The oncogenic B-raf V599E mutation occurs more frequently in melanomas at sun-protected body sites

Abstract

Downstream of Ras, the serine/threonine kinase, B-raf, has recently been reported to be mutated, among other carcinomas, in a substantial subset of primary melanomas with a preponderance of the oncogenic V599E transition. As the risk of melanoma is enhanced by intermittent ultraviolet (UV) exposure but is less with chronic UV exposure, we here studied B-raf kinase domain (exon 15) mutations in primary cutaneous melanomas with respect to anatomical locations reflecting chronic versus intermittent UV exposure. Investigating a representative number of 101 primary melanoma resection specimens for the presence of mutations within the activation segment (exon 15) of the B-raf kinase domain by polymerase chain reaction and single-strand conformation polymorphism gel electrophoresis, followed by DNA cloning and sequencing, we found 32 cases (32%) which harbour somatic B-raf exon 15 mutations. As to the B-raf protein sequence, the V599E mutation was predicted in 66% of these positive melanomas, followed in frequency by the V599K transition (16%). Only two Cright curved arrow T transitions, considered to be induced by UV irradiation, occurred in two melanomas located on the head. Among 23 melanomas located at body sites with chronic UV exposure, only a single tumour harboured the B-raf V599E mutation (4%), which was a significantly lower frequency in comparison to melanomas from sun-protected body sites (26%; Fisher's exact test, p=0.038; odds ratio, 7.59). Our observation parallels the epidemiological data of intermittent sunlight exposure on unacclimatised skin increasing the risk of melanoma development.