Compendium of Cancer Genome Aberrations

STBT5:Undifferentiated pleomorphic sarcoma: Difference between revisions

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{{DISPLAYTITLE:Undifferentiated pleomorphic sarcoma}}
{{DISPLAYTITLE:Undifferentiated pleomorphic sarcoma}}
[[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 J Sutcliffe, PhD, FACMG, CCMG<span style="color:#0070C0"> </span>
==WHO Classification of Disease==
==WHO Classification of Disease==
{| class="wikitable"
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!Structure
!Structure
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==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)*
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|-
|Other Classification
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<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==


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|Malignant fibrous histiocytoma of bone; pleomorphic fibrosarcoma of bone
|Malignant fibrous histiocytoma of bone; pleomorphic fibrosarcoma of bone
|}
|}
The WHO 5<sup>th</sup> Edition 2020 classifies Undifferentiated pleomorphic sarcoma (UPS) as a neoplasm of bone UPS-B.
Undifferentiated Pleomorphic Sarcoma (UPS) evidences in soft tissue and bone. <ref name=":0">{{Cite journal|last=Gusho|first=Charles A.|last2=Lee|first2=Linus|last3=Guntin|first3=Jonathan|last4=Blank|first4=Alan T.|date=2022-02|title=Comparison of Features and Outcomes of Undifferentiated Pleomorphic Sarcoma of Bone and Soft Tissue|url=https://pubmed.ncbi.nlm.nih.gov/34731728|journal=The Journal of Surgical Research|volume=270|pages=313–320|doi=10.1016/j.jss.2021.09.032|issn=1095-8673|pmid=34731728}}</ref>
* '''Soft Tissue (UPS-S):''' UPS, one of the most common soft-tissue sarcomas in adults, representing '''10–20%''' of all soft tissue sarcomas (STSs).
* '''Bone (UPS-B):''' UPS of bone is rare, accounting for only about '''2%''' of all primary bone neoplasms.
The majority of references quoted relate to UPS-S.


==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>
Undifferentiated Pleomorphic Sarcoma (UPS) lacks specific definable gene rearrangements rendering it a diagnosis of exclusion.<ref name=":1">{{Cite journal|last=Zheng|first=Biqiang|last2=Qu|first2=Yueting|last3=Wang|first3=Jian|last4=Shi|first4=Yingqiang|last5=Yan|first5=Wangjun|date=2019|title=Pathogenic and Targetable Genetic Alterations in Resected Recurrent Undifferentiated Pleomorphic Sarcomas Identified by Targeted Next-generation Sequencing|url=https://pubmed.ncbi.nlm.nih.gov/31018952|journal=Cancer Genomics & Proteomics|volume=16|issue=3|pages=221–228|doi=10.21873/cgp.20127|issn=1790-6245|pmc=6542646|pmid=31018952}}</ref> <ref name=":2">Menon G, Solis-Ledesma G. Undifferentiated Pleomorphic Sarcoma. 2025 Jun 23. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2026 Jan–. PMID: 34033374.</ref> UPS is typified by highly complex karyotype, extreme aneuploidy, polysomy, polyploidy, and excessive genomic instability, but without any identifiable, defining characterizing diagnostic aberrations.
 
*The term cancer “driver” genes in UPS refers to recurrent alterations in genes such as ''ATRX, RB1'' and ''TP53'' tumor suppressors. From a molecular standpoint, unlike other soft tissue sarcomas, UPS does not manifest any known translocations or driver/donor fusions. <ref name=":1" /><ref name=":2" />
* In this context, the term “cancer driver genes” (in addition to the cited tumor suppressors genes) documented in UPS include: ''H3F3A, ZFHX3, CSMD3, PRPRT, TRIO, CLTC, PDGFRB, ALK, PTVH1, RET, ERBB4, JAK3, GATA1, PIK3CG, RARA, MYH9''.<ref name=":3">{{Cite journal|last=Sun|first=Haitao|last2=Liu|first2=Jilu|last3=Hu|first3=Fangyuan|last4=Xu|first4=Meng|last5=Leng|first5=Ao|last6=Jiang|first6=Feng|last7=Chen|first7=Kefu|date=2023|title=Current research and management of undifferentiated pleomorphic sarcoma/myofibrosarcoma|url=https://pubmed.ncbi.nlm.nih.gov/36873946|journal=Frontiers in Genetics|volume=14|pages=1109491|doi=10.3389/fgene.2023.1109491|issn=1664-8021|pmc=9978151|pmid=36873946}}</ref>
 
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
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!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)
|''TRIO''
|<span class="blue-text">EXAMPLE:</span> Common (CML)
|''TERT''
|<span class="blue-text">EXAMPLE:</span> D, P, T
|Trio Rho Guanine Nucleotide Exchange Factor fusion involving the 5’ region of ''TRIO'' (5p15.2) exon 33,34 or 40 forming an in-frame chimeric transcript with 3’ Telomerase Reverse Transcription ''TERT'' exons. <ref name=":4">{{Cite journal|last=Delespaul|first=Lucile|last2=Lesluyes|first2=Tom|last3=Pérot|first3=Gaëlle|last4=Brulard|first4=Céline|last5=Lartigue|first5=Lydia|last6=Baud|first6=Jessica|last7=Lagarde|first7=Pauline|last8=Le Guellec|first8=Sophie|last9=Neuville|first9=Agnès|date=2017-02-01|title=Recurrent TRIO Fusion in Nontranslocation-Related Sarcomas|url=https://pubmed.ncbi.nlm.nih.gov/27528700|journal=Clinical Cancer Research: An Official Journal of the American Association for Cancer Research|volume=23|issue=3|pages=857–867|doi=10.1158/1078-0432.CCR-16-0290|issn=1557-3265|pmid=27528700}}</ref> <ref name=":3" />
|<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>
* Non-translational fusion ''TRIO::TERT'' leading to massive over-expression of ''TERT''. <ref name=":4" />
* ''TRIO'' is a target of 5p amplification in UPS.


''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).
Not specific to UPS
|-
|<span class="blue-text">EXAMPLE:</span> ''ALK''
|<span class="blue-text">EXAMPLE:</span> ''ELM4::ALK''


 
|Rare ~ 4% of UPS
Other fusion partners include ''KIF5B, NPM1, STRN, TFG, TPM3, CLTC, KLC1''
|N/A
|<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.
|No
|<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>
* ''TRIO::TERT'' fusion is a rare gene rearrangement in a small subset of non-translational soft tissue sarcomas including UPS.
 
