Compendium of Cancer Genome Aberrations

STBT5:Alveolar soft part sarcoma: Difference between revisions

[checked revision][checked revision]
← Older edit
VisualWikitext
No edit summary
No edit summary
 
(10 intermediate revisions by 3 users not shown)
Line 2: Line 2:
[[STBT5:Table_of_Contents|Soft Tissue and Bone Tumours (Who Classification, 5th ed.)]]
[[STBT5:Table_of_Contents|Soft Tissue and Bone Tumours (Who Classification, 5th ed.)]]


{{Under Construction}}
<span style="color:#0070C0">(''General Instructions – The focus of these pages is the clinically significant genetic alterations in each disease type. This is based on up-to-date knowledge from multiple resources such as PubMed and the WHO classification books. The CCGA is meant to be a supplemental resource to the WHO classification books; the CCGA captures in a continually updated wiki-stye manner the current genetics/genomics knowledge of each disease, which evolves more rapidly than books can be revised and published. If the same disease is described in multiple WHO classification books, the genetics-related information for that disease will be consolidated into a single main page that has this template (other pages would only contain a link to this main page). Use [https://www.genenames.org/ <u>HUGO-approved gene names and symbols</u>] (italicized when appropriate), [https://varnomen.hgvs.org/ <u>HGVS-based nomenclature for variants</u>], as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples); to add (or move) a row or column in a table, click nearby within the table and select the > symbol that appears. Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see'' </span><u>''[[Author_Instructions]]''</u><span style="color:#0070C0"> ''and [[Frequently Asked Questions (FAQs)|<u>FAQs</u>]] as well as contact your [[Leadership|<u>Associate Editor</u>]] or [mailto:CCGA@cancergenomics.org <u>Technical Support</u>].)''</span>
==Primary Author(s)*==
==Primary Author(s)*==
Put your text here<span style="color:#0070C0"> (''<span class="blue-text">EXAMPLE:</span>'' Jane Smith, PhD) </span>
Maxine Sutcliffe, PhD, FACMG, CCMG
==WHO Classification of Disease==
==WHO Classification of Disease==


Line 29: Line 26:
|}
|}


==WHO Essential and Desirable Genetic Diagnostic Criteria==
<span style="color:#0070C0">(''Instructions: The table will have the diagnostic criteria from the WHO book <u>autocompleted</u>; remove any <u>non</u>-genetics related criteria. If applicable, add text about other classification'' ''systems that define this entity and specify how the genetics-related criteria differ.'')</span>
{| class="wikitable"
|+
|WHO Essential Criteria (Genetics)*
|
|-
|WHO Desirable Criteria (Genetics)*
|
|-
|Other Classification
|
|}
<nowiki>*</nowiki>Note: These are only the genetic/genomic criteria. Additional diagnostic criteria can be found in the [https://tumourclassification.iarc.who.int/home <u>WHO Classification of Tumours</u>].
==Related Terminology==
==Related Terminology==


Line 55: Line 38:


