Soft Tissues: Alveolar rhabdomyosarcoma with t(2;13)(q35;q14) PAX3/FOXO1

2010-07-01   Frederic G Barr  

1.Department of Pathology, Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA

Clinics and Pathology

Phenotype stem cell origin

Alveolar rhabdomyosarcoma (ARMS).

Epidemiology

Occurs in ~60% of ARMS cases; patients tend to be older children (and young adults) compared to those with t(1;13)-positive ARMS tumors.

Clinics

Tumors tend to show higher invasiveness compared to those with t(1;13)-positive ARMS tumors. In metastatic cases. there is a high incidence of bone marrow involvement.

Prognosis

Outcome is worse than in rhabdomyosarcoma cases without a translocation (including embryonal rhabdomyosarcoma and translocation-negative ARMS). 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(2;13)-positive tumors had a significantly poorer outcome than those with t(1;13)-positive tumors. Note: these studies are based on molecular detection of the translocations.

Cytogenetics

Atlas Image
Diagram of t(2;13)(q35;q14) chromosomal translocation.

Cytogenetics morphological

Reciprocal balanced translocations are generally present in cases with the associated molecular fusion.

Cytogenetics molecular

The product of the 2;13 translocation is amplified in ~10% of t(2;13)-positive cases.

Additional anomalies

Amplification events involving 2p24 and 12q14 (as determined by DNA-based array studies).

Genes Involved and Proteins

Gene name

PAX3 (paired box gene 3 (Waardenburg syndrome 1))

Location

2q36.1

Protein description

Transcription factor - paired box (PAX) family.

Gene name

FOXO1 (Forkhead box O1)

Location

13q14.11

Protein description

Transcription factor - forkhead box (FOX) family.

Result of the chromosomal anomaly

Note

A variant PAX3-FOXO4 fusion (also known an PAX3-AFX1) associated with a t(X;13)(q13:q35) has been identified in one ARMS case.
Atlas Image
Generation of chimeric genes by the 2;13 translocation in ARMS. The exons of the wild-type and fusion genes are shown as boxes above each map and the translocation breakpoint distributions are shown as line segments below the map of the wild-type genes.

Description

The 2;13 translocation breaks within intron 7 of the PAX3 gene and intron 1 of the FOXO1 gene on chromosome 13 to generate PAX3-FOXO1 fusion gene as well as a reciprocal FOXO1-PAX3 fusion gene. In ~10% of PAX3-FOXO1-positive ARMS tumors, the FOXO1-PAX3 gene is not detectable.

Transcript

The PAX3-FOXO1 fusion transcript consists of the first 7 exons of PAX3 fused to FOXO1 exons 2 and 3, and the FOXO1-PAX3 fusion transcript consists of the first exon of FOXO1 fused to the last two exons of PAX3. In ~35% of PAX3-FOXO1-positive ARMS tumors (with evidence of PAX3-FOXO1 transcript), the FOXO1-PAX3 transcript is not detectable. There is evidence that the PAX3-FOXO1 fusion transcript is upregulated relative to the wild-type PAX3 transcript by a transcriptional mechanism.
Atlas Image
Comparison of wild-type and fusion products associated with the 2;13 translocation in ARMS. The conserved domains are indicated as open boxes, and functional domains are shown as solid bars. The vertical dash line indicates the translocation fusion point. Abbreviations: PB, paired box; HD, homeodomain; FD, forkhead domain.

Description

The PAX3-FOXO1 fusion gene has a 2508 nt open reading frame encoding an 836 amino acid fusion protein. This fusion protein is a transcription factor with a PAX3 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, survival, differentiation, and motility. In conjunction with other genetic changes, recipient cells show transformation in culture and tumorigenesis in injected mice. A conditional knock-in mouse model of the PAX3-FKHR fusion has been generated and successfully produces ARMS tumors.

