STBT5:Alveolar soft part sarcoma: Difference between revisions

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 <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)*==
-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==
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 !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)
+| ||<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
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+|''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 (1)(2)(3)(4).
+Breakpoints typically involve Type 1: exon 6(5)(6) or exon 4(2) or Type 2: exon5(5)(6) or exon 3(2) 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 (7)
+|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 (8)(9)(10).
+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).
+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::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(14), Breakpoints typically involve exon 3 of ''TFE3'' (NM_006521) and exon 10 of ''HNRNPH3'' (NM_194247)(14)
+|t(X;10)(p11.23;q21.31) in MiT family tRCC – single case of ASPS confirmed by FISH and targeted RNA sequencing(14).
+|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(14).
+|-
+|''PRCC''
 |
-|
+{| class="wikitable"
+|''PRCC::TFE3''
+|}
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