==Gene Rearrangements==
==Gene Rearrangements==
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: 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>
''ASPSCR1::TFE3'' is the definitive rearrangement for ASPS; however, other gene partners have been rarely described.
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
Line 64: Line 47:
!Clinical Relevance Details/Other Notes
!Clinical Relevance Details/Other Notes
|-
|-
|<span class="blue-text">EXAMPLE:</span> ''ABL1''||<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)
|''ASPSCR1'' (formerly ''ASPL'')
|<span class="blue-text">EXAMPLE:</span> Common (CML)
|''ASPSCR1::TFE3''
|<span class="blue-text">EXAMPLE:</span> D, P, T
|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. <ref>{{Cite journal|last=Buchberger|first=A.|last2=Howard|first2=M. J.|last3=Proctor|first3=M.|last4=Bycroft|first4=M.|date=2001-03-16|title=The UBX domain: a widespread ubiquitin-like module|url=https://pubmed.ncbi.nlm.nih.gov/11243799|journal=Journal of Molecular Biology|volume=307|issue=1|pages=17–24|doi=10.1006/jmbi.2000.4462|issn=0022-2836|pmid=11243799}}</ref><ref name=":0">{{Cite journal|last=Ladanyi|first=M.|last2=Lui|first2=M. Y.|last3=Antonescu|first3=C. R.|last4=Krause-Boehm|first4=A.|last5=Meindl|first5=A.|last6=Argani|first6=P.|last7=Healey|first7=J. H.|last8=Ueda|first8=T.|last9=Yoshikawa|first9=H.|date=2001-01-04|title=The der(17)t(X;17)(p11;q25) of human alveolar soft part sarcoma fuses the TFE3 transcription factor gene to ASPL, a novel gene at 17q25|url=https://pubmed.ncbi.nlm.nih.gov/11244503|journal=Oncogene|volume=20|issue=1|pages=48–57|doi=10.1038/sj.onc.1204074|issn=0950-9232|pmid=11244503}}</ref><ref name=":1">{{Cite journal|last=Pozner|first=Amir|last2=Li|first2=Li|last3=Verma|first3=Shiv Prakash|last4=Wang|first4=Shuxin|last5=Barrott|first5=Jared J.|last6=Nelson|first6=Mary L.|last7=Yu|first7=Jamie S. E.|last8=Negri|first8=Gian Luca|last9=Colborne|first9=Shane|date=2024-02-07|title=ASPSCR1-TFE3 reprograms transcription by organizing enhancer loops around hexameric VCP/p97|url=https://pubmed.ncbi.nlm.nih.gov/38326311|journal=Nature Communications|volume=15|issue=1|pages=1165|doi=10.1038/s41467-024-45280-5|issn=2041-1723|pmc=10850509|pmid=38326311}}</ref><ref>{{Cite journal|last=Kim|first=Seongryong|last2=Song|first2=Hyun-Sup|last3=Yu|first3=Jihyun|last4=Kim|first4=You-Me|date=2021-05-31|title=MiT Family Transcriptional Factors in Immune Cell Functions|url=https://pubmed.ncbi.nlm.nih.gov/33972476|journal=Molecules and Cells|volume=44|issue=5|pages=342–355|doi=10.14348/molcells.2021.0067|issn=0219-1032|pmc=8175148|pmid=33972476}}</ref>  
|<span class="blue-text">EXAMPLE:</span> Yes (WHO, NCCN)
Breakpoints typically involve Type 1: exon 6<ref name=":2">{{Cite journal|last=Zhao|first=Ming|last2=Rao|first2=Qiu|last3=Wu|first3=Cuiyun|last4=Zhao|first4=Zhongsheng|last5=He|first5=Xianglei|last6=Ru|first6=Guoqing|date=2015-09-15|title=Alveolar soft part sarcoma of lung: report of a unique case with emphasis on diagnostic utility of molecular genetic analysis for TFE3 gene rearrangement and immunohistochemistry for TFE3 antigen expression|url=https://pubmed.ncbi.nlm.nih.gov/26369552|journal=Diagnostic Pathology|volume=10|pages=160|doi=10.1186/s13000-015-0399-5|issn=1746-1596|pmc=4570486|pmid=26369552}}</ref><ref name=":3">{{Cite journal|last=Aulmann|first=S.|last2=Longerich|first2=T.|last3=Schirmacher|first3=P.|last4=Mechtersheimer|first4=G.|last5=Penzel|first5=R.|date=2007-06|title=Detection of the ASPSCR1-TFE3 gene fusion in paraffin-embedded alveolar soft part sarcomas|url=https://pubmed.ncbi.nlm.nih.gov/17543078|journal=Histopathology|volume=50|issue=7|pages=881–886|doi=10.1111/j.1365-2559.2007.02693.x|issn=0309-0167|pmid=17543078}}</ref>) or exon 4<ref name=":0" /> or Type 2: exon<ref name=":2" /><ref name=":3" /> or exon 3<ref name=":0" /> of ''TFE3'' (NM_006521) and exon 7 of ''ASPCR1'' (NM_024083).
|<span class="blue-text">EXAMPLE:</span>
|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).
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).
|Rare
|-
|D, P, T <ref name=":4">{{Cite journal|last=Bergsma|first=Emilie J.|last2=Elgawly|first2=Mariam|last3=Mancuso|first3=David|last4=Orr|first4=Roger|last5=Vuskovich|first5=Theresa|last6=Seligson|first6=Nathan D.|date=2024-04|title=Atezolizumab as the First Systemic Therapy Approved for Alveolar Soft Part Sarcoma|url=https://pubmed.ncbi.nlm.nih.gov/37466080|journal=The Annals of Pharmacotherapy|volume=58|issue=4|pages=407–415|doi=10.1177/10600280231187421|issn=1542-6270|pmid=37466080}}</ref>
|<span class="blue-text">EXAMPLE:</span> ''CIC''
|Yes (WHO, NCCN)
|<span class="blue-text">EXAMPLE:</span> ''CIC::DUX4''
|''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.<ref name=":5">{{Cite journal|last=Zhang|first=Runjiao|last2=Dong|first2=Li|last3=Yu|first3=Jinpu|date=2020|title=Concomitant Pathogenic Mutations and Fusions of Driver Oncogenes in Tumors|url=https://pubmed.ncbi.nlm.nih.gov/33520689|journal=Frontiers in Oncology|volume=10|pages=544579|doi=10.3389/fonc.2020.544579|issn=2234-943X|pmc=7844084|pmid=33520689}}</ref><ref name=":6">{{Cite journal|last=Sicinska|first=Ewa|last2=Kola|first2=Vijaya S. R.|last3=Kerfoot|first3=Joseph A.|last4=Taddei|first4=Madeleine L.|last5=Al-Ibraheemi|first5=Alyaa|last6=Hsieh|first6=Yi-Hsuan|last7=Church|first7=Alanna J.|last8=Landesman-Bollag|first8=Esther|last9=Landesman|first9=Yosef|date=2024-07-15|title=ASPSCR1::TFE3 Drives Alveolar Soft Part Sarcoma by Inducing Targetable Transcriptional Programs|url=https://pubmed.ncbi.nlm.nih.gov/38657118|journal=Cancer Research|volume=84|issue=14|pages=2247–2264|doi=10.1158/0008-5472.CAN-23-2115|issn=1538-7445|pmc=11250573|pmid=38657118}}</ref><ref name=":7">{{Cite journal|last=Tanaka|first=Miwa|last2=Chuaychob|first2=Surachada|last3=Homme|first3=Mizuki|last4=Yamazaki|first4=Yukari|last5=Lyu|first5=Ruyin|last6=Yamashita|first6=Kyoko|last7=Ae|first7=Keisuke|last8=Matsumoto|first8=Seiichi|last9=Kumegawa|first9=Kohei|date=2023-04-07|title=ASPSCR1::TFE3 orchestrates the angiogenic program of alveolar soft part sarcoma|url=https://pubmed.ncbi.nlm.nih.gov/37029109|journal=Nature Communications|volume=14|issue=1|pages=1957|doi=10.1038/s41467-023-37049-z|issn=2041-1723|pmc=10082046|pmid=37029109}}</ref>
|<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).
Potential significance of such novel programming may explain that, although genes involved in fusions are usually excellent potential targets for therapeutic intervention, <ref>{{Cite journal|last=Annala|first=M. J.|last2=Parker|first2=B. C.|last3=Zhang|first3=W.|last4=Nykter|first4=M.|date=2013-11-01|title=Fusion genes and their discovery using high throughput sequencing|url=https://pubmed.ncbi.nlm.nih.gov/23376639|journal=Cancer Letters|volume=340|issue=2|pages=192–200|doi=10.1016/j.canlet.2013.01.011|issn=1872-7980|pmc=3675181|pmid=23376639}}</ref> and despite the identification of ASPS >70yrs ago, ASPS currently remains a high-risk disease with limited treatment options.<ref name=":4" />  
|-
|<span class="blue-text">EXAMPLE:</span> ''ALK''
|<span class="blue-text">EXAMPLE:</span> ''ELM4::ALK''


