STBT5:Alveolar soft part sarcoma

Soft Tissue and Bone Tumours (Who Classification, 5th ed.)

Primary Author(s)*

Maxine Sutcliffe, PhD, FACMG, CCMG

WHO Classification of Disease

Structure	Disease
Book	Soft Tissue and Bone Tumours (5th ed.)
Category	Soft tissue tumours
Family	Tumours of uncertain differentiation
Type	Alveolar soft part sarcoma
Subtype(s)	N/A

Related Terminology

Acceptable	N/A
Not Recommended	N/A

Gene Rearrangements

ASPSCR1::TFE3 is the definitive rearrangement for ASPS; however, other gene partners have been rarely described.

Driver Gene	Fusion(s) and Common Partner Genes	Molecular Pathogenesis	Typical Chromosomal Alteration(s)	Prevalence -Common >20%, Recurrent 5-20% or Rare <5% (Disease)	Diagnostic, Prognostic, and Therapeutic Significance - D, P, T	Established Clinical Significance Per Guidelines - Yes or No (Source)	Clinical Relevance Details/Other Notes
ASPSCR1 (formerly ASPL)	ASPSCR1::TFE3	In frame fusion that results in constitutive activation of the ASPSCR1 N-terminal UBX domain interacting with VCP/p97 cofactor to fuse with the helix-loop-helix-leucin zipper (bHLH-LZ) and DNA-binding domains of the 3’TFE3 transcription factor. Breakpoints typically involve Type 1: exon 6) or exon 4 or Type 2: exon or exon 3 of TFE3 (NM_006521) and exon 7 of ASPCR1 (NM_024083).	Unbalanced der(17)t(X;17)(p11.23;q25) may also be reported (in older literature or cytogenetic suboptimal morphology) as add(17)t(X;17).	Rare	D, P, T	Yes (WHO, NCCN)	ASPSCR1::TFE3 is an unusual fusion; both genes are drivers and the atypical driver/partner fusion protein generated is itself a novel oncogenic regulator of transcriptional programs through direct interaction with core key epigenetic promoters and enhancers of cell proliferation, angiogenesis and mitochondrial biology. Potential significance of such novel programming may explain that, although genes involved in fusions are usually excellent potential targets for therapeutic intervention, and despite the identification of ASPS >70yrs ago, ASPS currently remains a high-risk disease with limited treatment options. Although not directly targetable itself, the fusion mechanism controls essential characteristics such as upregulating insulation receptor substrate 2 (IRS-2) expression resulting in PIK3/AKT signaling activation.  IRS-2 and PIK3/mTOR have been strategically identified as potentially promising novel transcriptional targets.  However, the ASPSCR1::TFE3 control on the tumorigenic landscape has also been identified as responsive to Immune Checkpoint Inhibitors (ICIs).. This led to the FDA approval of the ICI, Atezolizumab, that blocks the PD-1/PD-L1 pathway, for targeted therapy in ASPS. Unbalanced der(17)t(X;17) in the absence of it's reciprocal der(X)t(X;17) inducing transcriptional dysregulation is diagnostic of ASPS in the appropriate morphological and clinical context(3). Note the balanced ASPSCR1::TFE3 t(X;17) is diagnostic in a MiT family subset of translocation renal cell carcinoma (tRCC).
HNRNPH3	HNRNPH3::TFE3	In frame fusion resulting in constitutive activation of N-terminal HNRNPH3 with the helix-loop-helix leucin zipper transcription domains of the 3’TFE3 transcription factor. Breakpoints typically involve exon 3 of TFE3 (NM_006521) and exon 10 of HNRNPH3 (NM_194247).	t(X;10)(p11.23;q21.31) in MiT family tRCC. Single case of ASPS confirmed by FISH and targeted RNA sequencing.	Single case in ASPS	D	N/A	An index case of ASPS with a novel TFE3 fusion partner, HNRNPH3, an RNA-binding protein for pre-mRNA processing, splicing and RNA metabolism involved in regulating gene expression, indicates genetics diversity in ASPS.
PRCC	PRCC::TFE3	In frame fusion that results in constitutive activation of the N-terminal of PRCC with the helix-loop-helix and leucin zipper transcription domains of the 3’TFE3 transcription factor. Breakpoints typically involve exon 6 of TFE3 (NM_006521) and exon 1 of PRCC (NM_005973).	t(X;1)(p11.23;q23.1) in MiT family tRCC. Single case ASPS confirmed by karyotype, FISH and targeted RNA sequencing.	Rare in tRCC -(single case in ASPS)	D	N/A	A retrospective review of ASPS lacking ASPSCR1 revealed a fusion between PRCC mitotic checkpoint control factor gene with TFE3, emphasizing the kinship of ASPS and the MiT family subset tRCC and genetic diversity. Note the balanced PRCC::TFE3 t(X;1) is diagnostic in a MiT family subset of renal cell carcinoma tRCC and seen in other TFE3-driven tumors.
DVL2	DVL2::TFE3	In frame fusion that is predicted to result in constitutively activating the N-terminal of DVL2 (NM_004422) with the helix-loop-helix and leucin zipper transcription domains of the 3’TFE3 (NM_005973) transcription factor.	(X;17)(p11.2:p13) in MiT family tRCC. Single case ASPS confirmed by FISH.	Rare in tRCC -(single case in ASPS)	D	N/A	A retrospective review of ASPS lacking ASPCR1 demonstrated a fusion between DVL2, a gene involved in the Wnt signaling pathway with TFE3(13), also seen in the RCC MiT family subset tRCC and indicative of genetic diversity. Note the balanced DVL2::TFE3 t(X;17) is diagnostic in RCC subset tRCC.

