CNS5:Diffuse leptomeningeal glioneuronal tumour: Difference between revisions

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{{DISPLAYTITLE:Diffuse leptomeningeal glioneuronal tumour}}
[[CNS5:Table_of_Contents|Central Nervous System Tumours (WHO Classification, 5th ed.)]]
{{Under Construction}}
{{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 using various 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 will capture the current genetics/genomics knowledge that evolves more rapidly than books can be updated 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/ HGVS-based nomenclature for variants], 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 to a table, click 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>


__TOC__
<br />
==Primary Author(s)*==
==Primary Author(s)*==
Put your text here<span style="color:#0070C0"> (''<span class="blue-text">EXAMPLE:</span>'' Jane Smith, PhD) </span>
 
 
Laveniya Satgunaseelan, MBBS BMedSc FRCPA, Royal Prince Alfred Hospital
==WHO Classification of Disease==
==WHO Classification of Disease==
<span style="color:#0070C0">(''Instructions: This table’s content will be autogenerated.'')</span>
 
{| class="wikitable"
{| class="wikitable"
!Structure
!Structure
Line 12: Line 17:
|-
|-
|Book
|Book
|
|Central Nervous System Tumours (5th ed.)
|-
|-
|Category
|Category
|
|Gliomas, glioneuronal tumours, and neuronal tumours
|-
|-
|Family
|Family
|
|Gliomas, glioneuronal tumours, and neuronal tumours
|-
|-
|Type
|Type
|
|Glioneuronal and neuronal tumours
|-
|-
|Subtype(s)
|Subtype(s)
|
|Diffuse leptomeningeal glioneuronal tumour
|}
==WHO Essential and Desirable Genetic Diagnostic Criteria==
Put your text here <span style="color:#0070C0">(''Instructions: The table will have the diagnostic criteria from the WHO autopopulated; remove any non-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/login WHO Classification of Tumours].


==Related Terminology==
==Related Terminology==
<span style="color:#0070C0">(''Instructions: The table will have the related terminology from the WHO autopopulated'') </span>
 
{| class="wikitable"
{| class="wikitable"
|+
|Acceptable
|Acceptable
|
|N/A
|-
|-
|Not Recommended
|Not Recommended
|
|Disseminated oligodendroglioma-like leptomeningeal neoplasm; primary leptomeningeal oligodendrogliomatosis
|}
|}
==Chromosomal Rearrangements==
 