* Less frequent ''TRIO'' partners include ''LINC01504'' (9q21.3) or ''ZNF558'' (19p13.3).
Both balanced and unbalanced forms are observed by FISH (add references).
* The fusion is considered a secondary oncogenic event (rather than primary), hence non-diagnostic. <ref name=":4" /> <ref name=":5">{{Cite journal|last=Hames-Fathi|first=Shadi|last2=Nottley|first2=Steven W. G.|last3=Pillay|first3=Nischalan|date=2022-01|title=Unravelling undifferentiated soft tissue sarcomas: insights from genomics|url=https://pubmed.ncbi.nlm.nih.gov/34958500|journal=Histopathology|volume=80|issue=1|pages=109–121|doi=10.1111/his.14446|issn=1365-2559|pmid=34958500}}</ref>
|-
|-
|<span class="blue-text">EXAMPLE:</span> ''ABL1''
|''TMTC2''
|<span class="blue-text">EXAMPLE:</span> N/A
|''NTRK3''
|<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
|
|
|
* Intronic fusion involving Exons 1-9 of the N-terminal Transmembrane and Tetratricopeptide Repeat Containing 2 (''TMTC2'') gene acting as the 5’ driver partner with the 3’ Exons 15-36 kinase domain of the Neurotrophic Receptor Tyrosine Kinase 3 (''NTRK3''). <ref name=":6">{{Cite journal|last=Bai|first=Chujie|last2=Zhang|first2=Lu|last3=Wang|first3=Yaohui|last4=You|first4=Xia|last5=Ju|first5=Yongzhi|last6=Sun|first6=Tingting|last7=Fan|first7=Zhengfu|date=2022-10|title=A novel TMTC2-NTRK3 fusion in undifferentiated high-grade pleomorphic sarcoma|url=https://pubmed.ncbi.nlm.nih.gov/35933643|journal=Journal of Cancer Research and Clinical Oncology|volume=148|issue=10|pages=2933–2937|doi=10.1007/s00432-022-04249-x|issn=1432-1335|pmc=11800999|pmid=35933643}}</ref>
* ''NTRK'' family fusions typically lead to constitutive activation of the ''TRK'' signaling pathway that contributes to tumor proliferation and progression. <ref name=":3" />.
|''TMTC2'' 12q21.31 fused with ''NTRK3'' 15q25.3-q26.2
Methodology for fusion identification by NGS, confirmed by IHC and interphase FISH. <ref name=":6" />
|Single case in UPS
|N/A
|No
|Reported in a single case.  Implications of this fusion are it's potential responsiveness to ''TRK'' family of targeted therapies. <ref name=":6" />
|-
|-
|''LMNA''
|''NTRK1''
|
|
|
* Fusion involving Exons 1-2 of the N-terminal Lamin A/C (''LMNA'')  gene acting as the 5’ driver promoter  with the 3’ Exons 11-17 kinase domain of the Neurotrophic Receptor Tyrosine Kinase 1 (''NTRK1''). <ref name=":7">{{Cite journal|last=Zhou|first=Ning|last2=Schäfer|first2=Reinhold|last3=Li|first3=Tao|last4=Fang|first4=Meiyu|last5=Liu|first5=Luying|date=2018-08-22|title=A primary undifferentiated pleomorphic sarcoma of the lumbosacral region harboring a LMNA-NTRK1 gene fusion with durable clinical response to crizotinib: a case report|url=https://pubmed.ncbi.nlm.nih.gov/30134855|journal=BMC cancer|volume=18|issue=1|pages=842|doi=10.1186/s12885-018-4749-z|issn=1471-2407|pmc=6106902|pmid=30134855}}</ref> 
|
* ''NTRK'' family fusions result in constitutive activation of the ''TRK'' signaling pathway that contributes to tumor proliferation and progression. <ref name=":3" />
|
|''LMNNA'' 1q21.2-q21.3 fused with ''NTRK1'' 1q23.1.
|
Methodology for fusion identification by NGS. <ref name=":7" />
|
|Single case in UPS
|
|N/A
|
|No
|Disease progression in this case was not halted with typical management (resection, radiation and chemotherapy).  Identification of this ''LMNA::NTRK1'' fusion and the aggressive clinical presentation led to the patient receiving treatment with 450mg/day crizotinib orally.  Patient maintained near-complete clinical response (follow-up 18 months). <ref name=":7" /> 
|}
|}
==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>
Multiple numerical/structural chromosome aberrations are highly recurrent, but not definitive for UPS due to their extensive range, lack of specific pattern and seemingly random occurrence  <ref name=":0" /> <ref name=":8">{{Cite journal|last=Yoshimoto|first=Masato|last2=Yamada|first2=Yuichi|last3=Ishihara|first3=Shin|last4=Kohashi|first4=Kenichi|last5=Toda|first5=Yu|last6=Ito|first6=Yoshihiro|last7=Yamamoto|first7=Hidetaka|last8=Furue|first8=Masutaka|last9=Nakashima|first9=Yasuharu|date=2020-01|title=Comparative Study of Myxofibrosarcoma With Undifferentiated Pleomorphic Sarcoma: Histopathologic and Clinicopathologic Review|url=https://pubmed.ncbi.nlm.nih.gov/31651522|journal=The American Journal of Surgical Pathology|volume=44|issue=1|pages=87–97|doi=10.1097/PAS.0000000000001389|issn=1532-0979|pmid=31651522}}</ref>.  Also some reports combine soft tissue UPS with myxofibrosarcoma, others describe UPS of bone/soft tissue due to their same classification and relative indistinguishable morphology. <ref name=":0" /> <ref name=":8" />. Nonetheless, conventional chromosome analysis, CGH microarray, and FISH demonstrate frequent reoccurring CN change (bolded cited in multiple studies). <ref name=":3" /> <ref>{{Cite journal|last=Becerikli|first=Mustafa|last2=Wieczorek|first2=Stefan|last3=Stricker|first3=Ingo|last4=Nambiar|first4=Sandeep|last5=Rittig|first5=Andrea|last6=Epplen|first6=Joerg Thomas|last7=Tannapfel|first7=Andrea|last8=Lehnhardt|first8=Marcus|last9=Steinstraesser|first9=Lars|date=2014-12|title=Numerical and structural chromosomal anomalies in undifferentiated pleomorphic sarcoma|url=https://pubmed.ncbi.nlm.nih.gov/25503139|journal=Anticancer Research|volume=34|issue=12|pages=7119–7127|issn=1791-7530|pmid=25503139}}</ref>
 
Gain:
 
* Both p and q arms, chromosomes 1,2,'''7''',11,'''19''', '''X'''
* p arms chromosomes 3,4,'''5''',6,12,16,17
* q arms chromosomes 4,6,'''8''',9,12,'''14''',15,17,'''20''',22
 
Loss:
 
* Both p and q arms, chromosomes 8,9,'''10'''
* p arms chromosomes  '''8,9'''
* q arms 1,2,4,5,7,'''13''',16,'''18'''<span style="color:#0070C0">) </span>
 
