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.

Characterization of FN1–FGFR1 and novel FN1–FGF1 fusion genes in a large series of phosphaturic mesenchymal tumors

“…33 Both the FN1-FGF1 and FN1-EGF fusions involve secretory growth factors and may possibly drive tumorigenesis via autocrine mechanisms in mesenchymal tumors that typically show calcified matrix deposition, suggesting a common theme of fibronectin expression and interaction with extracellular matrix and growth factors in tumor formation. Interestingly, a reversely chimeric FGF1-FN1 protein engineered to fuse the cell-binding domain of fibronectin to the C-terminus of full-length FGF1 protein has been demonstrated to exert superior adhesion, mitogenesis, and differentiation effects on osteoblast-like cells, as compared with fibronectin or FGF1 alone.…”

Genetic profiling of a chondroblastoma‐like osteosarcoma/malignant phosphaturic mesenchymal tumor of bone reveals a homozygous deletion of CDKN2A, intragenic deletion of DMD, and a targetable FN1‐FGFR1 gene fusion

“…In addition to FN1‐FGFR1 , there are gene fusions that involve FN1 as the 5′ or FGFR1 as the 3′ partner, albeit with other partner genes. For example, FN1 is fused to ALK in inflammatory myofibroblastic tumor, leiomyomas of the gastrointestinal tract and ovarian cancer, to EGF in calcifying aponeurotic fibroma, and to ACVR2A in one case of chondrosarcoma and one case of osteochondromatosis . FGFR1 is fused to a large number of different 5′ partners in hematological malignancies, carcinomas and sarcomas .…”

Gene fusion involving the insulin‐like growth factor 1 receptor in an ALK‐negative inflammatory myofibroblastic tumour

“…5 Although variable portions of the FN1 gene have also been reported to be included in fusions in other tumour types, such as calcifying aponeurotic fibroma (exons 23-42) and phosphaturic mesenchymal tumour (exons 22-28), there is currently no indication that this variation in breakpoint localisation has any functional implications; it is assumed that the pathogenetic role of FN1 is to provide a strong transcriptional promotor. 18,19 The IGF1R gene maps to chromosome band 15q26.3 and encodes an RTK that binds insulin-like growth factor with a high affinity. IGF1R has been implicated in a variety of physiological and pathological processes, including several malignancies where it is thought to function as an anti-apoptotic agent by enhancing cell survival.…”