FN1–EGFgene fusions are recurrent in calcifying aponeurotic fibroma

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Calcifying aponeurotic fibroma (CAF) is a soft tissue neoplasm with a predilection for the hands and feet in children and adolescents. Its molecular basis is unknown. We used chromosome banding analysis, fluorescencein situhybridization (FISH), mRNA sequencing (RNA-seq), RT-PCR, and immunohistochemistry to characterize a series of CAFs. An insertion ins(2;4)(q35;q25q?) was identified in the index case. Fusion of theFN1andEGFgenes, mapping to the breakpoint regions on chromosomes 2 and 4, respectively, was detected by RNA-seq and confirmed by RT-PCR in the index case and two additional cases. FISH on five additional tumours identifiedFN1–EGFfusions in all cases. CAFs analysed by RT-PCR showed thatFN1exon 23, 27 or 42 was fused toEGFexon 17 or 19. High-level expression of the entireFN1gene in CAF suggests that strongFN1promoter activity drives inappropriate expression of the biologically active portion of EGF, which was detected immunohistochemically in 8/9 cases. TheFN1–EGFfusion, which has not been observed in any other neoplasm, appears to be the main driver mutation in CAF. Although further functional studies are required to understand the exact pathogenesis of CAF, the composition of the chimera suggests an autocrine/paracrine mechanism of transformation. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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