Put your text here and fill in the table <span style="color:#0070C0">(''Instruction: Can include references in the table. Do not delete table.'')</span>
==Gene Rearrangements==
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
!Driver Gene!!'''Fusion(s) and Common Partner Genes'''!!'''Molecular Pathogenesis'''!!'''Typical Chromosomal Alteration(s)'''
!Driver Gene!!Fusion(s) and Common Partner Genes!!Molecular Pathogenesis!!Typical Chromosomal Alteration(s)
!'''Prevalence - Common >20%, Recurrent 5-20% or Rare <5% (Disease)'''
!Prevalence -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, No)'''
!Established Clinical Significance Per Guidelines - Yes or No (Source)
!Notes
!Clinical Relevance Details/Other Notes
|-
|-
|<span class="blue-text">EXAMPLE:</span> ''ABL1''||<span class="blue-text">EXAMPLE:</span> ''BCR''::''ABL1''
|''BRAF''
|<span class="blue-text">EXAMPLE:</span> The pathogenic derivative is the der(22) resulting in fusion of 5’ ''BCR'' and  3’''ABL1''.
|''KIAA1549::BRAF''
|<span class="blue-text">EXAMPLE:</span> t(9;22)(q34;q11.2)
|Tandem duplication at chr7q34 - duplication and insertion of ~2Mb  fragment resulting in fusion of 5’ of ''KIAA1549'' with 3’ of ''BRAF''||t(7;7)(q34;q34)
|<span class="blue-text">EXAMPLE:</span> Common (CML)
|Common (72%; WHO)
|<span class="blue-text">EXAMPLE:</span> D,  P
|D, T
|<span class="blue-text">EXAMPLE:</span> Yes
|Yes (WHO)
|<span class="blue-text">EXAMPLE:</span>
|Case report evidence of efficacy of BRAF inhibitors in DLGNT case  harboring ''KIAA1549::BRAF'' fusion<ref>{{Cite journal|last=Valiakhmetova|first=Andge|last2=Papusha|first2=Ludmila|last3=Yasko|first3=Ludmila|last4=Druy|first4=Alexander|last5=Karachunsky|first5=Alexander|last6=Novichkova|first6=Galina|last7=Hwang|first7=Eugene I|last8=Packer|first8=Roger J|date=2020-12-04|title=LGG-26. DIFFUSE LEPTOMENINGEAL GLIONEURONAL TUMOR (DLGNT) IN CHILDREN: DIFFERENT CLINICAL PRESENTATIONS AND OUTCOMES|url=https://academic.oup.com/neuro-oncology/article/22/Supplement_3/iii371/6018960|journal=Neuro-Oncology|language=en|volume=22|issue=Supplement_3|pages=iii371–iii371|doi=10.1093/neuonc/noaa222.408|issn=1522-8517|pmc=7715974}}</ref>
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).
|-
|-
|<span class="blue-text">EXAMPLE:</span> ''CIC''
|''NTRK1/2/3''
|<span class="blue-text">EXAMPLE:</span> ''CIC''::''DUX4''
|Fusion partner not specified (PMID: 29766299)
|<span class="blue-text">EXAMPLE:</span> Typically, the last exon of ''CIC'' is fused to ''DUX4''. The fusion breakpoint in ''CIC'' is typically intra-exonic and removes an inhibitory sequence, upregulating ''PEA3'' genes downstream of ''CIC'' including ''ETV1'', ''ETV4'', and ''ETV5''.
|Downstream activation of MAPK/ERK signalling pathway  in CNS tumors
|<span class="blue-text">EXAMPLE:</span> t(4;19)(q25;q13)
|Not specified
|<span class="blue-text">EXAMPLE:</span> Common  (CIC-rearranged sarcoma)
|Rare
|<span class="blue-text">EXAMPLE:</span> D
|D,T
|
|Yes (WHO)
|<span class="blue-text">EXAMPLE:</span>
|3 cases with ''NTRK1/2/3'' fusions<ref>{{Cite journal|last=Deng|first=Maximilian Y.|last2=Sill|first2=Martin|last3=Chiang|first3=Jason|last4=Schittenhelm|first4=Jens|last5=Ebinger|first5=Martin|last6=Schuhmann|first6=Martin U.|last7=Monoranu|first7=Camelia-Maria|last8=Milde|first8=Till|last9=Wittmann|first9=Andrea|date=2018-08|title=Molecularly defined diffuse leptomeningeal glioneuronal tumor (DLGNT) comprises two subgroups with distinct clinical and genetic features|url=https://pubmed.ncbi.nlm.nih.gov/29766299|journal=Acta Neuropathologica|volume=136|issue=2|pages=239–253|doi=10.1007/s00401-018-1865-4|issn=1432-0533|pmid=29766299}}</ref>
''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).
|-
|''RAF1''
|''TRIM33:RAF1''
|Downstream activation of MAPK/ERK signalling  pathway in CNS tumors
|t(1;3)(p13;p25)
|Rare
|D
|Yes (WHO)
|1 case with ''TRIM33::RAF1'' fusion<ref>{{Cite journal|last=Deng|first=Maximilian Y.|last2=Sill|first2=Martin|last3=Chiang|first3=Jason|last4=Schittenhelm|first4=Jens|last5=Ebinger|first5=Martin|last6=Schuhmann|first6=Martin U.|last7=Monoranu|first7=Camelia-Maria|last8=Milde|first8=Till|last9=Wittmann|first9=Andrea|date=2018-08|title=Molecularly defined diffuse leptomeningeal glioneuronal tumor (DLGNT) comprises two subgroups with distinct clinical and genetic features|url=https://pubmed.ncbi.nlm.nih.gov/29766299|journal=Acta Neuropathologica|volume=136|issue=2|pages=239–253|doi=10.1007/s00401-018-1865-4|issn=1432-0533|pmid=29766299}}</ref>
|-
|-
|<span class="blue-text">EXAMPLE:</span> ''ALK''
| colspan="8" |
|<span class="blue-text">EXAMPLE:</span> ''EML4''::''ALK''
|}




