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Solid Tumour Section
Short Communication
Soft Tissue Tumors: Angiofibroma
Yuesheng Jin, Fredrik Mertens
Department of Clinical Genetics, University and Regional Laboratories, Skane University Hospital, Lund
University, Lund, Sweden (YJ, FM)
Published in Atlas Database: January 2013
Online updated version : http://AtlasGeneticsOncology.org/Tumors/Angiofibt0508p15q13ID6395.html
DOI: 10.4267/2042/51051
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2013 Atlas of Genetics and Cytogenetics in Oncology and Haematology
no atypia. There is also a complex network of
numerous thin-walled branching blood vessels, in
addition to larger round or branching blood vessels.
The stroma is variably collagenous or myxoid.
Clinics and pathology
Disease
Soft tissue angiofibroma
Treatment
Phenotype / cell stem origin
Local surgical resection is an adequate treatment.
Unknown.
Prognosis
Embryonic origin
These lesions behave in a benign manner with excellent
prognosis; few cases recur after local excision.
Unknown. Immunohistochemical evaluation suggests a
fibroblastic/myofibroblastic line of differentiation.
Etiology
Cytogenetics
Unknown.
Note
A balanced chromosome translocation t(5;8)(p15;q13)
is a specific aberration characterizing soft tissue
angiofibromas. This translocation was identified in five
of six angiofibromas investigated cytogenetically; the
sixth case had a t(7;8;14)(q11;q13;q31).
Epidemiology
Presumably rare, but differential diagnostic problems
may have hampered the distinction of these neoplasms
in the past. The tumor occurs most frequently in
middle-aged adults, affecting women twice as often as
men.
Clinics
The tumor typically presents as a slowly growing,
painless mass located in the soft tissue of the
extremities, mainly the lower extremities, often in
relation to joints or fibrotendinous structures.
It can, however, display a broad anatomic distribution.
The tumor is benign, with rare local recurrences and no
evidence of metastasis potential.
Representative partial karyogram from an angiofibroma
showing the translocation t(5;8)(p15;q13). Arrows indicate
breakpoints.
Pathology
Cytogenetics Molecular
The tumors are most often well circumscribed,
consisting of a patternless or vaguely lobulated spindle
cell proliferation accompanied by a prominent vascular
component.
The cytomorphology is non-distinctive, characterized
by bland fibroblastic spindle cells with a pale
eosinophilic cytoplasm and short ovoid nuclei. There is
Atlas Genet Cytogenet Oncol Haematol. 2013; 17(7)
In two tumors, the breakpoints of the t(5;8) were
mapped by FISH. The breakpoints at 5p15 and 8q13
were delineated by BAC clones RP11-1006P13,
covering the AHRR locus, and RP11-479K21,
harboring NCOA2, which both gave split signals.
Interphase FISH on cut sections from nine additional
cases of soft tissue angiofibroma using pools of BACs
498
Soft Tissue Tumors: Angiofibroma
Jin Y, Mertens F
The protein is about 160 kDa in size and contains 1464
aa including three structural domains. The N-terminal
bHLH/PAS domain is the most conserved region, and
can bind to DNA as well as heterodimerize with a
variety of proteins with similar regions to enhance
transcription of nuclear hormone receptor target genes.
The central region of the SRC proteins contains three
LXXLL motifs which interact with the nuclear
hormone receptors. The C-terminus has two
transcriptional activation domains (AD1 and AD2).
AD1, also known as CREB binding protein (CREBBP)
interacting domain (CID), binds other coactivators,
such as CREBBP and EP300 (E1A binding protein
p300), which leads to chromatin remodeling. AD2 is
responsible
for
interaction
with
histone
methyltransferases, coactivator-associated arginine
methyltransferase 1 and PRMT1.
covering AHRR and NCOA2 yielded fusion signals in
at least 10% of the nuclei in three cases.
Additional interphase FISH using a break-apart probe
for the NCOA2 gene in the six fusion-negative cases
did not reveal any split signals.
Probes
For metaphase FISH the BAC clones detecting the gene
fusion are RP11-1006P13 (AC113363.1), covering the
AHRR locus, and RP11-479K21 (AQ637276.1 and
AQ6379.1), harboring NCOA2.
Pools of RP11-323M9 and RP11-1006P13 as well as
RP11-479K21, RP11-746L20 (AC021558.10) and
RP11-333A23 (AC022730.7) were used to detect
AHRR/NCOA2 fusions in interphase nuclei. RP11152C15 and RP11-265O14 were used as a break-apart
probe to detect rearrangements of NCOA2.
