Download Solid Tumour Section Soft tissue tumors: t(1;13)(p36;q14) in alveolar rhabdomyosarcoma

Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Solid Tumour Section
Mini Review
Soft tissue tumors: t(1;13)(p36;q14) in alveolar
rhabdomyosarcoma
Frederic G Barr
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine,
Philadelphia, PA 19104, USA (FGB)
Published in Atlas Database: July 2010
Online updated version : http://AtlasGeneticsOncology.org/Tumors/t113p36q14AlvRhabdoID5012.html
DOI: 10.4267/2042/45007
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology
cases the balanced translocation is not visible. Instead
the molecular fusion is found associated with a
subsequent amplification event, usually double minute
chromosomes.
Clinics and pathology
Phenotype / cell stem origin
Generally found in alveolar rhabdomyosarcoma
(ARMS); also found in rare cases diagnosed as
embryonal rhabdomyosarcoma (ERMS).
Epidemiology
Occurs in ~20% ARMS cases and <5% of ERMS
cases: patients tend to be younger children compared to
those with t(2;13)-positive ARMS tumors.
Clinics
Tumors tend to show lower invasiveness compared to
those with t(2;13)-positive ARMS tumors. In metastatic
cases, there is a low incidence of bone marrow
involvement.
Prognosis
In one study, patients with localized t(2;13) and
t(1;13)-positive ARMS had comparable outcomes
whereas a recent study with small numbers suggested
that localized t(1;13) tumors had a better outcome than
those with localized t(2;13) tumors. Among patients
presenting with metastatic disease, those with t(1;13)positive tumors had a significantly better outcome than
those with t(2;13)-positive tumors. Note: these studies
are based on molecular detection of the translocations.
Cytogenetics Molecular
Cytogenetics
The product of the 1;13 translocation is amplified in
~90% of t(1;13)-positive cases.
Cytogenetics Morphological
Additional anomalies
Though a balanced 1;13 is sometimes visible in cases
with the associated molecular fusion event, in many
Amplification events involving 2p24 and 13q31 (as
determined by DNA-based array studies).
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(4)
Diagram of t(1;13)(p36;q14) chromosomal translocation.
378
Soft tissue tumors: t(1;13)(p36;q14) in alveolar rhabdomyosarcoma
Barr FG
Biegel JA, Meek RS, Parmiter AH, Conard K, Emanuel BS.
Chromosomal translocation t(1;13)(p36;q14) in a case of
rhabdomyosarcoma. Genes Chromosomes Cancer. 1991
Nov;3(6):483-4
Genes involved and proteins
PAX7
Location
1p36
Protein
Transcription factor - paired box (PAX) family.
Douglass EC, Rowe ST, Valentine M, Parham DM, Berkow R,
Bowman WP, Maurer HM. Variant translocations of
chromosome 13 in alveolar rhabdomyosarcoma. Genes
Chromosomes Cancer. 1991 Nov;3(6):480-2
FOXO1 (FKHR)
Whang-Peng J, Knutsen T, Theil K, Horowitz ME, Triche T.
Cytogenetic studies in subgroups of rhabdomyosarcoma.
Genes Chromosomes Cancer. 1992 Nov;5(4):299-310
Location
13q14
Protein
Transcription factor - forkhead box (FOX) family.
Davis RJ, D'Cruz CM, Lovell MA, Biegel JA, Barr FG. Fusion of
PAX7 to FKHR by the variant t(1;13)(p36;q14) translocation in
alveolar rhabdomyosarcoma. Cancer Res. 1994 Jun
1;54(11):2869-72
Result of the chromosomal
anomaly
Barr FG, Xiong QB, Kelly K. A consensus polymerase chain
reaction-oligonucleotide hybridization approach for the
detection of chromosomal translocations in pediatric bone and
soft tissue sarcomas. Am J Clin Pathol. 1995 Dec;104(6):62733
Hybrid Gene
Barr FG, Nauta LE, Davis RJ, Schäfer BW, Nycum LM, Biegel
JA. In vivo amplification of the PAX3-FKHR and PAX7-FKHR
fusion genes in alveolar rhabdomyosarcoma. Hum Mol Genet.