Other fusion partners include ''KIF5B, NPM1, STRN, TFG, TPM3, CLTC, KLC1''
==Individual Region Genomic Gain/Loss/LOH==
|<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.
{| class="wikitable sortable"
|<span class="blue-text">EXAMPLE:</span> N/A
|<span class="blue-text">EXAMPLE:</span> Rare (Lung adenocarcinoma)
|<span class="blue-text">EXAMPLE:</span> T
|
|<span class="blue-text">EXAMPLE:</span>
Both balanced and unbalanced forms are observed by FISH (add references).
|-
|-
|<span class="blue-text">EXAMPLE:</span> ''EGFRvIII''
!Chr #!!Gain, Loss, Amp, LOH!!Minimal Region Cytoband and/or Genomic Coordinates [Genome Build; Size]!!Relevant Gene(s)
|<span class="blue-text">EXAMPLE:</span> N/A
!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T
|<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.
!Established Clinical Significance Per Guidelines - Yes or No (Source)
|<span class="blue-text">EXAMPLE:</span> N/A
!Clinical Relevance Details/Other Notes
|<span class="blue-text">EXAMPLE:</span> Recurrent (IDH-wildtype Glioblastoma)
!
|<span class="blue-text">EXAMPLE:</span> D, P, T
|
|
|-
|
|
|
|
|
|
|
|
|}
==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. Can include references in the table. Can refer to CGC workgroup tables as linked on the homepage if applicable. Do not delete table.'') </span>
{| class="wikitable sortable"
|-
|-
!Chr #!!Gain / Loss / Amp / LOH!!Minimal Region Genomic Coordinates [Genome Build]!!Minimal Region Cytoband
|1p
!Diagnostic Significance (Yes, No or Unknown)
|Loss
!Prognostic Significance (Yes, No or Unknown)
|Complete arm loss (PMIDs: 22941225, 29766299)
!Therapeutic Significance (Yes, No or Unknown)
|Chr1p
!Notes
|Unknown
|D
|Yes (WHO)
|Prevalence common, between 59% (by FISH; PMIDs: 22596013,  17184079, 19486008, 22941225, 25720745) and 100% (by CNV calling from DNA methylation  array data<ref>{{Cite journal|last=Deng|first=Maximilian Y.|last2=Sill|first2=Martin|last3=Chiang|first3=Jason|last4=Schittenhelm|first4=Jens|last5=Ebinger|first5=Martin|last6=Schuhmann|first6=Martin U.|last7=Monoranu|first7=Camelia-Maria|last8=Milde|first8=Till|last9=Wittmann|first9=Andrea|date=2018-08|title=Molecularly defined diffuse leptomeningeal glioneuronal tumor (DLGNT) comprises two subgroups with distinct clinical and genetic features|url=https://pubmed.ncbi.nlm.nih.gov/29766299|journal=Acta Neuropathologica|volume=136|issue=2|pages=239–253|doi=10.1007/s00401-018-1865-4|issn=1432-0533|pmid=29766299}}</ref>).
|-
|-
|<span class="blue-text">EXAMPLE:</span> 7
|1q
|<span class="blue-text">EXAMPLE:</span> Loss
|Gain
|<span class="blue-text">EXAMPLE:</span> chr7:1-159,335,973 [hg38]
|Complete arm gain (PMIDs: 29766299, 30465258)
|<span class="blue-text">EXAMPLE:</span> chr7
|Chr1q
|<span class="blue-text">EXAMPLE:</span> Yes
|Unknown
|<span class="blue-text">EXAMPLE:</span> Yes
|D
|<span class="blue-text">EXAMPLE:</span> No
|Yes (WHO)
|<span class="blue-text">EXAMPLE:</span>
|Prevalence common, between 56% and 63% (by CNV calling from DNA methylation  array data<ref>{{Cite journal|last=Deng|first=Maximilian Y.|last2=Sill|first2=Martin|last3=Chiang|first3=Jason|last4=Schittenhelm|first4=Jens|last5=Ebinger|first5=Martin|last6=Schuhmann|first6=Martin U.|last7=Monoranu|first7=Camelia-Maria|last8=Milde|first8=Till|last9=Wittmann|first9=Andrea|date=2018-08|title=Molecularly defined diffuse leptomeningeal glioneuronal tumor (DLGNT) comprises two subgroups with distinct clinical and genetic features|url=https://pubmed.ncbi.nlm.nih.gov/29766299|journal=Acta Neuropathologica|volume=136|issue=2|pages=239–253|doi=10.1007/s00401-018-1865-4|issn=1432-0533|pmid=29766299}}</ref><ref>{{Cite journal|last=Chiang|first=Jason|last2=Dalton|first2=James|last3=Upadhyaya|first3=Santhosh A.|last4=Patay|first4=Zoltán|last5=Qaddoumi|first5=Ibrahim|last6=Li|first6=Xiaoyu|last7=Segura|first7=Annette D.|last8=Sharma|first8=Suash|last9=Ismail|first9=Azzam|date=2019-01|title=Chromosome arm 1q gain is an adverse prognostic factor in localized and diffuse leptomeningeal glioneuronal tumors with BRAF gene fusion and 1p deletion|url=https://pubmed.ncbi.nlm.nih.gov/30465258|journal=Acta Neuropathologica|volume=137|issue=1|pages=179–181|doi=10.1007/s00401-018-1940-x|issn=1432-0533|pmid=30465258}}</ref>)
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 reference).
 
