GAB2 amplifications refine molecular classification of melanoma

Purpose: Gain-of-function mutations in BRAF, NRAS, or KIT are associated with distinct melanoma subtypes with KIT mutations and/or copy number changes frequently observed among melanomas arising from sun-protected sites, such as acral skin (palms, soles, and nail bed) and mucous membranes. GAB2 has recently been implicated in melanoma pathogenesis, and increased copy numbers are found in a subset of melanomas.We sought to determine the association of increased copy numbers of GAB2 among melanoma subtypes in the context of genetic alterations in BRAF, NRAS, and KIT. Experimental Design: A total of 85 melanomas arising from sun-protected (n = 23) and sun-exposed sites (n = 62) were analyzed for copy number changes using array-based comparative genomic hybridization and for gain-of-functionmutations in BRAF, NRAS, and KIT. Results: GAB2 amplifications were found in 9% of the cases andwere associated with melanomas arising from acral and mucosal sites (P = 0.005). Increased copy numbers of the KIT locus were observed in 6% of the cases. The overall mutation frequencies for BRAF and NRAS were 43.5% and 14%, respectively, and were mutually exclusive. Among the acral and mucosal melanomas studied, the genetic alteration frequency was 26% for GAB2,13%for KIT, 30%for BRAF, and 4% for NRAS. Importantly, themajority of GAB2 amplifications occurred independent from genetic events in BRAF, NRAS, and KIT. Conclusions: GAB2 amplification is critical for melanomas arising from sun-protected sites.Genetic alterations in GAB2 will help refine the molecular classification of melanomas.