1996 Jan;5(1):15-21
Description
The 1;13 translocation breaks within intron 7 of the
PAX7 gene and intron 1 of the FOXO1 gene on
chromosome 13 to generate a PAX7-FOXO1 fusion
gene as well as a reciprocal FOXO1-PAX7 fusion
gene. In ~55% of PAX7-FOXO1-positive ARMS
tumors, this FOXO1-PAX3 gene is not detectable. In
cases with fusion gene amplification, the PAX7FOXO1 fusion gene is amplified whereas the reciprocal
FOXO1-PAX7 fusion gene is not.
Transcript
The PAX7-FOXO1 fusion transcript consists of the
first 7 exons of PAX3 fused to FOXO1 exons 2 and 3.
There is evidence that the PAX7-FOXO1 fusion
transcript is upregulated relative to the wild-type PAX7
transcript, presumably due to increased copy number of
the fusion gene by amplification.
Davis RJ, Barr FG. Fusion genes resulting from alternative
chromosomal translocations are overexpressed by genespecific mechanisms in alveolar rhabdomyosarcoma. Proc Natl
Acad Sci U S A. 1997 Jul 22;94(15):8047-51
Kenet G, Sharon N, Rosner E, Toren A, Neumann Y, Mandel
M, Kaplinsky C, Gipsh N, Berman S, Rechavi G. Chromosomal
translocation (1:13) in a case of alveolar rhabdomyosarcoma. J
Pediatr Hematol Oncol. 1998 Jan-Feb;20(1):86-7
Bennicelli JL, Advani S, Schäfer BW, Barr FG. PAX3 and
PAX7 exhibit conserved cis-acting transcription repression
domains and utilize a common gain of function mechanism in
alveolar
rhabdomyosarcoma.
Oncogene.
1999
Jul
29;18(30):4348-56
Gunawan B, Füzesi L, Granzen B, Keller U, Mertens R,
Steinau G, Schumpelick V. Clinical aspects of alveolar
rhabdomyosarcoma with translocation t(1;13)(p36;q14) and
hypotetraploidy. Pathol Oncol Res. 1999;5(3):211-3
Fusion Protein
Fitzgerald JC, Scherr AM, Barr FG. Structural analysis of PAX7
rearrangements in alveolar rhabdomyosarcoma. Cancer Genet
Cytogenet. 2000 Feb;117(1):37-40
Description
The fusion gene has a 2484 nt open reading frame
encoding an 828 amino acid fusion protein. This fusion
protein is a transcription factor with a PAX7 DNA
binding domain and FOXO1 transactivation domain.
Expression / Localisation
Nuclear.
Oncogenesis
Transcription dysregulation. At the cellular level there
is evidence of alterations in control of growth. In
conjunction with other genetic changes, recipient cells
show transformation in culture and tumorigenesis in
injected mice.
Frascella E, Lenzini E, Schafer BW, Brecevic L, Dorigo E,
Toffolatti L, Nanni P, De Giovanni C, Rosolen A. Concomitant
amplification and expression of PAX7-FKHR and MYCN in a
human rhabdomyosarcoma cell line carrying a cryptic
t(1;13)(p36;q14).
Cancer
Genet
Cytogenet.
2000
Sep;121(2):139-45
Anderson J, Gordon T, McManus A, Mapp T, Gould S, Kelsey
A, McDowell H, Pinkerton R, Shipley J, Pritchard-Jones K.
Detection of the PAX3-FKHR fusion gene in paediatric
rhabdomyosarcoma: a reproducible predictor of outcome? Br J
Cancer. 2001 Sep 14;85(6):831-5
Barr FG. Gene fusions involving PAX and FOX family
members in alveolar rhabdomyosarcoma. Oncogene. 2001
Sep 10;20(40):5736-46
References
Gordon T, McManus A, Anderson J, Min T, Swansbury J,
Pritchard-Jones K, Shipley J. Cytogenetic abnormalities in 42
rhabdomyosarcoma: a United Kingdom Cancer Cytogenetics
Group Study. Med Pediatr Oncol. 2001 Feb;36(2):259-67
Jostes B, Walther C, Gruss P. The murine paired box gene,
Pax7, is expressed specifically during the development of the
nervous and muscular system. Mech Dev. 1990 Dec;33(1):27-37
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(4)
379
Soft tissue tumors: t(1;13)(p36;q14) in alveolar rhabdomyosarcoma
Sorensen PH, Lynch JC, Qualman SJ, Tirabosco R, Lim JF,
Maurer HM, Bridge JA, Crist WM, Triche TJ, Barr FG. PAX3FKHR and PAX7-FKHR gene fusions are prognostic indicators
in alveolar rhabdomyosarcoma: a report from the children's
oncology group. J Clin Oncol. 2002 Jun 1;20(11):2672-9
Kazanowska B, Reich A, Stegmaier S, Békássy AN, Leuschner
I, Chybicka A, Koscielniak E. Pax3-fkhr and pax7-fkhr fusion
genes impact outcome of alveolar rhabdomyosarcoma in
children. Fetal Pediatr Pathol. 2007 Jan-Feb;26(1):17-31
Mercado GE, Barr FG. Fusions involving PAX and FOX genes
in the molecular pathogenesis of alveolar rhabdomyosarcoma:
recent advances. Curr Mol Med. 2007 Feb;7(1):47-61
Du S, Lawrence EJ, Strzelecki D, Rajput P, Xia SJ, Gottesman
DM, Barr FG. Co-expression of alternatively spliced forms of
PAX3, PAX7, PAX3-FKHR and PAX7-FKHR with distinct DNA
binding and transactivation properties in rhabdomyosarcoma.