Found in all cases of DLGNT methylation class (MC)-2<ref>{{Cite journal|last=Deng|first=Maximilian Y.|last2=Sill|first2=Martin|last3=Chiang|first3=Jason|last4=Schittenhelm|first4=Jens|last5=Ebinger|first5=Martin|last6=Schuhmann|first6=Martin U.|last7=Monoranu|first7=Camelia-Maria|last8=Milde|first8=Till|last9=Wittmann|first9=Andrea|date=2018-08|title=Molecularly defined diffuse leptomeningeal glioneuronal tumor (DLGNT) comprises two subgroups with distinct clinical and genetic features|url=https://pubmed.ncbi.nlm.nih.gov/29766299|journal=Acta Neuropathologica|volume=136|issue=2|pages=239–253|doi=10.1007/s00401-018-1865-4|issn=1432-0533|pmid=29766299}}</ref>
|-
|-
|<span class="blue-text">EXAMPLE:</span> 8
| colspan="8" |
|<span class="blue-text">EXAMPLE:</span> Gain
|<span class="blue-text">EXAMPLE:</span> chr8:1-145,138,636 [hg38]
|<span class="blue-text">EXAMPLE:</span> chr8
|<span class="blue-text">EXAMPLE:</span> No
|<span class="blue-text">EXAMPLE:</span> No
|<span class="blue-text">EXAMPLE:</span> No
|<span class="blue-text">EXAMPLE:</span>
Common recurrent secondary finding for t(8;21) (add reference).
|}
|}
==Characteristic Chromosomal or Other Global Mutational Patterns==
==Characteristic Chromosomal or Other Global Mutational Patterns==
Put your text here <span style="color:#0070C0">(''EXAMPLE PATTERNS: 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. Do not delete table.'')</span>
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
!Chromosomal Pattern
!Chromosomal Pattern
!'''Molecular Pathogenesis'''
!Molecular Pathogenesis
!'''Prevalence -Common >20%, Recurrent 5-20% or Rare <5% (Disease)'''
!Prevalence -  
!'''Diagnostic, Prognostic, and Therapeutic Significance (D, P, T)'''
Common >20%, Recurrent 5-20% or Rare <5% (Disease)
!'''Established Clinical Significance Per Guidelines (Yes, No)'''
!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T
!Notes
!Established Clinical Significance Per Guidelines - Yes or No (Source)
|-
!Clinical Relevance Details/Other Notes
|<span class="blue-text">EXAMPLE:</span> Co-deletion of 1p and 18q
|<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).
|<span class="blue-text">EXAMPLE:</span> Common (Oligodendroglioma)
|<span class="blue-text">EXAMPLE:</span> D, P
|
|
|-
|-
|<span class="blue-text">EXAMPLE:</span> Microsatellite instability - hypermutated
|Co-deletion of  1p and 19q
|
|Unknown
|<span class="blue-text">EXAMPLE:</span> Common (Endometrial carcinoma)
|Recurrent to common
|<span class="blue-text">EXAMPLE:</span> P, T
|D
|
|Yes  (WHO)
|
|Prevalence  between 18% and 33%<ref>{{Cite journal|last=Rodriguez|first=Fausto J.|last2=Schniederjan|first2=Matthew J.|last3=Nicolaides|first3=Theo|last4=Tihan|first4=Tarik|last5=Burger|first5=Peter C.|last6=Perry|first6=Arie|date=2015-04|title=High rate of concurrent BRAF-KIAA1549 gene fusion and 1p deletion in disseminated oligodendroglioma-like leptomeningeal neoplasms (DOLN)|url=https://pubmed.ncbi.nlm.nih.gov/25720745|journal=Acta Neuropathologica|volume=129|issue=4|pages=609–610|doi=10.1007/s00401-015-1400-9|issn=1432-0533|pmc=4696044|pmid=25720745}}</ref><ref>{{Cite journal|last=Deng|first=Maximilian Y.|last2=Sill|first2=Martin|last3=Chiang|first3=Jason|last4=Schittenhelm|first4=Jens|last5=Ebinger|first5=Martin|last6=Schuhmann|first6=Martin U.|last7=Monoranu|first7=Camelia-Maria|last8=Milde|first8=Till|last9=Wittmann|first9=Andrea|date=2018-08|title=Molecularly defined diffuse leptomeningeal glioneuronal tumor (DLGNT) comprises two subgroups with distinct clinical and genetic features|url=https://pubmed.ncbi.nlm.nih.gov/29766299|journal=Acta Neuropathologica|volume=136|issue=2|pages=239–253|doi=10.1007/s00401-018-1865-4|issn=1432-0533|pmid=29766299}}</ref>