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.<ref name=":8">{{Cite journal|last=Ishiguro|first=Naoko|last2=Nakagawa|first2=Mayumi|date=2024-11|title=ASPSCR1::TFE3-mediated upregulation of insulin receptor substrate 2 (IRS-2) activates PI3K/AKT signaling and promotes malignant phenotype|url=https://pubmed.ncbi.nlm.nih.gov/39419345|journal=The International Journal of Biochemistry & Cell Biology|volume=176|pages=106676|doi=10.1016/j.biocel.2024.106676|issn=1878-5875|pmid=39419345}}</ref>  IRS-2 and PIK3/mTOR have been strategically identified as potentially promising novel transcriptional targets.<ref name=":8" />  However, the ''ASPSCR1::TFE3'' control on the tumorigenic landscape has also been identified as responsive to Immune Checkpoint Inhibitors (ICIs).<ref>{{Cite journal|last=Hindi|first=N.|last2=Razak|first2=A.|last3=Rosenbaum|first3=E.|last4=Jonczak|first4=E.|last5=Hamacher|first5=R.|last6=Rutkowski|first6=P.|last7=Bhadri|first7=V. A.|last8=Skryd|first8=A.|last9=Brahmi|first9=M.|date=2023-12|title=Efficacy of immune checkpoint inhibitors in alveolar soft-part sarcoma: results from a retrospective worldwide registry|url=https://pubmed.ncbi.nlm.nih.gov/38016251|journal=ESMO open|volume=8|issue=6|pages=102045|doi=10.1016/j.esmoop.2023.102045|issn=2059-7029|pmc=10698259|pmid=38016251}}</ref>. This led to the FDA approval of the ICI, Atezolizumab, that blocks the PD-1/PD-L1 pathway, for targeted therapy in ASPS.<ref name=":4" />