{| 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>
|None currently diagnostic
7
|All aberrant mechanisms, occurring sequentially, or simultaneously, are demonstrated but none are diagnostically exclusive for UPS
|<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
|<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.
|-
|
|
|
|
|
|
|
|
* UPS lacks specific identifiable diagnosable chromosomal/molecular features or mechanisms rendering this classification having a “default” diagnosis subsequent to exclusion of other highly similar sarcomas.
* Other soft tissue sarcomas within the differential diagnosis for exclusion  include: dedifferentiated liposarcoma (DDLPS), leiomyosarcoma (LMS), myxofibrosarcoma (MFS), pleomorphic liposarcoma (PLS), malignant peripheral nerve sheath tumor (MPNST), angiosarcoma (AS) and extra-skeletal osteosarcoma (ESOS). <ref name=":2" /> <ref name=":9">{{Cite journal|last=Le Guellec|first=Sophie|last2=Chibon|first2=Frédéric|last3=Ouali|first3=Monia|last4=Perot|first4=Gaëlle|last5=Decouvelaere|first5=Anne-Valérie|last6=Robin|first6=Yves-Marie|last7=Larousserie|first7=Frédérique|last8=Terrier|first8=Philippe|last9=Coindre|first9=Jean-Michel|date=2014-03|title=Are peripheral purely undifferentiated pleomorphic sarcomas with MDM2 amplification dedifferentiated liposarcomas?|url=https://pubmed.ncbi.nlm.nih.gov/24525499|journal=The American Journal of Surgical Pathology|volume=38|issue=3|pages=293–304|doi=10.1097/PAS.0000000000000131|issn=1532-0979|pmid=24525499}}</ref> <ref name=":10">{{Cite journal|last=Lesovaya|first=Ekaterina A.|last2=Fetisov|first2=Timur I.|last3=Bokhyan|first3=Beniamin Yu|last4=Senchenko|first4=Maria A.|last5=Rogozhin|first5=Dmitry V.|last6=Maksimova|first6=Varvara P.|last7=Demko|first7=Anna N.|last8=Belitsky|first8=Gennady A.|last9=Yakubovskaya|first9=Marianna G.|date=2025-11-10|title=Genetic Heterogeneity of Undifferentiated Pleomorphic Sarcoma: Is There Potential for Targeted Therapy?|url=https://pubmed.ncbi.nlm.nih.gov/41300979|journal=Cancers|volume=17|issue=22|pages=3613|doi=10.3390/cancers17223613|issn=2072-6694|pmc=12651473|pmid=41300979}}</ref>
* Classifying/re-classifying soft tissue sarcomas is clearly important (eg. ''MDM2'' in DDLS). <ref name=":9" /> <ref name=":10" />
* Concurrently, in view of the incidence and high risk/poor prognostic outcome, multiple research studies to identify key features of UPS as well as specific biomarkers, prognostic indicators and targets or pathways for potential therapeutic strategies are sought to optimize patient management. <ref name=":1" /> <ref name=":2" /> <ref name=":3" /> <ref name=":4" /> <ref name=":11">{{Cite journal|last=Ma|first=Jiemin|last2=Groisberg|first2=Roman|last3=Shao|first3=Changxia|last4=Zhong|first4=Wenjun|date=2024|title=Incidence of Undifferentiated Pleomorphic Sarcoma (UPS) in the United States|url=https://pubmed.ncbi.nlm.nih.gov/39502684|journal=Sarcoma|volume=2024|pages=6735002|doi=10.1155/2024/6735002|issn=1357-714X|pmc=11537747|pmid=39502684}}</ref>
|}
|}
==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>
 
* UPS is “characterized” by a high degree of genomic instability which is a hallmark of its complex, chaotic and non-specific molecular profile but high-grade, high-risk morphology. <ref name=":1" /> <ref name=":2" /> Highly heterogeneous, complex karyotypes showing extensive copy number gain/loss including trisomy, pentasomy, hexasomy, and sex chromosome polysomy; bizarre structural changes such as dicentric, ring formation and unidentifiable “markers”. Evidence of massive instability results from amplification, chromothripsis, and LOH (loss of heterozygosity). <ref name=":10" /> <ref name=":11" /> 
* A distinctive phenotype seen in undifferentiated soft tissue sarcomas is genome-wide LOH reported from a pan-cancer analysis of >10,000 cancers (TCGA - (The Cancer Genome Atlas). <ref name=":5" /> Whole genome doubling (WGD) is a key macroevolutionary event that linked to chromothripsis.  WGD is rare in many tumor types but undifferentiated soft tissue sarcomas show >90% WGD. <ref name=":5" /> <ref name=":12">{{Cite journal|last=López|first=Saioa|last2=Lim|first2=Emilia L.|last3=Horswell|first3=Stuart|last4=Haase|first4=Kerstin|last5=Huebner|first5=Ariana|last6=Dietzen|first6=Michelle|last7=Mourikis|first7=Thanos P.|last8=Watkins|first8=Thomas B. K.|last9=Rowan|first9=Andrew|date=2020-03|title=Interplay between whole-genome doubling and the accumulation of deleterious alterations in cancer evolution|url=https://pubmed.ncbi.nlm.nih.gov/32139907|journal=Nature Genetics|volume=52|issue=3|pages=283–293|doi=10.1038/s41588-020-0584-7|issn=1546-1718|pmc=7116784|pmid=32139907}}</ref> <ref name=":13">{{Cite journal|last=Bowes|first=Amy L.|last2=Waise|first2=Sara|last3=Lesluyes|first3=Tom|last4=Butters|first4=Thomas|last5=English|first5=Christie|last6=Yan|first6=Haixi|last7=Verfaillie|first7=Annelien|last8=Davies|first8=Christopher|last9=Chen|first9=Jianan|date=2026-02-28|title=Profiling the genomic landscape and evolutionary history of polyploid giant cancer cells in undifferentiated pleomorphic sarcomas|url=https://pubmed.ncbi.nlm.nih.gov/41297660|journal=Cancer Letters|volume=639|pages=218173|doi=10.1016/j.canlet.2025.218173|issn=1872-7980|pmid=41297660}}</ref>  Coupling a near-haploid precursor with WGD is reported to have a pan-cancer prevalence of ~0.2%, but was observed in 3% of TCGA analyses and confirmed as enriched in UPS. <ref name=":5" /> <ref name=":12" />.
 