|-
|-
|
| colspan="6" |
|
|
|
|
|
|}
|}
==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. Can include references 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. Can include concomitant and mutually exclusive mutations in the notes section. Do not delete table.'') </span>
==Gene Mutations (SNV/INDEL)==
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
!Gene!!'''Genetic Alteration'''!!'''Tumor Suppressor Gene (TSG)/Oncogene/Other'''!!'''Prevalence - Common >20%, Recurrent 5-20% or Rare <5% (Disease)'''!!'''Diagnostic, Prognostic, and Therapeutic Significance (D, P, T)'''
!Gene!!Genetic Alteration!!Tumor Suppressor Gene, Oncogene, Other!!Prevalence -
!'''Established Clinical Significance Per Guidelines (Yes, No)'''
Common >20%, Recurrent 5-20% or Rare <5% (Disease)
!Notes
!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T  
!Established Clinical Significance Per Guidelines - Yes or No (Source)
!Clinical Relevance Details/Other Notes
|-
|-
|<span class="blue-text">EXAMPLE:</span> ''TP53''
|''BRAF''
|p.V600E (activating mutation)
|Oncogene
<br />
|Rare
|D, T
|Yes (WHO, NCCN)
|Rare reports  of DLGNTs harboring ''BRAF'' p.V600E mutations\<ref>{{Cite journal|last=Dodgshun|first=Andrew J.|last2=SantaCruz|first2=Nadine|last3=Hwang|first3=Jaeho|last4=Ramkissoon|first4=Shakti H.|last5=Malkin|first5=Hayley|last6=Bergthold|first6=Guillaume|last7=Manley|first7=Peter|last8=Chi|first8=Susan|last9=MacGregor|first9=Duncan|date=2016-06|title=Disseminated glioneuronal tumors occurring in childhood: treatment outcomes and BRAF alterations including V600E mutation|url=https://pubmed.ncbi.nlm.nih.gov/26994902|journal=Journal of Neuro-Oncology|volume=128|issue=2|pages=293–302|doi=10.1007/s11060-016-2109-x|issn=1573-7373|pmid=26994902}}</ref><ref>{{Cite journal|last=Appay|first=Romain|last2=Pages|first2=Mélanie|last3=Colin|first3=Carole|last4=Jones|first4=David T. W.|last5=Varlet|first5=Pascale|last6=Figarella-Branger|first6=Dominique|date=2020-06-30|title=Diffuse leptomeningeal glioneuronal tumor: a double misnomer? A report of two cases|url=https://pubmed.ncbi.nlm.nih.gov/32605662|journal=Acta Neuropathologica Communications|volume=8|issue=1|pages=95|doi=10.1186/s40478-020-00978-7|issn=2051-5960|pmc=7325675|pmid=32605662}}</ref>, including abstracts detailing efficacy of BRAF inhibtors in ''BRAF''-mutant  DLGNT<ref>{{Cite journal|last=Valiakhmetova|first=Andge|last2=Papusha|first2=Ludmila|last3=Yasko|first3=Ludmila|last4=Druy|first4=Alexander|last5=Karachunsky|first5=Alexander|last6=Novichkova|first6=Galina|last7=Hwang|first7=Eugene I|last8=Packer|first8=Roger J|date=2020-12-04|title=LGG-26. DIFFUSE LEPTOMENINGEAL GLIONEURONAL TUMOR (DLGNT) IN CHILDREN: DIFFERENT CLINICAL PRESENTATIONS AND OUTCOMES|url=https://academic.oup.com/neuro-oncology/article/22/Supplement_3/iii371/6018960|journal=Neuro-Oncology|language=en|volume=22|issue=Supplement_3|pages=iii371–iii371|doi=10.1093/neuonc/noaa222.408|issn=1522-8517|pmc=7715974}}</ref><ref>{{Cite journal|last=Aung|first=Le Le|date=2020-12-01|title=HGG-06. REMARKABLE RESPONSE TO BRAF INHIBITOR IN AN INFANT WITH DISSEMINATED DIFFUSE LEPTOMENINGEAL GLIONEURONAL TUMOR (DLGNT)|url=https://doi.org/10.1093/neuonc/noaa222.297|journal=Neuro-Oncology|volume=22|issue=Supplement_3|pages=iii345|doi=10.1093/neuonc/noaa222.297|issn=1522-8517|pmc=7715114}}</ref>)
<br />
<br />
|<span class="blue-text">EXAMPLE:</span> Variable LOF mutations
|<span class="blue-text">EXAMPLE:</span> TSG
|<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>
|''PIK3CA''
 
