Frequency of mutations associated with targeted therapy in malignant melanoma patients.

Abstract

8597 Background: BRAF, RAS, KIT, and TP53 genes are frequently mutated in primary malignant melanomas, and activating mutations involving RAS and BRAF V600, as well as imatinib-sensitive KIT mutations, have been exploited for targeted therapy. Here we studied the prevalence of mutations in these four genes in primary malignant melanoma samples to establish a strategy to identify patients who might benefit from targeted gene therapy. In addition, results were cross-referenced with pathological and histogenetic indicators. Methods: 198 confirmed formalin-fixed, paraffin embedded (FFPE) primary melanoma tissue samples were screened for mutations in BRAF (exons 11, 12 and 15), RAS (H-, K-, N-, exons 1 and 2), KIT (exons 8, 9, 11, 13, and 17), and TP53 (exons 4-9) using direct DNA sequencing. Results: Overall, 140 (70.7%) of the 198 melanoma samples had mutations in one or more of the genes analyzed. BRAF mutations were the most prevalent, with the majority involving codon V600 (Table). Among the BRAF V600 mutations, 66% were V600E and 30% were V600K. NRAS and KIT had similar mutation frequencies. Most NRAS mutations occurred at position Q61, of which 50% were Q61L and 33% were Q61R. About one-third of the KIT mutations were those likely to be sensitive to imatinib. BRAF V600, NRAS Q61, and imatinib-sensitive CKIT mutations were mutually exclusive. TP53 mutations were observed in approximately one-third of samples, often concurrent with other mutations. Conclusions: BRAF, NRAS, CKIT, and TP53 genes are frequently mutated in primary malignant melanomas. The predominance of BRAF V600, NRAS Q61, and imatinib-sensitive KIT mutations signifies the potential for targeted therapeutic strategies in melanoma patients. The high percentage of BRAF V600K mutation illustrates the importance of expanding clinical trials of BRAF inhibitors to include patients with V600K and possibly other V600 mutations. The mutually exclusive pattern of mutations also provides a hierarchical screening strategy for samples that have limited tissue availability. Gene Prevalence, % Predominant mutations BRAF 44.9 V600 (88%) NRAS 18.7 Q61 (89%) CKIT 17.1 Imatinib sensitive (33%) TP53 34.6 None