Other fusion partners include ''KIF5B, NPM1, STRN, TFG, TPM3, CLTC, KLC1''
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).<ref>{{Cite journal|last=Argani|first=P.|last2=Antonescu|first2=C. R.|last3=Illei|first3=P. B.|last4=Lui|first4=M. Y.|last5=Timmons|first5=C. F.|last6=Newbury|first6=R.|last7=Reuter|first7=V. E.|last8=Garvin|first8=A. J.|last9=Perez-Atayde|first9=A. R.|date=2001-07|title=Primary renal neoplasms with the ASPL-TFE3 gene fusion of alveolar soft part sarcoma: a distinctive tumor entity previously included among renal cell carcinomas of children and adolescents|url=https://pubmed.ncbi.nlm.nih.gov/11438465|journal=The American Journal of Pathology|volume=159|issue=1|pages=179–192|doi=10.1016/S0002-9440(10)61684-7|issn=0002-9440|pmc=1850400|pmid=11438465}}</ref>
|<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
|''HNRNPH3''
|<span class="blue-text">EXAMPLE:</span> Rare (Lung adenocarcinoma)
|''HNRNPH3::TFE3''
|<span class="blue-text">EXAMPLE:</span> T
|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.<ref name=":9">{{Cite journal|last=Dickson|first=Brendan C.|last2=Chung|first2=Catherine T.-S.|last3=Hurlbut|first3=David J.|last4=Marrano|first4=Paula|last5=Shago|first5=Mary|last6=Sung|first6=Yun-Shao|last7=Swanson|first7=David|last8=Zhang|first8=Lei|last9=Antonescu|first9=Cristina R.|date=2020-01|title=Genetic diversity in alveolar soft part sarcoma: A subset contain variant fusion genes, highlighting broader molecular kinship with other MiT family tumors|url=https://pubmed.ncbi.nlm.nih.gov/31433528|journal=Genes, Chromosomes & Cancer|volume=59|issue=1|pages=23–29|doi=10.1002/gcc.22803|issn=1098-2264|pmc=7057290|pmid=31433528}}</ref> Breakpoints typically involve exon 3 of ''TFE3'' (NM_006521) and exon 10 of ''HNRNPH3'' (NM_194247).<ref name=":9" />
|
|t(X;10)(p11.23;q21.31) in MiT family tRCC. <ref name=":10">{{Cite journal|last=Ge|first=Yan|last2=Lin|first2=Xingtao|last3=Zhang|first3=Qingling|last4=Lin|first4=Danyi|last5=Luo|first5=Luqiao|last6=Wang|first6=Huiling|last7=Li|first7=Zhi|date=2021|title=Xp11.2 Translocation Renal Cell Carcinoma With TFE3 Rearrangement: Distinct Morphological Features and Prognosis With Different Fusion Partners|url=https://pubmed.ncbi.nlm.nih.gov/34917511|journal=Frontiers in Oncology|volume=11|pages=784993|doi=10.3389/fonc.2021.784993|issn=2234-943X|pmc=8668609|pmid=34917511}}</ref> Single case of ASPS confirmed by FISH and targeted RNA sequencing.<ref name=":9" />
|<span class="blue-text">EXAMPLE:</span>
|Single case in ASPS
 