|p.E545A
''EGFR''
|Oncogene
|<span class="blue-text">EXAMPLE:</span> Exon 18-21 activating mutations
<br />
|<span class="blue-text">EXAMPLE:</span> Oncogene
|Rare
|<span class="blue-text">EXAMPLE:</span> Common (lung cancer)
|Nil
|<span class="blue-text">EXAMPLE:</span> T
|No
|
|Case report of co-occurring ''PIK3CA'' variant<ref>{{Cite journal|last=Appay|first=Romain|last2=Pages|first2=Mélanie|last3=Colin|first3=Carole|last4=Jones|first4=David T. W.|last5=Varlet|first5=Pascale|last6=Figarella-Branger|first6=Dominique|date=2020-06-30|title=Diffuse leptomeningeal glioneuronal tumor: a double misnomer? A report of two cases|url=https://pubmed.ncbi.nlm.nih.gov/32605662|journal=Acta Neuropathologica Communications|volume=8|issue=1|pages=95|doi=10.1186/s40478-020-00978-7|issn=2051-5960|pmc=7325675|pmid=32605662}}</ref>
|<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.
|-
|-
|<span class="blue-text">EXAMPLE:</span>
|''TERT''
 
|Activating mutations in promoter region
''BRAF''
|Oncogene
|<span class="blue-text">EXAMPLE:</span> Activating mutations
|Rare
|<span class="blue-text">EXAMPLE:</span> Oncogene
|Nil
|<span class="blue-text">EXAMPLE:</span> Common (melanoma)
|No
|<span class="blue-text">EXAMPLE:</span> T
|Point mutations described include C228T and  C228A<ref>{{Cite journal|last=Deng|first=Maximilian Y.|last2=Sill|first2=Martin|last3=Chiang|first3=Jason|last4=Schittenhelm|first4=Jens|last5=Ebinger|first5=Martin|last6=Schuhmann|first6=Martin U.|last7=Monoranu|first7=Camelia-Maria|last8=Milde|first8=Till|last9=Wittmann|first9=Andrea|date=2018-08|title=Molecularly defined diffuse leptomeningeal glioneuronal tumor (DLGNT) comprises two subgroups with distinct clinical and genetic features|url=https://pubmed.ncbi.nlm.nih.gov/29766299|journal=Acta Neuropathologica|volume=136|issue=2|pages=239–253|doi=10.1007/s00401-018-1865-4|issn=1432-0533|pmid=29766299}}</ref>
|
|
|-
|-
|
|
Line 215: Line 178:
|
|
|
|
|}Note: A more extensive list of mutations can be found in cBioportal (https://www.cbioportal.org/), COSMIC (https://cancer.sanger.ac.uk/cosmic), ICGC (https://dcc.icgc.org/) 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
 
