Compendium of Cancer Genome Aberrations

STBT5:Alveolar soft part sarcoma: Difference between revisions

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!Established Clinical Significance Per Guidelines - Yes or No (Source)
!Established Clinical Significance Per Guidelines - Yes or No (Source)
!Clinical Relevance Details/Other Notes
!Clinical Relevance Details/Other Notes
|-
| ||<span class="blue-text">EXAMPLE:</span> ''BCR::ABL1''||<span class="blue-text">EXAMPLE:</span> The pathogenic derivative is the der(22) resulting in fusion of 5’ BCR and 3’ABL1.||<span class="blue-text">EXAMPLE:</span> t(9;22)(q34;q11.2)
|<span class="blue-text">EXAMPLE:</span> Common (CML)
|<span class="blue-text">EXAMPLE:</span> D, P, T
|<span class="blue-text">EXAMPLE:</span> Yes (WHO, NCCN)
|<span class="blue-text">EXAMPLE:</span>
The t(9;22) is diagnostic of CML in the appropriate morphology and clinical context (add reference). This fusion is responsive to targeted therapy such as Imatinib (Gleevec) (add reference). BCR::ABL1 is generally favorable in CML (add reference).
|-
|<span class="blue-text">EXAMPLE:</span> ''CIC''
|<span class="blue-text">EXAMPLE:</span> ''CIC::DUX4''
|<span class="blue-text">EXAMPLE:</span> Typically, the last exon of ''CIC'' is fused to ''DUX4''. The fusion breakpoint in ''CIC'' is usually intra-exonic and removes an inhibitory sequence, upregulating ''PEA3'' genes downstream of ''CIC'' including ''ETV1'', ''ETV4'', and ''ETV5''.
|<span class="blue-text">EXAMPLE:</span> t(4;19)(q25;q13)
|<span class="blue-text">EXAMPLE:</span> Common (CIC-rearranged sarcoma)
|<span class="blue-text">EXAMPLE:</span> D
|
|<span class="blue-text">EXAMPLE:</span>
''DUX4'' has many homologous genes; an alternate translocation in a minority of cases is t(10;19), but this is usually indistinguishable from t(4;19) by short-read sequencing (add references).
|-
|<span class="blue-text">EXAMPLE:</span> ''ALK''
|<span class="blue-text">EXAMPLE:</span> ''ELM4::ALK''
Other fusion partners include ''KIF5B, NPM1, STRN, TFG, TPM3, CLTC, KLC1''
|<span class="blue-text">EXAMPLE:</span> Fusions result in constitutive activation of the ''ALK'' tyrosine kinase. The most common ''ALK'' fusion is ''EML4::ALK'', with breakpoints in intron 19 of ''ALK''. At the transcript level, a variable (5’) partner gene is fused to 3’ ''ALK'' at exon 20. Rarely, ''ALK'' fusions contain exon 19 due to breakpoints in intron 18.
|<span class="blue-text">EXAMPLE:</span> N/A
|<span class="blue-text">EXAMPLE:</span> Rare (Lung adenocarcinoma)
|<span class="blue-text">EXAMPLE:</span> T
|
|<span class="blue-text">EXAMPLE:</span>
Both balanced and unbalanced forms are observed by FISH (add references).
|-
|<span class="blue-text">EXAMPLE:</span> ''ABL1''
|<span class="blue-text">EXAMPLE:</span> N/A
|<span class="blue-text">EXAMPLE:</span> Intragenic deletion of exons 2–7 in ''EGFR'' removes the ligand-binding domain, resulting in a constitutively active tyrosine kinase with downstream activation of multiple oncogenic pathways.
|<span class="blue-text">EXAMPLE:</span> N/A
|<span class="blue-text">EXAMPLE:</span> Recurrent (IDH-wildtype Glioblastoma)
|<span class="blue-text">EXAMPLE:</span> D, P, T
|
|
|-
|-
|''ASPSCR1'' (formerly ''ASPL'')
|''ASPSCR1'' (formerly ''ASPL'')
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Potential significance of such novel programming may explain that, although genes involved in fusions are usually excellent potential targets for therapeutic intervention(11), and despite the identification of ASPS >70yrs ago, ASPS currently remains a high-risk disease with limited treatment options(7).  
Potential significance of such novel programming may explain that, although genes involved in fusions are usually excellent potential targets for therapeutic intervention(11), and despite the identification of ASPS >70yrs ago, ASPS currently remains a high-risk disease with limited treatment options(7).  