{| 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>
|Numerical Gain/Loss
Co-deletion of 1p and 18q
Polysomy
|<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).
|Copy Number (CN) Gain/Loss primarily trisomy but also pentasomy, hexasomy etc: 2,11,12,14,18,21,22,Y. <ref name=":3" /> <ref name=":4" />
|<span class="blue-text">EXAMPLE:</span> Common (Oligodendroglioma)
Sex chromosome polysomy.
|<span class="blue-text">EXAMPLE:</span> D, P
|Common
|P.  Features such as giant nuclei recognized as adverse prognostic indicators. <ref name=":13" />
|No
|
|
* Marked chromosome aneuploidy cell-to-cell variability.
* Range from near-haploid to hypo-octoploid with modal chromosome 22-180 count. <ref name=":5" /> <ref name=":10" />
|-
| ''AMPD2'' CN Gain
|CN gain at 1p13.3 Adenosine Monophosphate Deaminase 2 (''AMPD2'') locus leads to high level expression. <ref name=":14">{{Cite journal|last=Orth|first=Martin F.|last2=Gerke|first2=Julia S.|last3=Knösel|first3=Thomas|last4=Altendorf-Hofmann|first4=Annelore|last5=Musa|first5=Julian|last6=Alba-Rubio|first6=Rebeca|last7=Stein|first7=Stefanie|last8=Hölting|first8=Tilman L. B.|last9=Cidre-Aranaz|first9=Florencia|date=2019-02-15|title=Functional genomics identifies AMPD2 as a new prognostic marker for undifferentiated pleomorphic sarcoma|url=https://pubmed.ncbi.nlm.nih.gov/30267407|journal=International Journal of Cancer|volume=144|issue=4|pages=859–867|doi=10.1002/ijc.31903|issn=1097-0215|pmid=30267407}}</ref>
|Unknown
|P.  Robust prognostic biomarker for worse outcome in UPS. <ref name=":14" />
|No
|
|
* Survival association-testing of ''AMPD2'' gene expression and survival data significantly highly correlated with poor outcome. <ref name=":14" />
* Knockdown of ''AMPD2'' in vitro confirmed inhibited proliferation and ''in vivo'' tumorigenesis. <ref name=":14" />
|-
|-
|<span class="blue-text">EXAMPLE:</span>
|Polyploidy. PGCC
Microsatellite instability - hypermutated
|Chromothripsis and Whole Genome Doubling (WGD) presents as histopathologically identifiable giant nuclei.  Single cell DNA sequencing revealed polyploid giant cancer cells (PGCC). <ref name=":4" /> <ref name=":5" /> <ref name=":12" /> <ref name=":13" />  
|
|Rare-Recurrent
|<span class="blue-text">EXAMPLE:</span> Common (Endometrial carcinoma)
|P.  Evidence of instability associated with high risk and adverse prognosis
|<span class="blue-text">EXAMPLE:</span> P, T
|No
|
|
* Whole genome doubling (WGD), a key macroevolutionary event, associated with instability resulting from chromothripsis and LOH. <ref name=":12" />
* WGD shows variable percentage in some cancers but reported prevalence 90% in undifferentiated sarcomas.
* 5-10 copies of each chromosome in >4% of nuclei correlated with giant nuclei reported in histopathology in a percentage of cells in UPS. <ref name=":4" /> <ref name=":13" />
* Chromothripsis-like events leading to polyploid giant cancer cells (PGCCs), confirm the role of chomothripsis as a key-driver phenomenon. <ref name=":13" />
* Clonal and subclonal multinucleation was demonstrated with twice WGD of 6.2n against a tumor background of 3.3n. <ref name=":13" />
|-
|Structural aberrations, resulting in highly complex karyotypes.
Preferential chromosomal deletions of tumor suppressor genes.
|
|
* Chromosome segmental loss, deletions and chromothripsis lead to formation of rings, dicentric chromosomes, telomere associations and unidentifiable markers.
* Intra-chromosomal deletions preferentially involve loss of key tumor suppressor genes: 17p13.1 (''TP53'') (50%), 13q14.2 (''RB1'')(68%), 9p21 (''CDKN2A)'', 10q23.31 (''PTEN''), 11q22.3 (''ATM''), Xq21.1 (''ATRX''). <ref name=":1" /> <ref name=":3" /> <ref name=":15">{{Cite journal|last=Li|first=George Z.|last2=Okada|first2=Tomoyo|last3=Kim|first3=Young-Mi|last4=Agaram|first4=Narasimhan P.|last5=Sanchez-Vega|first5=Francisco|last6=Shen|first6=Yawei|last7=Tsubokawa|first7=Norifumi|last8=Rios|first8=Jordan|last9=Martin|first9=Axel S.|date=2020-06-15|title=Rb and p53-Deficient Myxofibrosarcoma and Undifferentiated Pleomorphic Sarcoma Require Skp2 for Survival|url=https://pubmed.ncbi.nlm.nih.gov/32161142|journal=Cancer Research|volume=80|issue=12|pages=2461–2471|doi=10.1158/0008-5472.CAN-19-1269|issn=1538-7445|pmc=7299798|pmid=32161142}}</ref>
|Common
|P.  Evidence of instability associated with high risk and adverse prognosis.
|No
|Multiple mechanism, associated with tumor suppressor gene loss including homozygous and heterozygous deletion/alteration, mainly but not exclusively loss-of-function. <ref name=":15" /> <ref name=":16">{{Cite journal|last=Anderson|first=William J.|last2=Doyle|first2=Leona A.|date=2021-04|title=Updates from the 2020 World Health Organization Classification of Soft Tissue and Bone Tumours|url=https://pubmed.ncbi.nlm.nih.gov/33438273|journal=Histopathology|volume=78|issue=5|pages=644–657|doi=10.1111/his.14265|issn=1365-2559|pmid=33438273}}</ref>
|-
|-
|Amplification
|
|
* Genome wide amplification, double minutes (dmin), homogeneously staining regions (hsr) with frequently involving 1q,5p,6q and 12q, 20q. <ref name=":5" />
* Recurrent amplification of regions overlapping oncogenes, significance unknown. 1p36,3q26,4q,7q,8q. <ref name=":3" /> <ref name=":5" /> <ref name=":16" />
* Subset (~10%) amplification of 11q22 (YAP1) and 3p11 (''VGLL3''). <ref name=":5" />
* Amplification of locational subsets including 4q12 (''PDGFRA''), 5q32 (''PDGFRB)'', 7p11.2 (''EGFR''), 4q12 (''KIT''), 4q11-q12 (''KDR'' aka V''EGFR2''). <ref name=":1" />
* Amplification of Interleukin-7 receptor protein (''IL7R''). IL7R often occurring alongside mutated ''KMT2C''. <ref name=":1" /> <ref name=":17">{{Cite journal|last=Remiszewski|first=Piotr|last2=Tysarowski|first2=Andrzej|last3=Seliga|first3=Katarzyna A.|last4=Bobak|first4=Klaudia|last5=Piątkowski|first5=Jakub|last6=Golik|first6=Paweł|last7=Spałek|first7=Mateusz J.|last8=Szumera-Ciećkiewicz|first8=Anna|last9=Wągrodzki|first9=Michał|date=2025-12-19|title=Clinicopathological and genomic profiling in undifferentiated pleomorphic sarcoma: Small series, clear message|url=https://pubmed.ncbi.nlm.nih.gov/41413689|journal=Journal of Applied Genetics|doi=10.1007/s13353-025-01036-5|issn=2190-3883|pmid=41413689}}</ref>
|Recurrent
|P.  Evidence of instability associated with high risk and adverse prognosis
Significance-potentially targetable. <ref name=":1" /> <ref name=":17" />
|No
|
|
* Amplification, key mechanism of instability, often involves over-expression of oncogenes that drive cell cycle and tumor progression. <ref name=":5" /> <ref name=":16" />
* Amplification 12q13-q15 (''MDM2,CDK4'') frequently associated with liposarcoma. UPS demonstrating ''MDM2''-amp, although histologically indistinguishable from dedifferentiated liposarcoma (''DDLPS''), is resulting in reclassification. <ref name=":9" />
* Amplification of 11q22 (''YAP1'')/3p11 (VGLL3), identified in 10% of UPS.  Activating genes involved in cellular survival and proliferation. <ref name=":5" />
* ''IL7R'' associated with gain of function/over-expression alterations noted in many cancer types.  In UPS, ''IL7RA'' amplification was described in 19% along with ''KMT2C'' alterations in 16%. <ref name=":1" /> <ref name=":17" />
|-
|LOH
|Loss of Heterozygosity (LOH), often coupled with whole genome doubling (WGD), significant UPS.  Not withstanding LOH contributing to massive genomic instability, it is not entirely random in UPS. However, pan-cancer solid tumor studies, highlight high frequency of LOH, not specific to soft tissue sarcomas.  
|Genome-wide
|P.  Evidence of instability associated with high risk and adverse prognosis
|No
|Although UPS is characterized by high genomic instability, recurrent regions are described. In particular “double hits” that occur as a result of alteration/LOH noted in key tumor suppressor gene regions such as 13q14-q21 (''RB1''), 17p13.1 (''TP53''), 9p21.1-21.1 (''CDKN2A''), and 10q21.1-q23.2 (''PTEN''). <ref name=":10" /> <ref name=":12" />
|-
|Chromothripsis
|
|
|
* Chromothripsis, describes a phenomenon of catastrophic shattering leading to thousands of clustered rearrangements of one or more chromosomes or chromosomal regions and is a hall mark of high genomic instability.
|
* Chromothripsis is especially prevalent in UPS and similar sarcomas with some studies indicating a frequency >70%. <ref name=":18">{{Cite journal|last=Shoshani|first=Ofer|last2=Brunner|first2=Simon F.|last3=Yaeger|first3=Rona|last4=Ly|first4=Peter|last5=Nechemia-Arbely|first5=Yael|last6=Kim|first6=Dong Hyun|last7=Fang|first7=Rongxin|last8=Castillon|first8=Guillaume A.|last9=Yu|first9=Miao|date=2021-03-04|title=Chromothripsis drives the evolution of gene amplification in cancer|url=https://www.nature.com/articles/s41586-020-03064-z|journal=Nature|language=en|volume=591|issue=7848|pages=137–141|doi=10.1038/s41586-020-03064-z|issn=0028-0836|pmc=7933129|pmid=33361815}}</ref>
|
* Although occurring anywhere in the genome, chromosome “hotspots” demonstrate that chromothripsis is not entirely random. <ref name=":5" /> <ref name=":18" />
* Chromothripsis is a key driver of heterogeneity in the formation of giant nuclei and PGCC in UPS. <ref name=":13" />
|Genome-wide
|P.  Evidence of instability associated with high risk and adverse prognosis
|No
|Chromothripsis “hotspots” appear to highlight a phenomenon of selective pressure for survival, a conclusion based on more frequently observed in the location of tumor suppressor and onco-genes such as:
17p13.1 (''TP53''), 9p21.3 (''CDKN2A/CDKN2B''). 13q14-q21 (''RB1''), 8q24.12-q24.13 (''MYC''), 11q13.3 (''CCND1''). <ref name=":5" /> <ref name=":18" />
|}
|}
==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>
UPS is associated with a number of highly significant, often highly recurrent, key cancer gene aberrations that are used in adverse risk stratification and management but, of themselves, are not exclusive to UPS and therefore are not “diagnostic”.  
{| 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''
|''TP53''