Individual Region Genomic Gain/Loss/LOH

ASPS is extremely rare (<1% of sarcomas) with a paucity of publications especially involving karyotypes.  A CMA/SNP microarray of a single ASPS case demonstrated 46.9Mb gain Xp22.3-p11.23 and 1.0Mb loss of 17q25.2-q25.3, consistent with der(17)t(X;17), together with whole chromosome gain 12 and loss of heterozygosity of whole chromosome 21.

Chr #	Gain, Loss, Amp, LOH	Minimal Region Cytoband and/or Genomic Coordinates [Genome Build; Size]	Relevant Gene(s)	Diagnostic, Prognostic, and Therapeutic Significance - D, P, T	Established Clinical Significance Per Guidelines - Yes or No (Source)	Clinical Relevance Details/Other Notes
N/A	N/A	N/A	N/A	N/A	N/A	N/A

Characteristic Chromosomal or Other Global Mutational Patterns

None.  ASPS is extremely rare (<1% of sarcomas) with a paucity of publications especially involving global mutational patterns, so currently none known.  

Chromosomal Pattern	Molecular Pathogenesis	Prevalence - Common >20%, Recurrent 5-20% or Rare <5% (Disease)	Diagnostic, Prognostic, and Therapeutic Significance - D, P, T	Established Clinical Significance Per Guidelines - Yes or No (Source)	Clinical Relevance Details/Other Notes
N/A	N/A	N/A	N/A	N/A	N/A

Gene Mutations (SNV/INDEL)

None.

Gene	Genetic Alteration	Tumor Suppressor Gene, Oncogene, Other	Prevalence - Common >20%, Recurrent 5-20% or Rare <5% (Disease)	Diagnostic, Prognostic, and Therapeutic Significance - D, P, T	Established Clinical Significance Per Guidelines - Yes or No (Source)	Clinical Relevance Details/Other Notes
N/A	N/A	N/A	N/A	N/A	N/A	N/A

Note: A more extensive list of mutations can be found in cBioportal, COSMIC, and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.

Epigenomic Alterations

The ASPSCR1::TFE3 fusion significantly alters the epigenome through a variety of mechanisms and effects including:

• Binding and modulating super enhancers (SEs) crucial in gene regulation such as enhancer loops.

• Along with VCP/p97 co-factors organizes chromatin and interacts with promoters and enhancers.

• Directly activating gene expression related to vascular networks (angiogenesis), cell cycle, especially driving Cyclin D1 (cell proliferation), mitochondrial biogenesis and lipid metabolism.

Genes and Main Pathways Involved

Although TFE3 fusions (HNRNPH3, PRCC, DVL2) have been described in ASPS and these genes regulate gene expression and cell proliferation, currently ASPSCR1::TFE3 is the definitive rearrangement driving unique transcriptional and metabolic processes.

Gene; Genetic Alteration	Pathway	Pathophysiologic Outcome
ASPSCR1::TFE3	c-MET: receptor tyrosine kinase gene is directly targeted and upregulated, activating it’s downstream signaling pathway. PI3K/AKT:  upregulation of the adaptor protein Insulin Receptor Substrate 2 (IRD-2) activates PI3K/ALK signaling pathway.	ASPSCR1::TFE3 fusion protein exerts its oncogenic effect through a complex mutli-program, multi-pathway mechanism including: Angiogenesis (VEGF, ANGPTL2) Cell cycle progression (CCND1, CDK4) transcriptional programs.

Genetic Diagnostic Testing Methods

• Fusion testing:
  • Targeted sequencing using RT-PCR or Next Generation Sequencing (NGS) panel
  • Whole Genome RNA sequencing

• Fluorescent in-situ hybridization (FISH):
  • Dual-color break-apart probes for ASPSCR1 and TFE3 will identify the rearrangement in ASPS.  Customized probes can identify PRCC, HNRNPH3 and DVL2
  • Dual-color fusion probes for ASPSCR1, TFE3 and PRCC can confirm the specific fusions.  Customized probes can confirm HNRNPH3 and DVL2 fusions
• Karyotyping:
  • Can identify the der(17)t(X;17) rearrangement
  • Can identify the translocations involving HNRNPH3 (X;10), PRCC t(X;1) and DVL2 t(X;17)

Although ASPSCR1::TFE3 is the definitive rearrangement, relying solely on ASPSCR1 testing, if negative, in an appropriate morphological and clinical setting could potentially miss an ASPS diagnosis.

Familial Forms

• None known associated with ASPS

Additional Information

• Although several drugs such as Sunitinib and Palbociclib are discussed in the literature, there is currently only one FDA approved drug Atezolizumab, a PD-L1 antibody for systemic administration in adult and children >2 years.
• Recent studies are revealing mechanisms, pathways and programs by which ASPSCR1::TFE3 in ASPS controls tumorigenesis and identify therapeutic targeted strategies.
• The close overlap of ASPSCR1::TFE3 fusion in diverse cancers (sarcoma vs carcinoma), ASPS and tRCC, is further highlighted by other genes, namely PRCC and DVL2. in fusions with TFE3 implicated in both tumor types.
• A minority of ASPS cases have been reported with a purportedly balanced t(X;17).  Of significance is the distinguishing feature of ASPS being unbalanced vs tRCC being balanced, as a feature of diagnosis.  There is currently no evidence of karyotypic, FISH and/or RNA sequencing that confirms a balanced rearrangement in clinically established ASPS.

Links

None

Notes

*Primary authors will typically be those that initially create and complete the content of a page.  If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the Associate Editor or other CCGA representative.  When pages have a major update, the new author will be acknowledged at the beginning of the page, and those who contributed previously will be acknowledged below as a prior author.

Prior Author(s): *Citation of this Page: “Alveolar soft part sarcoma”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 12/24/2025, https://ccga.io/index.php/STBT5:Alveolar soft part sarcoma.