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(12).  IRS-2 and PIK3/mTOR have been strategically identified as potentially promising novel transcriptional targets(12).  However, the ASPSCR1::TFE3 control on the tumorigenic landscape has also been identified as responsive to Immune Checkpoint Inhibitors (ICIs)(12). This led to the FDA approval of the ICI, Atezolizumab, that blocks the PD-1/PD-L1 pathway, for targeted therapy in ASPS(7).
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(12).  IRS-2 and PIK3/mTOR have been strategically identified as potentially promising novel transcriptional targets(12).  However, the ''ASPSCR1::TFE3'' control on the tumorigenic landscape has also been identified as responsive to Immune Checkpoint Inhibitors (ICIs)(12). This led to the FDA approval of the ICI, Atezolizumab, that blocks the PD-1/PD-L1 pathway, for targeted therapy in ASPS(7).


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)(13).
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)(13).
|-
|-
|''HNRNPH3''
|''HNRNPH3''
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|D
|D
|N/A
|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(14).  
|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(14).  
|-
|-
|''PRCC''
|''PRCC''
|
{| class="wikitable"
|''PRCC::TFE3''
|''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 (13). Breakpoints typically involve exon 6 of ''TFE3'' (NM_006521) and exon 1 of ''PRCC'' (NM_005973)(15).
|
|t(X;1)(p11.23;q23.1) in MiT family tRCC(12) - single case ASPS confirmed by karyotype, FISH and targeted RNA sequencing (15).
|
|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(14), emphasizing the kinship of ASPS and the MiT family subset tRCC and genetic diversity(14).
|
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(14)(15)
|-
|''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(14).
|(X;17)(p11.2:p13) in MiT family tRCC (12) - single case ASPS confirmed by FISH(14).
|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(14).
 
Note the balanced ''DVL2::TFE3'' t(X;17) is diagnostic in RCC subset tRCC(14)(15)
|}
|}
==Individual Region Genomic Gain/Loss/LOH==
==Individual Region Genomic Gain/Loss/LOH==
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Includes aberrations not involving gene rearrangements. Details on clinical significance such as prognosis and other important information can be provided in the notes section. Can refer to CGC workgroup tables as linked on the homepage if applicable. Please include references throughout the table. Do not delete the table.'') </span>
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. doi.org/101016/j.cancergen.2022.10.11. (in preparation).
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!Clinical Relevance Details/Other Notes
!Clinical Relevance Details/Other Notes
|-
|-
|<span class="blue-text">EXAMPLE:</span>
|N/A
7
|N/A
|<span class="blue-text">EXAMPLE:</span> Loss
|N/A
|<span class="blue-text">EXAMPLE:</span>
|N/A
chr7
|N/A
|<span class="blue-text">EXAMPLE:</span>
|N/A
Unknown
|N/A
|<span class="blue-text">EXAMPLE:</span> D, P
|<span class="blue-text">EXAMPLE:</span> No
|<span class="blue-text">EXAMPLE:</span>
Presence of monosomy 7 (or 7q deletion) is sufficient for a diagnosis of AML with MDS-related changes when there is ≥20% blasts and no prior therapy (add reference).  Monosomy 7/7q deletion is associated with a poor prognosis in AML (add references).
|-
|<span class="blue-text">EXAMPLE:</span>
8
|<span class="blue-text">EXAMPLE:</span> Gain
|<span class="blue-text">EXAMPLE:</span>
chr8
|<span class="blue-text">EXAMPLE:</span>
Unknown
|<span class="blue-text">EXAMPLE:</span> D, P
|
|<span class="blue-text">EXAMPLE:</span>
Common recurrent secondary finding for t(8;21) (add references).
|-
|<span class="blue-text">EXAMPLE:</span>
17
|<span class="blue-text">EXAMPLE:</span> Amp
|<span class="blue-text">EXAMPLE:</span>
17q12; chr17:39,700,064-39,728,658 [hg38; 28.6 kb]
|<span class="blue-text">EXAMPLE:</span>
''ERBB2''
|<span class="blue-text">EXAMPLE:</span> D, P, T
|
|<span class="blue-text">EXAMPLE:</span>
Amplification of ''ERBB2'' is associated with HER2 overexpression in HER2 positive breast cancer (add references). Add criteria for how amplification is defined.
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==Characteristic Chromosomal or Other Global Mutational Patterns==
==Characteristic Chromosomal or Other Global Mutational Patterns==
Put your text here and fill in the table <span style="color:#0070C0">(I''nstructions: Included in this category are alterations such as hyperdiploid; gain of odd number chromosomes including typically chromosome 1, 3, 5, 7, 11, and 17; co-deletion of 1p and 19q; complex karyotypes without characteristic genetic findings; chromothripsis; microsatellite instability; homologous recombination deficiency; mutational signature pattern; etc. Details on clinical significance such as prognosis and other important information can be provided in the notes section. Please include references throughout the table. Do not delete the table.'')</span>
None.  ASPS is extremely rare (<1% of sarcomas) with a paucity of publications especially involving global mutational patterns, so currently none known.  
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!Clinical Relevance Details/Other Notes
!Clinical Relevance Details/Other Notes
|-
|-
|<span class="blue-text">EXAMPLE:</span>
|N/A
Co-deletion of 1p and 18q
|N/A
|<span class="blue-text">EXAMPLE:</span> See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).
|N/A
|<span class="blue-text">EXAMPLE:</span> Common (Oligodendroglioma)
|N/A
|<span class="blue-text">EXAMPLE:</span> D, P
|N/A
|
|N/A
|
|-
|<span class="blue-text">EXAMPLE:</span>
Microsatellite instability - hypermutated
|
|<span class="blue-text">EXAMPLE:</span> Common (Endometrial carcinoma)
|<span class="blue-text">EXAMPLE:</span> P, T
|
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|}
==Gene Mutations (SNV/INDEL)==
==Gene Mutations (SNV/INDEL)==
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: This table is not meant to be an exhaustive list; please include only genes/alterations that are recurrent or common as well either disease defining and/or clinically significant. If a gene has multiple mechanisms depending on the type or site of the alteration, add multiple entries in the table. For clinical significance, denote associations with FDA-approved therapy (not an extensive list of applicable drugs) and NCCN or other national guidelines if applicable; Can also refer to CGC workgroup tables as linked on the homepage if applicable as well as any high impact papers or reviews of gene mutations in this entity. Details on clinical significance such as prognosis and other important information such as concomitant and mutually exclusive mutations can be provided in the notes section. Please include references throughout the table. Do not delete the table.'') </span>
None.
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!Clinical Relevance Details/Other Notes
!Clinical Relevance Details/Other Notes
|-
|-
|<span class="blue-text">EXAMPLE:</span>''EGFR''
|N/A
 
