RELEVANCE OF ULTRAVIOLET-INDUCED N-RAS ONCOGENE POINT MUTATIONS IN DEVELOPMENT OF PRIMARY HUMAN CUTANEOUS MELANOMA

Intermittent or recreational exposure to sunlight is thought to contri bute to development of human cutaneous melanoma. We investigated the i ncidence of ras oncogene mutation in human cutaneous melanoma in conne ction to sun-exposed body sites in the patient, using a large series o f DNA samples derived from paraffin-embedded material as well as from fresh tumor samples and cell lines. We first show that, of the ras fam ily, predominantly N-ras is activated (15%), whereas rarely H-ras or K -ras are mutated. The occurrence of N-ras mutations correlates with co ntinuous exposure to sunlight of the primary tumor site. Of all tumors initiated on chronically sun-exposed body sites, 26% contained mutate d N-ras, in contrast to 0% of sun-protected melanomas. Melanoma lesion s obtained from patients from North or Centra Europe contained fewer N -ras mutations (12%) as compared with patients from Australia (24%). M utations were specifically associated with nodular melanoma and to a l esser extend with lentigo malignant melanoma. N-ras mutations did not correlate with metastasis or survival parameters. This study identifie s a subset of cutaneous melanomas that contain in the primary lesion u ltraviolet-induced N-ras mutations, which are maintained through furth er progression.