Highly cited references

Pubmed IDYearTitleCitations
373451592023Genomic and Epigenetic Changes Drive Aberrant Skeletal Muscle Differentiation in Rhabdomyosarcoma.214
234327282013A call to ARMS: targeting the PAX3-FOXO1 gene in alveolar rhabdomyosarcoma.196
303733182018Therapeutic Approaches Targeting PAX3-FOXO1 and Its Regulatory and Transcriptional Pathways in Rhabdomyosarcoma.175
262092352016Uncovering metabolism in rhabdomyosarcoma.145
358576432022Targeting KDM4 for treating PAX3-FOXO1-driven alveolar rhabdomyosarcoma.110
379682772023PAX3-FOXO1 dictates myogenic reprogramming and rhabdomyosarcoma identity in endothelial progenitors.104
391072802024HDAC3 genetic and pharmacologic inhibition radiosensitizes fusion positive rhabdomyosarcoma by promoting DNA double-strand breaks.98
331825562020FAK Signaling in Rhabdomyosarcoma.97
348369712021BAF complexes drive proliferation and block myogenic differentiation in fusion-positive rhabdomyosarcoma.93
358793662022Therapeutic targeting of ATR in alveolar rhabdomyosarcoma.86
346390122021MS-275 (Entinostat) Promotes Radio-Sensitivity in PAX3-FOXO1 Rhabdomyosarcoma Cells.85
286150692017Regulatory landscape fusion in rhabdomyosarcoma through interactions between the PAX3 promoter and FOXO1 regulatory elements.85
376395932023Myo-differentiation reporter screen reveals NF-Y as an activator of PAX3-FOXO1 in rhabdomyosarcoma.83
389920402024The transcriptional co-repressor Runx1t1 is essential for MYCN-driven neuroblastoma tumorigenesis.82
33490904202117-DMAG dually inhibits Hsp90 and histone lysine demethylases in alveolar rhabdomyosarcoma.81
336277852021FOXF1 is required for the oncogenic properties of PAX3-FOXO1 in rhabdomyosarcoma.80
347205292021Transcription factors specificity protein and nuclear receptor 4A1 in pancreatic cancer.80
293677562018PAX3-FOXO1 drives miR-486-5p and represses miR-221 contributing to pathogenesis of alveolar rhabdomyosarcoma.78
243344542014Alveolar rhabdomyosarcoma-associated PAX3-FOXO1 promotes tumorigenesis via Hippo pathway suppression.73
277600492016Helicase CHD4 is an epigenetic coregulator of PAX3-FOXO1 in alveolar rhabdomyosarcoma.73
331176712020Effects of the Oncoprotein PAX3-FOXO1 on Modulation of Exosomes Function and Protein Content: Implications on Oxidative Stress Protection and Enhanced Plasticity.70
384740362024Transforming Growth Factor Beta and Alveolar Rhabdomyosarcoma: A Challenge of Tumor Differentiation and Chemotherapy Response.68
345733552021High Frequency of Tumor Propagating Cells in Fusion-Positive Rhabdomyosarcoma.61
384022122024KDM3B inhibitors disrupt the oncogenic activity of PAX3-FOXO1 in fusion-positive rhabdomyosarcoma.60
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260714852015Secreted Frizzled-Related Protein 3 (SFRP3) Is Required for Tumorigenesis of PAX3-FOXO1-Positive Alveolar Rhabdomyosarcoma.57
298696122018PAX3-FOXO1 transgenic zebrafish models identify HES3 as a mediator of rhabdomyosarcoma tumorigenesis.56
318248512019A Perspective on Polo-Like Kinase-1 Inhibition for the Treatment of Rhabdomyosarcomas.55
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274540802016Comparative transcriptomic analysis reveals the oncogenic fusion protein PAX3-FOXO1 globally alters mRNA and miRNA to enhance myoblast invasion.54
331825482020Synthetic MIR143-3p Suppresses Cell Growth in Rhabdomyosarcoma Cells by Interrupting RAS Pathways Including PAX3-FOXO1.54
258068262015The PAX3-FOXO1 fusion protein present in rhabdomyosarcoma interferes with normal FOXO activity and the TGF-β pathway.53
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381021362023PAX3-FOXO1 uses its activation domain to recruit CBP/P300 and shape RNA Pol2 cluster distribution.52
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335895192021A Fusion Transcription Factor-Driven Cancer Progresses to a Fusion-Independent Relapse via Constitutive Activation of a Downstream Transcriptional Target.51
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241074482013Small molecule inhibition of PAX3-FOXO1 through AKT activation suppresses malignant phenotypes of alveolar rhabdomyosarcoma.44
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376270612023Preclinical Evaluation of the FGFR-Family Inhibitor Futibatinib for Pediatric Rhabdomyosarcoma.35
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318888892020Aurora A Kinase Inhibition Destabilizes PAX3-FOXO1 and MYCN and Synergizes with Navitoclax to Induce Rhabdomyosarcoma Cell Death.0
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392110842024PAX fusion proteins deregulate gene networks controlling mitochondrial translation in pediatric rhabdomyosarcoma.0
292777582018Sphingosine Induces Apoptosis and Down-regulation of MYCN in PAX3-FOXO1-positive Alveolar Rhabdomyosarcoma Cells Irrespective of TP53 Mutation.0
342182272022A Review of Effusion Cytomorphology of Small Round Cell Tumors.0

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Citation

Frederic G Barr

Soft Tissues: Alveolar rhabdomyosarcoma with t(2;13)(q35;q14) PAX3/FOXO1

Atlas Genet Cytogenet Oncol Haematol. 2010-07-01

Online version: http://atlasgeneticsoncology.org/solid-tumor/5013/soft-tissues-alveolar-rhabdomyosarcoma-with-t(2;13)(q35;q14)-pax3-foxo1