<br />
<br />
|<span class="blue-text">EXAMPLE:</span> Exon 18-21 activating mutations
|
|<span class="blue-text">EXAMPLE:</span> Oncogene
* Deletion, and/or loss of function leading to p53 pathway inactivation, tumor progression and genomic instability.
|<span class="blue-text">EXAMPLE:</span> Common (lung cancer)
* Additionally, ''TP53'' can acquire oncogenic gain of function activity through missense variation. <ref name=":19">{{Cite journal|last=Thoenen|first=Elizabeth|last2=Curl|first2=Amanda|last3=Iwakuma|first3=Tomoo|date=2019-10|title=TP53 in bone and soft tissue sarcomas|url=https://pubmed.ncbi.nlm.nih.gov/31276706|journal=Pharmacology & Therapeutics|volume=202|pages=149–164|doi=10.1016/j.pharmthera.2019.06.010|issn=1879-016X|pmc=6746598|pmid=31276706}}</ref> <ref name=":20">{{Cite journal|last=Chen|first=Xiaohua|last2=Zhang|first2=Taotao|last3=Su|first3=Wei|last4=Dou|first4=Zhihui|last5=Zhao|first5=Dapeng|last6=Jin|first6=Xiaodong|last7=Lei|first7=Huiwen|last8=Wang|first8=Jing|last9=Xie|first9=Xiaodong|date=2022-11-18|title=Mutant p53 in cancer: from molecular mechanism to therapeutic modulation|url=https://pubmed.ncbi.nlm.nih.gov/36400749|journal=Cell Death & Disease|volume=13|issue=11|pages=974|doi=10.1038/s41419-022-05408-1|issn=2041-4889|pmc=9674619|pmid=36400749}}</ref>  
|<span class="blue-text">EXAMPLE:</span> T
|''TP53'' is typically a Tumor Suppressor Gene, but when mutated has oncogenic activity. <ref name=":1" />
|<span class="blue-text">EXAMPLE:</span> Yes (NCCN)
|Common
|<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).
Occurs in 12-20% of UPS. Part of broader highly heterogeneous landscape. Seen in high grade or recurrent UPS cases. <ref name=":3" />
|P.  Adverse prognosis, especially when exhibiting oncogenic activity
Potentially significant-targetable, therapeutic. <ref name=":3" />
|No
|
* ''TP53''’s role as the “guardian of the genome” is preventing cell proliferation, promoting apoptosis and maintaining DNA integrity.
* ''TP53'' is highly prevalent in UPS reported in 33-50% often co-occurring with loss of ''RB1''. <ref name=":3" />
* Typically, loss of ''TP53'' is associated with an adverse prognosis.  A mutant gain of function is also noted and highly associated with advanced malignancies and poor prognosis. 
* Gain of function alterations are potentially significant in the development of targeted therapeutic strategies. <ref name=":19" /> <ref name=":20" />
|-
|-
|<span class="blue-text">EXAMPLE:</span> ''TP53''; Variable LOF mutations
|''RB1''
<br />
<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.
* Deletion/loss of function alterations of ''RB1'' often co-occur with loss of function of ''TP53'' gene.
|-
* Alterations in ''RB1'' lead to dysfunctional cell cycle control by removing cell cycle checkpoints that result in uncontrolled cell proliferation.
|<span class="blue-text">EXAMPLE:</span> ''BRAF''; Activating mutations
|Tumor Supressor Gene
|<span class="blue-text">EXAMPLE:</span> Activating mutations
|Common.
|<span class="blue-text">EXAMPLE:</span> Oncogene
88% of UPS demonstrate alterations in either ''RB1'' or ''TP53'' and co-occurrence of both is seen in 60%. <ref name=":15" />
|<span class="blue-text">EXAMPLE:</span> Common (melanoma)
|P. Adverse prognosis
|<span class="blue-text">EXAMPLE:</span> T
|
|
|
|
* ''RB1'' is highly altered, one of the most frequent genes associated with CN loss in UPS.
* Co-occurrence of loss of both ''RB1'' and ''TP53'' is described as a hallmark of high grade UPS. <ref name=":15" />
* Skp2 is an oncogenic protein that drives cell proliferation via its p1 and p27 binding sites. P27 is a cyclin-dependent kinase that is targeted for degradation by Skp2. <ref name=":15" /> 
* A correlation was found between absent Rb and p53 expression and positive expression of Skp2 illustrating a co-dependency of Rb/p53 on Skp for cellular survival. It is suggested that this features could potentially be exploited for therapeutic strategies. <ref name=":3" /> <ref name=":15" />                               
|-
|-
|''ATRX''
|
|
* Loss and/or loss-of-function alterations of Alpha-Thalassemia/ Mental Retardation Syndrome X-linked gene results in DNA methylation loss and increased transposable element expression.
* ''ATRX'' loss affects it’s role as an epigenetic regulator of chromatin accessibility. (''ATRX'' functions in histone modification and heterochromatin remodeling).
* Additionally, ''ATRX'' deficiency negatively interferes with telomere maintenance through interaction with the ALT telomere length pathway. <ref name=":21">''Denu, Ryan Austin; et al. (2024-05-29). “Impact of ATRX loss on survival and immune microenvironment in multiple sarcoma subtypes” Journal of Clinical Oncology. 42 (16): suppl.11511. doi: 10.1200/JCO.2024.42.16_suppl.11511''</ref>
|Tumor Supressor Gene
|Common.
Variously reported occurring in 20-37% of UPS cases. <ref name=":3" /> <ref name=":22">{{Cite journal|last=Fang|first=Yan|last2=Barrows|first2=Douglas|last3=Dabas|first3=Yakshi|last4=Carroll|first4=Thomas S.|last5=Singer|first5=Sam|last6=Tap|first6=William D.|last7=Nacev|first7=Benjamin A.|date=2024-05-22|title=ATRX guards against aberrant differentiation in mesenchymal progenitor cells|url=https://pubmed.ncbi.nlm.nih.gov/38477352|journal=Nucleic Acids Research|volume=52|issue=9|pages=4950–4968|doi=10.1093/nar/gkae160|issn=1362-4962|pmc=11109985|pmid=38477352}}</ref>
|P.  Adverse prognosis
|No
|
|
* ''ATRX'' loss of function alterations are seen in ~35% of sarcomas including UPS. <ref name=":22" />
* Significantly associated in UPS with worse disease-specific survival (DSS). <ref name=":21" /> <ref name=":22" />
* Aggressive tumor proliferation especially if loss in combination with deletion ''TP53''. <ref name=":21" /> <ref name=":22" />
|-
|''CDKN2A''
|Deletion, including homozygous loss resulting in uncontrolled cell cycle progression.
|Tumor Supressor Gene
|Common
|P.  Adverse prognosis
|No
|
|
* Notably high frequency deletion in common with ''RB1'' deletion/ alterations and alterations in ''MYC'' in USP-B. <ref name=":3" />
* Deletion along loss of ''TP53'' in the absence of ''MDM2'' amplification described in very rare cardiac UPS. <ref name=":3" /> <ref>{{Cite journal|last=Cui|first=Yayan|last2=Han|first2=Liyuan|last3=Shang|first3=Jianfeng|last4=Fang|first4=Wei|last5=Zhao|first5=Meng|last6=Chen|first6=Dong|last7=Liu|first7=Honggang|date=2022-05|title=Primary cardiac undifferentiated pleomorphic sarcoma is associated with TP53 mutation during lack of MDM2 amplification, and targeted sequencing analysis reveals potentially actionable targets|url=https://pubmed.ncbi.nlm.nih.gov/35181378|journal=Human Pathology|volume=123|pages=113–122|doi=10.1016/j.humpath.2022.02.006|issn=1532-8392|pmid=35181378}}</ref>
* In USP-S, loss along with ''TP53, RB1'' and dependency on Skp2. <ref name=":3" />
|-
|''PIK3CA''
|Missense variant within exons 9 or 20, activating the P13K/mTOR pathway.
Co-occurrence described with ''PTEN'' loss or ''KRAS'' alterations. <ref name=":23">{{Cite journal|last=Li|first=Bingcheng|last2=Li|first2=Li|last3=Li|first3=Xiaoying|last4=Wang|first4=Yuanyuan|last5=Xie|first5=Yuwen|last6=Liu|first6=Chunxia|last7=Li|first7=Feng|date=2015|title=Undifferentiated pleomorphic sarcoma with co-existence of KRAS/PIK3CA mutations|url=https://pubmed.ncbi.nlm.nih.gov/26339434|journal=International Journal of Clinical and Experimental Pathology|volume=8|issue=7|pages=8563–8567|issn=1936-2625|pmc=4555762|pmid=26339434}}</ref>
|Oncogene (but not as primary driver)
|Rare
|P. Adverse prognosis.
|No
|
|
* ''PIK3CA'' alterations co-occurs with ''PTEN'' loss reported in 12-18% of soft tissue sarcomas including UPS; part of complex genetic changes. <ref name=":23" />
* ''KRAS'' alterations are rarely reported in soft tissue sarcomas but noted in a small subset of UPS co-occurring with ''PIK3CA'', ''NF1'' alterations, or ''TP53'' loss''.'' <ref name=":23" /> <ref name=":24">{{Cite journal|last=Zhang|first=Peng|last2=Huang|first2=Lingling|last3=Ma|first3=Pengwei|last4=Niu|first4=Xiaoying|date=2022|title=Altered Expressions of NF1 and NF1-Related microRNAs as Biomarkers in the Diagnosis of Undifferentiated Pleomorphic Sarcoma|url=https://pubmed.ncbi.nlm.nih.gov/35559021|journal=Frontiers in Genetics|volume=13|pages=870191|doi=10.3389/fgene.2022.870191|issn=1664-8021|pmc=9086456|pmid=35559021}}</ref>
* Potentially significant as a therapeutic target. <ref name=":3" />
|-
|''KMT2C''
|Loss of function, by truncation/missense variation that reduces or eliminates histone methylation activity
|Acts as a tumor suppressor since loss leads to impaired ''H3K4'' methylation. <ref name=":17" />
|Recurrent
|
|
* Alterations correlate with increased tumor burden.
* Potential targetable significance
|No
|Noted in 16% of UPS, co-occurs with amplification of ''IL7R'' in 19% of UPS. <ref name=":1" /> <ref name=":17" />.
|-
|''NF1''
|Loss of function alteration or deletion
|Acts as a tumor suppressor gene in UPS leading to increased ''RAS'' signaling and tumor development. <ref name=":23" />
|Recurrent
|Potential significance as a-biomarker for UPS..
|No
|
|
|
* NF1-related microRNAs used to quantify mRNA and expression levels were found to be significantly decreased in UPS. <ref name=":24" />
|}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.
* Occasionally, ''NF1'' appears to co-occur with ''RAS'' oncogenes, eg ''KRAS'' variation. <ref name=":24" />
|}
==Epigenomic Alterations==
==Epigenomic Alterations==
Put your text here
UPS is not defined by specific epigenetic changes, however:.  
 
