title: Fusion of the AHRR and NCOA2 genes through a recurrent translocation t(5;8)(p15;q13) in soft tissue angiofibroma results in upregulation of aryl hydrocarbon receptor target genes.
abstract: 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)(p15;q13). 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 three 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 CYP1A1 as well as other typical target genes of this pathway, such as those encoding toll-like receptors. Apart from providing a diagnostic marker for soft tissue angiofibroma, the results also suggest that this tumor constitutes an interesting model for evaluating the cellular effects of AHR signaling.
authors.affiliation: Department of Clinical Genetics, University and Regional Laboratories, Skåne University Hospital, Lund University, Lund, Sweden.
authors.forename: Yuesheng
authors.initials: Y
authors.lastname: Jin
authors.forename: Emely
authors.initials: E
authors.lastname: Möller
authors.forename: Karolin H
authors.initials: KH
authors.lastname: Nord
authors.forename: Nils
authors.initials: N
authors.lastname: Mandahl
authors.forename: Fredrik Vult
authors.initials: FV
authors.lastname: Von Steyern
authors.forename: Henryk A
authors.initials: HA
authors.lastname: Domanski
authors.forename: Adrian
authors.initials: A
authors.lastname: Mariño-Enríquez
authors.forename: Linda
authors.initials: L
authors.lastname: Magnusson
authors.forename: Jenny
authors.initials: J
authors.lastname: Nilsson
authors.forename: Raf
authors.initials: R
authors.lastname: Sciot
authors.forename: Christopher D M
authors.initials: CD
authors.lastname: Fletcher
authors.forename: Maria
authors.initials: M
authors.lastname: Debiec-Rychter
authors.forename: Fredrik
authors.initials: F
authors.lastname: Mertens
mesh_terms: D059786:Abnormal Karyotype; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018322:Angiofibroma / Q000235:genetics*; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D002648:Child; D002871:Chromosome Banding; D056905:Chromosome Breakpoints; D002895:Chromosomes, Human, Pair 5; D002898:Chromosomes, Human, Pair 8; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D023061:Gene Order; D006801:Humans; D008297:Male; D008875:Middle Aged; D051958:Nuclear Receptor Coactivator 2 / Q000235:genetics*; D050596:Oncogene Fusion; D012333:RNA, Messenger / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics*; D012983:Soft Tissue Neoplasms / Q000235:genetics*; D014178:Translocation, Genetic; D015854:Up-Regulation; D055815:Young Adult
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051958:Nuclear Receptor Coactivator 2; D012333:RNA, Messenger; D012097:Repressor Proteins; C492162:AHRR protein, human