STBT5:Alveolar soft part sarcoma: Difference between revisions

|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>

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).

|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>

|''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>

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" />

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" />

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>

|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" />

|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" />

|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" />

|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" />

|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" />

|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" />

|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" />

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>

* 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" />

|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>

PI3K/AKT:  upregulation of the adaptor protein Insulin Receptor Substrate 2 (IRD-2) activates PI3K/ALK signaling pathway.<ref name=":8" />

Angiogenesis (VEGF, ANGPTL2)<ref name=":7" />

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>

* '''Fusion testing:'''

** 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)

* None known associated with ASPS

* 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" />