Soft tissue angiofibroma is a recently delineated tumor type of unknown cellular origin.Cytogenetic analysis of four cases showed that they shared a t(5;8)(p1 5;q1 3).In three of them it was the sole change, underlining its pathogenetic significance.FISH mapping suggested the involvement of the aryl hydrocarbon receptor repressor (AHRR) and nuclear receptor coactivator 2 (NCOA2) genes in 5p15 and 8q13, respectively.RT-PCR revealed in-frame AHRR/NCOA2 and NCOA2/AHHR transcripts in all four cases.Interphase FISH on paraffin-embedded tissue from 10 further cases without cytogenetic data showed that 3 were positive for fusion of AHRR and NCOA2.While AHRR has never been implicated in gene fusions before, NCOA2 is the 3 partner in fusions with MYST3 and ETV6 in leukemias and with PAX3 and HEY1 in sarcomas.As in the previously described fusion proteins, NCOA2 contributes with its two activation domains to the AHRR/NCOA2 chimera, substituting for the repressor domain of AHRR.Because the amino terminal part of the transcription factor AHRR, responsible for the recognition of xenobiotic response elements in target genes and for heterodimerization, shows extensive homology with the aryl hydrocarbon receptor (AHR), the fusion is predicted to upregulate the AHR/ARNT signaling pathway.Indeed, global gene expression analysis showed upregulation of CYP1A 1 as well as other typical target genes of this pathway, such as those encoding toll-like receptors.The presented findings can be used to separate soft tissue angiofibroma from other soft tissue tumors, and also suggest that soft tissue angiofibroma constitutes an interesting model for evaluating the cellular effects of AHR signaling.