* Epigenetic regulators and miRMA have been identified, and elevated DNA methylation patterns are noted. <ref name=":10" />
* ''DNMT3'' shows increased methylation and methylation of histones H3K4me3 and H3K9 me3 also reported to be elevated. <ref name=":10" />
* Tumor-associated macrophages (TAMs) produce cytokines including TGFβ which could aberrantly activate downstream signaling.  The percentage of TAMs has been found to be a prognostic factor in UPS. In a clinical trial, the percentage of TAMs expressing PD-L1 were more likely to respond to Pembrolizumab and had a better progression-free survival <ref name=":3" />
* Studies indicate UPS has an inflammatory microenvironment, high expression of antigen presentation genes and regulatory T-cell genes.<ref name=":3" />
* Numerous genetic and epigenetic aberrations in UPS have been investigated and are contributing to the development of targeted therapies.<ref name=":3" />
* Hyperactivation of the immune system makes UPS a potential candidate for immunotherapy with checkpoint inhibitors (ICIs). <ref name=":5" />  Although ICIs are not epigenomic alterations, their expression is often regulated by underlying epigenomic alterations. <ref name=":3" /> <ref name=":5" />
 
==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>
UPS is associated with a number of highly significant genetic pathways.  Despite not having a definitive diagnosis, identification of these pathways is leading to potential therapeutic strategies for UPS management Put your text here and fill in the table  
{| 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
|''YAP, LATS1/2''
|<span class="blue-text">EXAMPLE:</span> MAPK signaling
* Large tumor suppressors are core kinases, functionally phosphorylating and inhibiting the effector Yes-Associated Protein. <ref name=":25">{{Cite journal|last=Eisinger-Mathason|first=T. S. Karin|last2=Mucaj|first2=Vera|last3=Biju|first3=Kevin M.|last4=Nakazawa|first4=Michael S.|last5=Gohil|first5=Mercy|last6=Cash|first6=Timothy P.|last7=Yoon|first7=Sam S.|last8=Skuli|first8=Nicolas|last9=Park|first9=Kyung Min|date=2015-06-30|title=Deregulation of the Hippo pathway in soft-tissue sarcoma promotes FOXM1 expression and tumorigenesis|url=https://pubmed.ncbi.nlm.nih.gov/26080399|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=112|issue=26|pages=E3402–3411|doi=10.1073/pnas.1420005112|issn=1091-6490|pmc=4491775|pmid=26080399}}</ref> <ref name=":26">{{Cite journal|last=Plouffe|first=Steven W.|last2=Meng|first2=Zhipeng|last3=Lin|first3=Kimberly C.|last4=Lin|first4=Brian|last5=Hong|first5=Audrey W.|last6=Chun|first6=Justin V.|last7=Guan|first7=Kun-Liang|date=2016-12-01|title=Characterization of Hippo Pathway Components by Gene Inactivation|url=https://pubmed.ncbi.nlm.nih.gov/27912098|journal=Molecular Cell|volume=64|issue=5|pages=993–1008|doi=10.1016/j.molcel.2016.10.034|issn=1097-4164|pmc=5137798|pmid=27912098}}</ref>
|<span class="blue-text">EXAMPLE:</span> Increased cell growth and proliferation
* Nonsense/frameshift alterations disrupt the ''LATS1/2'' function.
* ''YAP/TAZ'' with PDZ-binding motif, transcriptional coactivators. <ref name=":26" />
* ''YAP'' co-regulating with ''FOXM1'' transcription factor, are critical in  sarcomagenesis - specifically fibrosarcoma, liposarcoma and undifferentiated pleomorphic sarcoma. <ref name=":25" />
|Hippo pathway
A highly conserved signaling transduction kinase cascade involving ''MST1/2'' and ''LATS1/2''
|
* Deregulated in >25% of soft tissue sarcomas via stabilization of ''YAP'' expression. <ref name=":25" />
* Disruption affects organ size, cell regeneration and tissue homeostasis via control of cell proliferation and apoptosis.
 