|D
Both balanced and unbalanced forms are observed by FISH (add references).
|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.<ref name=":9" />
|-
|-
|<span class="blue-text">EXAMPLE:</span> ''ABL1''
|''PRCC''
|<span class="blue-text">EXAMPLE:</span> N/A
|''PRCC::TFE3''
|<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.
|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.<ref name=":9" /> Breakpoints typically involve exon 6 of ''TFE3'' (NM_006521) and exon 1 of ''PRCC'' (NM_005973).<ref name=":9" />
|<span class="blue-text">EXAMPLE:</span> N/A
|t(X;1)(p11.23;q23.1) in MiT family tRCC.<ref name=":10" /> Single case ASPS confirmed by karyotype, FISH and targeted RNA sequencing.<ref name=":9" />
|<span class="blue-text">EXAMPLE:</span> Recurrent (IDH-wildtype Glioblastoma)
|Rare in tRCC -(single case in ASPS)
|<span class="blue-text">EXAMPLE:</span> D, P, T
|D
|
|N/A
|
|A retrospective review of ASPS lacking ASPSCR1 revealed a fusion between PRCC mitotic checkpoint control factor gene with TFE3,<ref name=":9" /> emphasizing the kinship of ASPS and the MiT family subset tRCC and genetic diversity.<ref name=":9" />  
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.<ref name=":9" /><ref name=":10" />
|-
|-
|
|''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.<ref name=":9" />
|
|(X;17)(p11.2:p13) in MiT family tRCC. <ref name=":10" />  Single case ASPS confirmed by FISH.<ref name=":9" />
|
|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.<ref name=":9" />
 
