title: FN1-EGF gene fusions are recurrent in calcifying aponeurotic fibroma.
abstract: 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, fluorescence in situ hybridization (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 the FN1 and EGF genes, 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 identified FN1-EGF fusions in all cases. CAFs analysed by RT-PCR showed that FN1 exon 23, 27 or 42 was fused to EGF exon 17 or 19. High-level expression of the entire FN1 gene in CAF suggests that strong FN1 promoter activity drives inappropriate expression of the biologically active portion of EGF, which was detected immunohistochemically in 8/9 cases. The FN1-EGF fusion, 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.
authors.affiliation: Department of Musculoskeletal Pathology, Royal Orthopaedic Hospital NHS Foundation Trust, Birmingham, UK.
authors.forename: Florian
authors.initials: F
authors.lastname: Puls
authors.affiliation: Department of Clinical Genetics, University and Regional Laboratories, Skåne University Hospital, Lund University, Lund, Sweden.
authors.forename: Jakob
authors.initials: J
authors.lastname: Hofvander
authors.affiliation: Department of Clinical Genetics, University and Regional Laboratories, Skåne University Hospital, Lund University, Lund, Sweden.
authors.forename: Linda
authors.initials: L
authors.lastname: Magnusson
authors.affiliation: Department of Clinical Genetics, University and Regional Laboratories, Skåne University Hospital, Lund University, Lund, Sweden.
authors.forename: Jenny
authors.initials: J
authors.lastname: Nilsson
authors.affiliation: Department of Musculoskeletal Pathology, Royal Orthopaedic Hospital NHS Foundation Trust, Birmingham, UK.
authors.forename: Elaine
authors.initials: E
authors.lastname: Haywood
authors.affiliation: Department of Musculoskeletal Pathology, Royal Orthopaedic Hospital NHS Foundation Trust, Birmingham, UK.
authors.forename: Vaiyapuri P
authors.initials: VP
authors.lastname: Sumathi
authors.affiliation: Department of Musculoskeletal Pathology, Royal Orthopaedic Hospital NHS Foundation Trust, Birmingham, UK.|Department of Histopathology, Robert Jones & Agnes Hunt Orthopaedic Hospital, Oswestry, UK.
authors.forename: D Chas
authors.initials: DC
authors.lastname: Mangham
authors.affiliation: Department of Musculoskeletal Pathology, Royal Orthopaedic Hospital NHS Foundation Trust, Birmingham, UK.
authors.forename: Lars-Gunnar
authors.initials: LG
authors.lastname: Kindblom
authors.affiliation: Department of Clinical Genetics, University and Regional Laboratories, Skåne University Hospital, Lund University, Lund, Sweden.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Mertens
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D002871:Chromosome Banding / Q000379:methods; D004815:Epidermal Growth Factor / Q000235:genetics*; D005091:Exons; D005260:Female; D005350:Fibroma / Q000235:genetics / Q000473:pathology*; D005353:Fibronectins / Q000235:genetics*; D050939:Gene Fusion; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D017404:In Situ Hybridization, Fluorescence / Q000379:methods; D008297:Male; D012008:Recurrence; D012983:Soft Tissue Neoplasms / Q000235:genetics* / Q000473:pathology*
chemical_list: C067625:FN1 protein, human; D005353:Fibronectins; D004815:Epidermal Growth Factor
keywords: calcifying aponeurotic fibroma; epidermal growth factor; fibronectin; gene fusion; juvenile aponeurotic fibroma; soft tissue neoplasm