|-
|''YAP1, VGLL3, TEAD''
* Amplification of 11q22 (''YAP1'') and 3p11 Vestigial-like family member 3 (''VGLL3'') are opposing co-expressed factors that compete for the ''TEAD-''binding domain transcription factors.  
* ''VGLL3''-''TEAD'' promotes expression of ''LATS2'', inactivating ''YAP/RAZ''.
* ''YAP1-TEAD'' transcriptional activity also dysregulated by loss of ATRX tumor suppressor gene. <ref name=":25" />
|Hippo pathway
|
* Subset (~10%) of UPS with amplification of ''YAP1'' and ''VGLL3''. potential for therapeutic intervention. <ref name=":1" /> <ref name=":5" />
* Subset of ''ATRX''-deficient UPS potential therapeutic intervention using TAD domain inhibitors. <ref name=":21" /> <ref name=":22" />
|-
|''TP53, ATRX, RB1''
* Dysregulation principally due to upstream/indirect mechanisms (e.g.epigenetic modulation) rather than direct pathway oncogenic mutations.<ref name=":27">''Serrano C, Romagosa C, Hernández-Losa J, Simonetti S, Valverde C, Moliné T, Somoza R, Pérez M, Vélez R, Vergés R, Domínguez R, Carles J, Ramón Y Cajal S. RAS/MAPK pathway hyperactivation determines poor prognosis in undifferentiated pleomorphic sarcomas. Cancer. 2016 Jan 1;122(1):99-107. doi: 10.1002/cncr.29733. Epub 2015 Oct 19. PMID: 26479291.''</ref>   
* ''TP53, ATRX, RB1'' loss indirectly hyperactivates signaling pathways including ''RAS/MAPK''. <ref name=":27" />.
|RAS-MAPK (Ras/Raf/MEK/ERK)
Intracellular signaling cascade that transduce extracellular signals from cell surface receptors to nucleus to activate/regulate/drive gene expression in cycle progression. <ref name=":1" /> <ref name=":3" />
|
* Hyperactivated in >80% of UPS cases. <ref name=":27" />.
* Dysregulation results in unregulated pathway activity, driving tumor growth but also resistance to therapies. <ref name=":3" /> <ref name=":27" />
|-
|-
|<span class="blue-text">EXAMPLE:</span> ''CDKN2A''; Inactivating mutations
|''IGF1R, PTEN''
|<span class="blue-text">EXAMPLE:</span> Cell cycle regulation
* Dysregulation of pathway components demonstrated, but not direct oncogenic alteration in the majority of UPS. <ref name=":3" />.
|<span class="blue-text">EXAMPLE:</span> Unregulated cell division
* Insulin-like Growth Factor 1 Receptor (''1GF1R'') heavily implicated in invasive disruption via co-inhibition with pathway. Significantly reducing cell growth, migration, and adaptive resistance. <ref name=":1" /> <ref name=":3" />
* Loss of ''PTEN'' gene function, as well as other indirect upstream alterations. <ref name=":28">{{Cite journal|last=Glaviano|first=Antonino|last2=Foo|first2=Aaron S. C.|last3=Lam|first3=Hiu Y.|last4=Yap|first4=Kenneth C. H.|last5=Jacot|first5=William|last6=Jones|first6=Robert H.|last7=Eng|first7=Huiyan|last8=Nair|first8=Madhumathy G.|last9=Makvandi|first9=Pooyan|date=2023-08-18|title=PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer|url=https://pubmed.ncbi.nlm.nih.gov/37596643|journal=Molecular Cancer|volume=22|issue=1|pages=138|doi=10.1186/s12943-023-01827-6|issn=1476-4598|pmc=10436543|pmid=37596643}}</ref>
|P13K/mTOR and P13K/AKT,mTOR
Highly conserved signaling pathway cascade acting as a driver, promotes cell growth, survival and cell cycle progression. <ref name=":1" /> <ref name=":3" />
|
* Most frequently activated signaling pathway;  also frequently implicated in therapy resistance. <ref name=":3" /> <ref name=":28" />
* Subset (~20%) of UPS associated with phosphorylation/elevation of downstream marker, PI3K, AKT, and mTOR inhibitors are potential targeted therapeutics. <ref name=":28" />
|-
|-
|<span class="blue-text">EXAMPLE:</span> ''KMT2C'' and ''ARID1A''; Inactivating mutations
|PD-1, PD-L1, PD-L2
|<span class="blue-text">EXAMPLE:</span> Histone modification, chromatin remodeling
 
|<span class="blue-text">EXAMPLE:</span> Abnormal gene expression program
* Programmed cell death protein 1 is key transmembrane inhibitory receptors on immune cells that binds to distinct ligands PD-L1/PD-L2.  Although different expression and affinity, both inhibit T-cell activation. PD-L2 has more restricted expression and higher affinity. <ref name=":3" /> <ref name=":29">{{Cite journal|last=Schöniger|first=Sandra|last2=Jasani|first2=Bharat|date=2022-10-04|title=The PD-1/PD-L1 Pathway: A Perspective on Comparative Immuno-Oncology|url=https://pubmed.ncbi.nlm.nih.gov/36230402|journal=Animals: an open access journal from MDPI|volume=12|issue=19|pages=2661|doi=10.3390/ani12192661|issn=2076-2615|pmc=9558501|pmid=36230402}}</ref>
* Malfunction is pathogenic, involving upregulation of PD-L1 attenuating the activity of immune cells in tumorigenesis. <ref name=":3" /> <ref name=":29" />
|PD-1/PD-L1, PD-1/PD-L2
 
* Fundamental mechanism of immune resistance to provide for immune tolerance and prevent immune-mediated tissue destruction. <ref name=":3" /> <ref name=":5" /> <ref name=":25" />
* When bound to ligands to form PD-L1 and PD-L2, T-cell activation is inhibited, i.e. halting T-cells killing and reducing T-cell proliferation: serves as a checkpoint to prevent auto immunity. <ref name=":3" /> <ref name=":5" /> <ref name=":25" />
|
* Expression is highly elevated in soft tissue sarcomas including UPS
* Anti PD-L1/PD-L2 drugs. e.g. Pembrolizumab and Nivolumab, block pathway to restore antitumor immune response.
* Immune check-point therapy, being evaluated in clinical trials for soft tissue sarcomas including UPS. <ref name=":3" /> <ref name=":5" /> <ref name=":25" />
* UPS is rare in pediatrics, most commonly associated with older (50-70yr) age group, with a proportion being immunocompromised due to an underlying CLL. Within this group, a rare subset, PDS, refers to undifferentiated pleomorphic dermal sarcoma. Factors for consideration during evaluation of potential therapeutic options.
|-
|-
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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>
Because UPS lacks identifiable specific diagnostic characteristics, diagnosis is one of exclusion of other histopathologically comparable sarcomas. Yet UPS exhibits high-grade, high-risk features that demonstrate an aggressive course, high incidence of local recurrence, potential for metastasis and impact overall survival.  Thus any, and all, testing modalities may be considered or used, mainly dependent on institutional genetic knowledgebase and resource availability to eliminate other similar but definable soft tissue sarcomas  
 