|N/A
<br />
|N/A
|<span class="blue-text">EXAMPLE:</span> Exon 18-21 activating mutations
|N/A
|<span class="blue-text">EXAMPLE:</span> Oncogene
|N/A
|<span class="blue-text">EXAMPLE:</span> Common (lung cancer)
|N/A
|<span class="blue-text">EXAMPLE:</span> T
|N/A
|<span class="blue-text">EXAMPLE:</span> Yes (NCCN)
|<span class="blue-text">EXAMPLE:</span> Exons 18, 19, and 21 mutations are targetable for therapy. Exon 20 T790M variants cause resistance to first generation TKI therapy and are targetable by second and third generation TKIs (add references).
|-
|<span class="blue-text">EXAMPLE:</span> ''TP53''; Variable LOF mutations
<br />
|<span class="blue-text">EXAMPLE:</span> Variable LOF mutations
|<span class="blue-text">EXAMPLE:</span> Tumor Supressor Gene
|<span class="blue-text">EXAMPLE:</span> Common (breast cancer)
|<span class="blue-text">EXAMPLE:</span> P
|
|<span class="blue-text">EXAMPLE:</span> >90% are somatic; rare germline alterations associated with Li-Fraumeni syndrome (add reference). Denotes a poor prognosis in breast cancer.
|-
|<span class="blue-text">EXAMPLE:</span> ''BRAF''; Activating mutations
|<span class="blue-text">EXAMPLE:</span> Activating mutations
|<span class="blue-text">EXAMPLE:</span> Oncogene
|<span class="blue-text">EXAMPLE:</span> Common (melanoma)
|<span class="blue-text">EXAMPLE:</span> T
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|}Note: A more extensive list of mutations can be found in [https://www.cbioportal.org/ <u>cBioportal</u>], [https://cancer.sanger.ac.uk/cosmic <u>COSMIC</u>], and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.
|}Note: A more extensive list of mutations can be found in [https://www.cbioportal.org/ <u>cBioportal</u>], [https://cancer.sanger.ac.uk/cosmic <u>COSMIC</u>], and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.
==Epigenomic Alterations==
==Epigenomic Alterations==
Put your text here
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(3)
 
* along with VCP/p97 co-factors organizes chromatin and interacts with promoters and enhancers(3)
 
* directly activates gene expression related to vascular networks (angiogenesis), cell cycle, especially driving Cyclin D1 (cell proliferation), mitochondrial biogenesis and lipid metabolism(3)(8)(10)
 