Genes involved and proteins
Result of the chromosomal
anomaly
AHRR
Location
5p15
DNA / RNA
The AHRR gene consists of 12 exons with a transcript
length of 5661 bp. It has a TATA-less promoter and
several transcription start sites.
The translation initiation codon is located in exon 2.
Intron 1 contains a functional regulatory sequence
called xenobiotic response element (XRE).
The bHLH domain of the AHRR protein is located in
the aminoterminal part (encoded by exon 3), followed
by the PAS domain (exons 5 and 6). The
carboxyterminal part has a repression domain.
Protein
The open reading frame of AHRR encodes a 719 amino
acid protein, the aryl hydrocarbon receptor repressor, a
key regulator of the activity of the aryl hydrocarbon
receptor (AHR).
AHR is a crucial mediator of the cellular response to
xenobiotics such as polycyclic aromatic hydrocarbons,
including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD),
better known as dioxin.
AHRR is a putative tumor suppressor gene implicated
in several tumor types.
Hybrid Gene
Note
The translocation t(5;8) has so far been reported in five
soft tissue angiofibromas. Breakpoint mapping by
metaphase FISH followed by RT-PCR has disclosed
that this translocation results in a fusion between the
AHRR and NCOA2 genes; in-frame AHRR/NCOA2 as
well as NCOA2/AHRR were found in all four cases
investigated so far. The location of the breakpoints has
been characterized in a few cases with the t(5;8). In
three tumors nt 1018 (the last nt of exon 9;
NM_020731) of AHRR was joined with nt 3321 (the
first nt of exon 16; NM_006540) of NCOA2.
In one case, the fusion was most likely between nt 1080
(last nt of exon 10) of AHRR and nt 2975 (first nt of
exon 14) of NCOA2.
As the case with the three-way t(7;8;14)(q11;q13;q31)
resulted in a GTF2I/NCOA2 fusion, it seems
reasonable to assume that it is the transcripts with
NCOA2 as 3' partner that are pathogenetically relevant.
Detection
A detailed description of a protocol for the detection of
AHRR/NCOA2 and NCOA2/AHRR chimeras has been
reported.
NCOA2
Location
8q13
DNA / RNA
The NCOA2 gene consists of 23 exons with a transcript
length of 8447 bp. NCOA2 has been identified as the
3'-partner in gene fusions involved in various
leukemias and sarcomas.
Protein
NCOA2, nuclear receptor co-activator 2, (also known
as TIF2 and SRC2) is one of three members of the
p160 steroid receptor coactivator (SRC) family.
Atlas Genet Cytogenet Oncol Haematol. 2013; 17(7)
Fusion Protein
Note
The
function
of
the
AHRR/NCOA2
and
NCOA2/AHRR chimeras is unknown. Based on
previously reported fusion genes involving the p160
SRC gene family, as well as the finding of an
alternative GTF2I/NCOA2 fusion in one case, we
assume that it is the AHRR/NCOA2 transcript that is
pathogenetically significant. As the amino terminal part
of the transcription factor AHRR, responsible for the
recognition of xenobiotic response elements in target
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Soft Tissue Tumors: Angiofibroma
Jin Y, Mertens F
repressor is a putative tumor suppressor gene in multiple
human cancers. J Clin Invest. 2008 Feb;118(2):640-50
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. However, the relative
impact of the reciprocal NCOA2/AHRR transcript, as
well as of the individual domains contributed by each
partner in the chimeric proteins, will have to be studied
in experimental models.
Description
The fusion protein AHRR/NCOA2 contains the Nterminal AHRR, i.e., the bHLH (encoded by exon 3)
and PAS (encoded by exon 5) domains, and the Cterminal NCOA2, including two transcriptional
activation domains (AD1 and AD2), which replaces the
repression domain of AHRR (C-terminal).
Hahn ME, Allan LL, Sherr DH. Regulation of constitutive and
inducible AHR signaling: complex interactions involving the
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Xu J, Wu RC, O'Malley BW. Normal and cancer-related
functions of the p160 steroid receptor co-activator (SRC)
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Fujii-Kuriyama Y, Kawajiri K. Molecular mechanisms of the
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Sumegi J, Streblow R, Frayer RW, Dal Cin P, Rosenberg A,
Meloni-Ehrig A, Bridge JA. Recurrent t(2;2) and t(2;8)
translocations in rhabdomyosarcoma without the canonical
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This article should be referenced as such:
Jin Y, Mertens F. Soft Tissue Tumors: Angiofibroma. Atlas
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