Soft Tissues: Alveolar rhabdomyosarcoma with t(2;2)(p23;q35) PAX3/NCOA1

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 a small subset of ARMS cases (

Pathology

No information available.

Cytogenetics

Cytogenetics morphological

Of the five reported cases, cytogenetics was only performed on one case and demonstrated a normal karyotype.

Cytogenetics molecular

Several of these cases were detected using fluorescence in situ hybridization analysis by the finding of PAX3 rearrangement without evidence of a PAX3-FOXO1 fusion or FOXO1 rearrangement. Other cases were detected by directly assaying cases with a PAX3-NCOA1 fusion-specific RT-PCR assay.

Genes Involved and Proteins

Note

A variant t(2;8)(q35;q13) translocation has been identified, both in ARMS and in cases of embryonal rhabdomyosarcoma.

Gene name

NCOA1 (nuclear receptor coactivator 1)

Location

2p23.3

Protein description

Nuclear receptor transcriptional coactivator - p160 family.

Gene name

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

Location

2q36.1

Note

The NCOA2 gene (encoding another member of the p160 family of transcriptional coactivators) is located at 8q13 and involved in the variant t(2;8).

Protein description

Transcription factor - paired box (PAX) family.

Result of the chromosomal anomaly

Atlas Image
Generation of chimeric genes by the 2;2 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

Based on the cloned cDNA, there appears to be two possible scenarios for formation of fusion genes. In some cases, the translocation apparently breaks within PAX3 intron 6 and NCOA1 intron 12 (type 1), and in other cases the translocation breaks within PAX3 intron 7 and NCOA1 intron 11 (type 2).

Transcript

The type 1 fusion transcript consists of the first six PAX3 exons fused to the last nine NCOA1 exons (from exon 13 onward) and the type 2 fusion transcript consists of the first seven PAX3 exons fused to the last ten NCOA1 exons (from exon 12 onward).
Atlas Image
Comparison of wild-type and fusion products associated with the 2;2 translocation in ARMS. Conserved domains are indicated as open boxes, and functional domains are shown as solid bars. The vertical dash line indicates the translocation fusion points in the type 1 (black) and type 2 (red) fusions. Abbreviations: PB, paired box; HD, homeodomain; bHLH/PAS, basic helix-loop-helix/Per/ARNT/Sim homologous domain; LXXLL, typical LXXLL alpha-helix motifs; HAT, histone acetyltransferase (NCOA1 map adapted from Xu & Li, 2003).

Description

The type 1 fusion gene encodes a 894 amino acid fusion protein and the type 2 fusion gene encodes a 1026 amino acid fusion protein. The fusion proteins encode novel transcription factors with the PAX3 DNA binding domain and the NCOA1 transcriptional activation domains.

Oncogenesis

Transcription dysregulation. At the cellular level there is evidence of alterations in control of growth, resulting in transformation of recipient cells (NIH3T3) in culture.

Highly cited references

Pubmed IDYearTitleCitations
199536352010Recurrent t(2;2) and t(2;8) translocations in rhabdomyosarcoma without the canonical PAX-FOXO1 fuse PAX3 to members of the nuclear receptor transcriptional coactivator family.48
263717832016Novel PAX3-NCOA1 Fusions in Biphenotypic Sinonasal Sarcoma With Focal Rhabdomyoblastic Differentiation.29
344246072021PAX3-NCOA1 alveolar rhabdomyosarcoma of the tongue: A rare entity with challenging diagnosis and management.0
392094432024Sinonasal alveolar rhabdomyosarcoma with PAX3::NCOA1 fusion expressing SOX10 and with nodal metastases: a double diagnostic pitfall.0
391470322024Novel PAX3::MAML3 Fusion Identified in Alveolar Rhabdomyosarcoma, Using DNA Methylation Profiling to Expand the Genetic Spectrum of "Fusion-Positive" Cases.0
301094752018Biphenotypic sinonasal sarcoma: demographics, clinicopathological characteristics, molecular features, and prognosis of a recently described entity.0
274545702016Fusion gene profile of biphenotypic sinonasal sarcoma: an analysis of 44 cases.0

Article Bibliography

Pubmed IDLast YearTitleAuthors
116078232001Gene fusions involving PAX and FOX family members in alveolar rhabdomyosarcoma.Barr FG et al
175066892007The role of Pax genes in the development of tissues and organs: Pax3 and Pax7 regulate muscle progenitor cell functions.Buckingham M et al
173115322007Fusions involving PAX and FOX genes in the molecular pathogenesis of alveolar rhabdomyosarcoma: recent advances.Mercado GE et al
166073812006Use of a novel FISH assay on paraffin-embedded tissues as an adjunct to diagnosis of alveolar rhabdomyosarcoma.Nishio J et al
199536352010Recurrent t(2;2) and t(2;8) translocations in rhabdomyosarcoma without the canonical PAX-FOXO1 fuse PAX3 to members of the nuclear receptor transcriptional coactivator family.Sumegi J et al
153138872004Gene expression signatures identify rhabdomyosarcoma subtypes and detect a novel t(2;2)(q35;p23) translocation fusing PAX3 to NCOA1.Wachtel M et al
203513262010Fusion gene-negative alveolar rhabdomyosarcoma is clinically and molecularly indistinguishable from embryonal rhabdomyosarcoma.Williamson D et al
128054122003Review of the in vivo functions of the p160 steroid receptor coactivator family.Xu J et al
197012412009Normal and cancer-related functions of the p160 steroid receptor co-activator (SRC) family.Xu J et al

Citation

Frederic G Barr

Soft Tissues: Alveolar rhabdomyosarcoma with t(2;2)(p23;q35) PAX3/NCOA1

Atlas Genet Cytogenet Oncol Haematol. 2010-07-01

Online version: http://atlasgeneticsoncology.org/solid-tumor/5445/soft-tissues-alveolar-rhabdomyosarcoma-with-t(2;2)(p23;q35)-pax3-ncoa1