogén H-Ras 38 , y el tipo de tumor predominante es el papiloma, una lesión exofítica que no se produce en la piel humana, salvo en presencia de algunos tipos de virus del papiloma. Por otro lado, en el cáncer cutáneo no melanoma humano, la frecuencia de mutaciones en oncogenes Ras es relativamente baja 39 . Otro ejemplo que marca la diferencia entre ratones y humanos es que, en el ratón, la reparación del daño producido en el DNA por la radiación solar, mediante el mecanismo conocido como escisión global de nucleótidos (G-NER), es menos relevante que en la piel humana, de ahí que para reproducir experimentalmente el síndrome del Xeroderma Pigmentoso en el ratón se requieran dosis de radiación UV extremadamente altas.…”

p53 suppression overwhelms DNA polymerase η deficiency in determining the cellular UV DNA damage response

“…The ultraviolet (UV) component of sunlight is the major carcinogen involved in the etiology of skin cancer [1,2]. UV irradiation produces DNA photoproducts that are blocks to DNA replication by normal replicative DNA polymerases.…”

“…TP53 is mutated in the majority of human cancers [13,14], including skin cancers of the BCC and SCC type [1]. Mutations in TP53 are found with high frequency (>50%) in sporadic BCC, and at a slightly lower frequency (up to 45%) in sporadic SCC and these usually bear the UV signature CC to TT and C to T transitions indicative of ultraviolet radiation B (UV-B) exposure [1,15].…”

“…Mutations in TP53 are found with high frequency (>50%) in sporadic BCC, and at a slightly lower frequency (up to 45%) in sporadic SCC and these usually bear the UV signature CC to TT and C to T transitions indicative of ultraviolet radiation B (UV-B) exposure [1,15]. The role of p53 in melanoma remains somewhat controversial, with some groups reporting mutation rates between 13-25% and others documenting much lower rates [1]. Since XP-V cells lack Pol η, they must employ other mechanisms aside from Pol η-dependent translesional synthesis to negotiate blocks to DNA replication, such as those posed by UV lesions in DNA.…”