Int J Cancer. 2005 May 20;115(1):85-92
Parham DM, Qualman SJ, Teot L, Barr FG, Morotti R,
Sorensen PH, Triche TJ, Meyer WH. Correlation between
histology and PAX/FKHR fusion status in alveolar
rhabdomyosarcoma: a report from the Children's Oncology
Group. Am J Surg Pathol. 2007 Jun;31(6):895-901
Barr FG, Smith LM, Lynch JC, Strzelecki D, Parham DM,
Qualman SJ, Breitfeld PP. Examination of gene fusion status in
archival samples of alveolar rhabdomyosarcoma entered on
the Intergroup Rhabdomyosarcoma Study-III trial: a report from
the Children's Oncology Group. J Mol Diagn. 2006
May;8(2):202-8
Ren YX, Finckenstein FG, Abdueva DA, Shahbazian V, Chung
B, Weinberg KI, Triche TJ, Shimada H, Anderson MJ. Mouse
mesenchymal stem cells expressing PAX-FKHR form alveolar
rhabdomyosarcomas by cooperating with secondary
mutations. Cancer Res. 2008 Aug 15;68(16):6587-97
Davicioni E, Finckenstein FG, Shahbazian V, Buckley JD,
Triche TJ, Anderson MJ. Identification of a PAX-FKHR gene
expression signature that defines molecular classes and
determines the prognosis of alveolar rhabdomyosarcomas.
Cancer Res. 2006 Jul 15;66(14):6936-46
Barr FG, Duan F, Smith LM, Gustafson D, Pitts M, Hammond
S, Gastier-Foster JM. Genomic and clinical analyses of 2p24
and 12q13-q14 amplification in alveolar rhabdomyosarcoma: a
report from the Children's Oncology Group. Genes
Chromosomes Cancer. 2009 Aug;48(8):661-72
Krsková L, Mrhalová M, Sumerauer D, Kodet R.
Rhabdomyosarcoma: molecular diagnostics of patients
classified by morphology and immunohistochemistry with
emphasis on bone marrow and purged peripheral blood
progenitor cells involvement. Virchows Arch. 2006
Apr;448(4):449-58
Davicioni E, Anderson MJ, Finckenstein FG, Lynch JC,
Qualman SJ, Shimada H, Schofield DE, Buckley JD, Meyer
WH, Sorensen PH, Triche TJ. Molecular classification of
rhabdomyosarcoma--genotypic and phenotypic determinants
of diagnosis: a report from the Children's Oncology Group. Am
J Pathol. 2009 Feb;174(2):550-64
Nishio J, Althof PA, Bailey JM, Zhou M, Neff JR, Barr FG,
Parham DM, Teot L, Qualman SJ, Bridge JA. Use of a novel
FISH assay on paraffin-embedded tissues as an adjunct to
diagnosis of alveolar rhabdomyosarcoma. Lab Invest. 2006
Jun;86(6):547-56
This article should be referenced as such:
Barr FG. Soft tissue tumors: t(1;13)(p36;q14) in alveolar
rhabdomyosarcoma. Atlas Genet Cytogenet Oncol Haematol.
2011; 15(4):378-380.
Buckingham M, Relaix F. The role of Pax genes in the
development of tissues and organs: Pax3 and Pax7 regulate
muscle progenitor cell functions. Annu Rev Cell Dev Biol.
2007;23:645-73
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(4)
Barr FG
380