'''Karyotyping:''' Highly complex
 
* Chromosome number (aneuploidy, individual chromosome(s) trisomy, pentasomy, hexasomy, aneuploidy
* Structural changes (deletions, telomere association, dicentric chromosomes, unidentifiable markers)
* Amplification (dmins, homologous staining regions)
 
'''Fluorescence in-''situ'' hybridization (FISH):''' Interphase nuclei analysis
 
* Copy number variation (gain or loss) using centromeric or locus specific probes
* Loss of specific gene regions with locus specific probes such as ''TP53, CDKN2A, RB1, ATRX''  
 
'''Chromosome Microarray Analysis:  *'''SNPs
 
* CN variation. whole chromosome and region/gene locus specific gain/loss
* Amplification
* Chromothripsis
* *Loss of Heterozygosity (LOH)
 
'''Next Generation Sequencing (NGS):''' Targeted panels
 
* Actionable genetic alterations including SNVs, indels, CNVs and fusions within specific cancer- or disease-related genes
* Comprehensive tumor profiling, identifying driver/recipient alterations related to prognosis, resistance and therapy
* Some panels detect low level minimal residual disease (MRD)
 
'''Whole Genome Sequencing (WGS):'''
 
* Comprehensive view of genetic variation that, in cancer, identifies specific actionable alterations within tumor cells
* Tailors targeted treatment 
 
'''RNA expression analysis:'''
 
* Active gene functioning of oncogenes and functional alterations leading to defining cancer subtypes
* Tumor heterogeneity, tissue of origin, tumor evolution
* Real-time treatment response, resistance and MRD
 
==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>
Undifferentiated pleomorphic sarcoma of bone UPS-B rarely presents as a primary tumor.
 
The majority of UPS-B occur as a secondary neoplasm to bone avascular necrosis further to history of radiation or prosthetic placement or familial/inherited genetic disorder such as:
 
* Paget disease (alteration in ''SQSTM1'' (50% familial, 10% sporadic). <ref>{{Cite journal|last=Albagha|first=Omar Me|date=2015|title=Genetics of Paget's disease of bone|url=https://pubmed.ncbi.nlm.nih.gov/26587225|journal=BoneKEy Reports|volume=4|pages=756|doi=10.1038/bonekey.2015.125|issn=2047-6396|pmc=4635861|pmid=26587225}}</ref>
* Diaphyseal medullary stenosis (rare AD, alteration in 9p21 ''MTAP''). <ref>{{Cite journal|last=Martignetti|first=J. A.|last2=Desnick|first2=R. J.|last3=Aliprandis|first3=E.|last4=Norton|first4=K. I.|last5=Hardcastle|first5=P.|last6=Nade|first6=S.|last7=Gelb|first7=B. D.|date=1999-03|title=Diaphyseal medullary stenosis with malignant fibrous histiocytoma: a hereditary bone dysplasia/cancer syndrome maps to 9p21-22|url=https://pubmed.ncbi.nlm.nih.gov/10053015|journal=American Journal of Human Genetics|volume=64|issue=3|pages=801–807|doi=10.1086/302297|issn=0002-9297|pmc=1377798|pmid=10053015}}</ref>
 
==Additional Information==
==Additional Information==
Put your text here
The WHO 5<sup>th</sup> Edition 2020 describes Undifferentiated pleomorphic sarcoma (UPS) as a neoplasm of bone UPS-B.
 
Arising from similar '''primitive mesenchymal''' embryonic origin whose '''cells''' lack a specific line of differentiation, there are two presentations of UPS: bone UPS-B and more commonly UPS-S soft tissue.
 
Strong similarity:
 
* Clinical behavior - high grade, highly aggressive course
* Pathology - usually histologically indistinguishable, lacking specific markers,
* Imaging - high grade pleomorphism
* High metastatic potential
 
Comparative analysis highlights differences:
 
* Location - medullary cavity of long bones
* Presentation - often painful, history of bone fractures
* Frequency difference in G1/S checkpoint genes (e.g. homozyogus deletions of ''CDKN2A'', deletions/alterations in ''RB1''). <ref name=":3" /> <ref>{{Cite journal|last=Niini|first=Tarja|last2=Lahti|first2=Leo|last3=Michelacci|first3=Francesca|last4=Ninomiya|first4=Shinsuke|last5=Hattinger|first5=Claudia Maria|last6=Guled|first6=Mohamed|last7=Böhling|first7=Tom|last8=Picci|first8=Piero|last9=Serra|first9=Massimo|date=2011-05|title=Array comparative genomic hybridization reveals frequent alterations of G1/S checkpoint genes in undifferentiated pleomorphic sarcoma of bone|url=https://pubmed.ncbi.nlm.nih.gov/21254299|journal=Genes, Chromosomes & Cancer|volume=50|issue=5|pages=291–306|doi=10.1002/gcc.20851|issn=1098-2264|pmid=21254299}}</ref>
* UPS-B typically younger age of onset*, poorer prognosis than UPS-S. <ref name=":28" /> . 
* Due to the positional tumor microenvironment, at genome level, some molecular characteristics may be different
<nowiki>*</nowiki>Sarcomas are very rare (1%) in adults but more prevalent (15-20%) in pediatrics.  The classification of UPS comprises only 3-8% of sarcomas and is primarily a cancer of advanced age.  Even though UPS-B presents at a younger age, it is extremely rare, especially so in pediatrics. <ref>Saoud C, Gundem G, Vanderbilt CM, Wexler LH, Reed DR, Tap W, Singer S, Villafania LB, Papaemmanouil E, Benhamida J, Bale TA, Antonescu CR. Undifferentiated Pleomorphic Sarcoma in Children and Young Adults: A Comprehensive Clinicopathologic, Genomic, and Epigenetic Comparison With Adult Counterparts. Mod Pathol. 2025 Aug;38(8):100769. doi: 10.1016/j.modpat.2025.100769. Epub 2025 Apr 11. PMID: 40222653; PMCID: PMC12353165.</ref>
 
* An iliac bone/soft tissue mass from a 13yr old male was submitted with a differential diagnosis of OS, MFS, LS, FS, UPHGS.  FISH and microarray analyses demonstrated FISH negative for split signal using SS18, EWSR1 and BCOR probes, but CN gain of x4-10, x3-6 and x2-5 respectively. CMA/SNP demonstrated a highly heterogeneous/complex karyotype including multiple structural and CN gain/loss (including deletion 17p13 TP53), chromothripsis 11 chromosomes/regions (including entire chromosomes 3,17,18,22), LOH 11 chromosomes/regions (including entire chromosome 13) and amplification 6 chromosomes/regions (including 11q22 YAP1 and apoptosis inhibitors BIRC3, BIRC2). <ref>Sutcliffe, Maxine J.; et al. (2022). "Harnessing the power of microarray in the analysis of rarer pediatric sarcomas". Cancer Genetics. 268-269: suppl.1(8). doi.org.10.1016/jcancergen.2022.30.011</ref>37  
 
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==References==
==References==
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<references />
 
==Notes==
==Notes==
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