Note the balanced ''DVL2::TFE3'' t(X;17) is diagnostic in RCC subset tRCC.<ref name=":9" /><ref name=":10" />
|}
|}
==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.<ref>doi.org/101016/j.cancergen.2022.10.11.</ref>
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
!Chr #!!'''Gain, Loss, Amp, LOH'''!!'''Minimal Region Cytoband and/or Genomic Coordinates [Genome Build; Size]'''!!'''Relevant Gene(s)'''
!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'''
!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T
!'''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>
|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.
|-
|
|
|
|
|
|
|
|}
|}
==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.  
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
!Chromosomal Pattern
!Chromosomal Pattern
!Molecular Pathogenesis
!Molecular Pathogenesis
!'''Prevalence -'''
!Prevalence -  
'''Common >20%, Recurrent 5-20% or Rare <5% (Disease)'''
Common >20%, Recurrent 5-20% or Rare <5% (Disease)
!'''Diagnostic, Prognostic, and Therapeutic Significance - D, P, T'''
!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T
!'''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>
|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
|
|
|-
|
|
|
|
|
|
|}
|}
==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.
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
!Gene!!'''Genetic Alteration'''!!'''Tumor Suppressor Gene, Oncogene, Other'''!!'''Prevalence -'''
!Gene!!Genetic Alteration!!Tumor Suppressor Gene, Oncogene, Other!!Prevalence -
'''Common >20%, Recurrent 5-20% or Rare <5% (Disease)'''
Common >20%, Recurrent 5-20% or Rare <5% (Disease)
!'''Diagnostic, Prognostic, and Therapeutic Significance - D, P, T  '''
!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T  
!'''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>''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
|
|
|-
|
|
|
|
|
|
|
|}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.<ref name=":1" />
 
* Along with VCP/p97 co-factors organizes chromatin and interacts with promoters and enhancers.<ref name=":1" />
 
* Directly activating gene expression related to vascular networks (angiogenesis), cell cycle, especially driving Cyclin D1 (cell proliferation), mitochondrial biogenesis and lipid metabolism.<ref name=":1" /><ref name=":5" /><ref name=":7" />
 
==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.<ref>{{Cite journal|last=Ge|first=Yan|last2=Lin|first2=Xingtao|last3=Zhang|first3=Qingling|last4=Lin|first4=Danyi|last5=Luo|first5=Luqiao|last6=Wang|first6=Huiling|last7=Li|first7=Zhi|date=2021|title=Xp11.2 Translocation Renal Cell Carcinoma With TFE3 Rearrangement: Distinct Morphological Features and Prognosis With Different Fusion Partners|url=https://pubmed.ncbi.nlm.nih.gov/34917511|journal=Frontiers in Oncology|volume=11|pages=784993|doi=10.3389/fonc.2021.784993|issn=2234-943X|pmc=8668609|pmid=34917511}}</ref>
|<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.<ref name=":8" />
|-
|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)<ref name=":7" />
|<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.<ref name=":6" /><ref>Sarcoma Foundation of America: Characterizing and targeting the oncogenic program in Alveolar Soft Part Sarcoma</ref>
|-
|<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
|-
|
|
|
|}
|}
==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>
 
* '''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 ''PRC''C 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==
==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 ASPS
 
==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.<ref name=":4" />
* Recent studies are revealing mechanisms, pathways and programs by which ''ASPSCR1::TFE3'' in ASPS controls tumorigenesis and identify therapeutic targeted strategies.<ref name=":1" /><ref name=":3" /><ref name=":9" />
* 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>
None
==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>
==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.  


Prior Author(s):
Prior Author(s):
<nowiki>*</nowiki>''Citation of this Page'': “Alveolar soft part sarcoma”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated {{REVISIONMONTH}}/{{REVISIONDAY}}/{{REVISIONYEAR}}, <nowiki>https://ccga.io/index.php/STBT5:Alveolar soft part sarcoma</nowiki>.
<nowiki>*</nowiki>''Citation of this Page'': “Alveolar soft part sarcoma”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated {{REVISIONMONTH}}/{{REVISIONDAY}}/{{REVISIONYEAR}}, <nowiki>https://ccga.io/index.php/STBT5:Alveolar soft part sarcoma</nowiki>.  
 
==References==
 
 
[[Category:STBT5]][[Category:DISEASE]][[Category:Diseases A]]
[[Category:STBT5]][[Category:DISEASE]][[Category:Diseases A]]
Retrieved from "https://test.ccga.io/index.php/STBT5:Alveolar_soft_part_sarcoma"