==Genes and Main Pathways Involved==
==Genes and Main Pathways Involved==
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Please include references throughout the table. Do not delete the table.)''</span>
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.
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
|-
|-
|<span class="blue-text">EXAMPLE:</span> ''BRAF'' and ''MAP2K1''; Activating mutations
|''ASPSCR1::TFE3''
|<span class="blue-text">EXAMPLE:</span> MAPK signaling
|c-MET: receptor tyrosine kinase gene is directly targeted and upregulated, activating it’s downstream signaling pathway (16)
|<span class="blue-text">EXAMPLE:</span> Increased cell growth and proliferation
PI3K/AKT:  upregulation of the adaptor protein Insulin Receptor Substrate 2 (IRD-2) activates PI3K/ALK signaling pathway(12)
|-
|ASPSCR1::TFE3 fusion protein exerts its oncogenic effect through a complex mutli-program, multi-pathway mechanism including:
|<span class="blue-text">EXAMPLE:</span> ''CDKN2A''; Inactivating mutations
Angiogenesis (VEGF, ANGPTL2)(10)
|<span class="blue-text">EXAMPLE:</span> Cell cycle regulation
 
|<span class="blue-text">EXAMPLE:</span> Unregulated cell division
Cell cycle progression (CCND1, CDK4) transcriptional programs (17)
|-
|<span class="blue-text">EXAMPLE:</span> ''KMT2C'' and ''ARID1A''; Inactivating mutations
|<span class="blue-text">EXAMPLE:</span> Histone modification, chromatin remodeling
|<span class="blue-text">EXAMPLE:</span> Abnormal gene expression program
|-
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==Genetic Diagnostic Testing Methods==
==Genetic Diagnostic Testing Methods==
Put your text here <span style="color:#0070C0">(''Instructions: Include recommended testing type(s) to identify the clinically significant genetic alterations.'')</span>
'''1. Fusion testing:'''
 
* Targeted sequencing using RT-PCR or Next Generation Sequencing (NGS) panels
* Whole Genome RNA sequencing
 
'''2. 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 ''PRC''C can confirm the specific fusions.  Customized probes can confirm ''HNRNPH3'' and ''DVL2'' fusions
 
'''3. 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==
==Familial Forms==
Put your text here <span style="color:#0070C0">(''Instructions: Include associated hereditary conditions/syndromes that cause this entity or are caused by this entity.'') </span>
 
* None known associated with fusions.
* Individual genes, if mutated, may be associated with:
** ''ASPSCR1'': none
** ''TFE3'': ''TFE3''-Associated Neurodevelopmental Disorder (TFE3-AND),
** ''HNRNPH3'': Specifically none, but hnRNP family linked to rare neurodevelopmental disorders
** ''PRCC'': Hereditary Papillary RCC (HPRC), Hereditary Leiomyomatosis and Renal Cell Carcinoma (HLRCC),
** ''DVL2'': Robinow syndrome
 
==Additional Information==
==Additional Information==
Put your text here
 
* 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(7).
* Recent studies are revealing mechanisms, pathways and programs by which ''ASPSCR1::TFE3'' in ASPS controls tumorigenesis and identify therapeutic targeted strategies(3)(6)(16).  
* 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==
==Links==
Put a link here or anywhere appropriate in this page <span style="color:#0070C0">(''Instructions: Highlight the text to which you want to add a link in this section or elsewhere, select the "Link" icon at the top of the wiki page, and search the name of the internal page to which you want to link this text, or enter an external internet address by including the "<nowiki>http://www</nowiki>." portion.'')</span>
 
==Notes==
==Notes==
<nowiki>*</nowiki>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 [[Leadership|''<u>Associate Editor</u>'']] 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.  
<nowiki>*</nowiki>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 [[Leadership|''<u>Associate Editor</u>'']] 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.  
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==References==
==References==
(use the "Cite" icon at the top of the page) <span style="color:#0070C0">(''Instructions: Add each reference into the text above by clicking where you want to insert the reference, selecting the “Cite” icon at the top of the wiki page, and using the “Automatic” tab option to search by PMID to select the reference to insert. If a PMID is not available, such as for a book, please use the “Cite” icon, select “Manual” and then “Basic Form”, and include the entire reference. To insert the same reference again later in the page, select the “Cite” icon and “Re-use” to find the reference; DO NOT insert the same reference twice using the “Automatic” tab as it will be treated as two separate references. The reference list in this section will be automatically generated and sorted''</span><span style="color:#0070C0">''.''</span><span style="color:#0070C0">)</span>
 


[[Category:STBT5]][[Category:DISEASE]][[Category:Diseases A]]
[[Category:STBT5]][[Category:DISEASE]][[Category:Diseases A]]
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