454 Occurrence of TRKAIII splice variant in melanoma: a pilot study

Abstract

TrkA is a member of the transmembrane neurotrophin receptor family with a critical role in cell proliferation, survival and differentiation. TrkA oncogenic activation is an emerging driver in a wide variety of solid tumors, and TrkA-targeted therapies using inhibitors have been reported to exhibit marked and durable efficacy. An alternative TrkA splice variant, the TrkAIII, characterized by exon 6-7 skipping, exhibits spontaneous aberrant activation. We aimed to explore a potential oncogenic role for TrkA in cutaneous melanoma. Cutaneous melanoma samples from patients of stage III-IV have been collected from the Department of Dermatology of University of L’Aquila. DNA and RNA was extracted from FFPE sections. The cDNA was amplified using TrkA-specific primers. The copy number variation of TrkA gene was evaluated by TaqMan Copy Number assays. Somatic mutations in the region spanning TrkA intron/exon 6 to the intron/exon 8 were analyzed by Sanger Sequencing. Overall, we collected 30 primary melanomas tissue and 12 normal skin specimens. We identified predominant alternative TrkAIII splice variant in 16 of 30 (53%) primary melanomas, while the remaining 14 (47%) cases express mainly the full length TrkA. Normal skin samples exhibit low to undetectable full length TrkA expression. The presence of TrkAIII was always confirmed by sequencing. Somatic DNA mutations in intron/exon boundary that could explain the exons skipping were not found. TrkA gene amplification was detected in 4 of 30 (13%) melanomas. Our results could open the way to new personalized therapeutic approaches for melanoma patients by targeting TrkA oncogenic signals.