Analysis of the B-RafV600E mutation in cutaneous melanoma patients with occupational sun exposure

Abstract

Sun-exposure is one of the risk factors associated with the development of a cutaneous neoplasm. In melanoma, the Ras-Raf-MEK-ERK (MAPK) signaling pathway is constitutively activated through multiple mechanisms, including B-Raf mutation. It has been hypothesized that B-Raf mutations in melanocytic lesions arise from DNA damage induced by ultraviolet (UV) radiation. However, it is still discussed if B-Raf mutations are associated with melanoma patients exposed to the sun. Therefore, in the present study, the known B-RafV600E mutation was analysed in melanoma samples from 30 indoor and 38 outdoor workers. B-RafV600E mutation was detected in 52 and 73% of outdoor workers and indoor workers, respectively. Of note, this mutation was identified in 12 of 14 (85%) melanoma of the trunk diagnosed in indoor workers and in 9 of 19 (47%) samples from outdoor workers (p=0.03). By analyzing melanomas of other body sites, no statistical difference in the frequency of B-RafV600E mutation was identified between the groups of workers. It appears that the mutation detected among indoor workers may be associated with a recreational or intermittent exposure to the sun, as usually the trunk is a sun-protected body site. Overall, these data indicate that the B-RafV600E mutation detected in melanoma is not associated with a chronic exposure to the sun. Mutations detected in other genes may also contribute to melanoma development in the subset of patients exposed to UV radiation.

Figure 1

Potential mechanism of melanoma development and progression after UV-damage. UVA, Ultraviolet A; UVB, ultraviolet B; CPDs, cyclobutane pyrimidine dimers; Fapy, formamidopyrimidines; 8-oxo-dG, 8-Oxo-2′-deoxyguanosine; G^T, guanine to thymidine transversion; B-RAF, v-raf murine sarcoma viral oncogene homolog B; CDKN2A, cyclin-dependent kinase inhibitor 2A; NRAS, neuroblastoma RAS viral (v-ras) oncogene homolog; PTEN, phosphatase and tensin homolog; TP53, tumor protein p53; PIK3CA phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit α; MITF, microphthalmia-associated transcription factor; APAF-1, apoptotic peptidase activating factor 1; AKT3, v-akt murine thymoma viral oncogene homolog 3.