On methylation profiling of a large series of DLGNTs, two methylation classes have been defined - DLGNT methylation class (MC)-1 and DLGNT methylation class (MC)-2. All cases of DLGNT-MC-2 exhibited gain of chr1q, with 1p/19q codeletion more common in DLGNT-MC-1<ref>{{Cite journal|last=Deng|first=Maximilian Y.|last2=Sill|first2=Martin|last3=Chiang|first3=Jason|last4=Schittenhelm|first4=Jens|last5=Ebinger|first5=Martin|last6=Schuhmann|first6=Martin U.|last7=Monoranu|first7=Camelia-Maria|last8=Milde|first8=Till|last9=Wittmann|first9=Andrea|date=2018-08|title=Molecularly defined diffuse leptomeningeal glioneuronal tumor (DLGNT) comprises two subgroups with distinct clinical and genetic features|url=https://pubmed.ncbi.nlm.nih.gov/29766299|journal=Acta Neuropathologica|volume=136|issue=2|pages=239–253|doi=10.1007/s00401-018-1865-4|issn=1432-0533|pmid=29766299}}</ref>.
==Genes and Main Pathways Involved==
==Genes and Main Pathways Involved==
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Can include references in the table. Do not delete table.'')</span>
{| 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
|''BRAF,  FGFR1''; Activating mutations
|<span class="blue-text">EXAMPLE:</span> MAPK signaling
|MAPK signaling
|<span class="blue-text">EXAMPLE:</span> Increased cell growth and proliferation
|Increased cell growth and proliferation
|-
|-
|<span class="blue-text">EXAMPLE:</span> ''CDKN2A''; Inactivating mutations
|''FGFR1,  PIK3CA''; Activating mutations
|<span class="blue-text">EXAMPLE:</span> Cell cycle regulation
|PI3K–Akt  signaling pathway
|<span class="blue-text">EXAMPLE:</span> Unregulated cell division
|Increased  cell growth, proliferation, survival and motility
|-
|-
|<span class="blue-text">EXAMPLE:</span> ''KMT2C'' and ''ARID1A''; Inactivating mutations
| colspan="3" |
|<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 detection via targeted NGS (RNA or DNA panels) or FISH
 
-         Chromosomal alterations can be detected by FISH, SNP array, methylation array or NGS
 
-         Methylation profiling via CNS tumor classifiers for DLGNT-MCs
 
==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>
 
==Additional Information==
One case of DLGNT in which a germline mutation in ''RAF1'' has been documented<ref>{{Cite journal|last=Dodgshun|first=Andrew J.|last2=SantaCruz|first2=Nadine|last3=Hwang|first3=Jaeho|last4=Ramkissoon|first4=Shakti H.|last5=Malkin|first5=Hayley|last6=Bergthold|first6=Guillaume|last7=Manley|first7=Peter|last8=Chi|first8=Susan|last9=MacGregor|first9=Duncan|date=2016-06|title=Disseminated glioneuronal tumors occurring in childhood: treatment outcomes and BRAF alterations including V600E mutation|url=https://pubmed.ncbi.nlm.nih.gov/26994902|journal=Journal of Neuro-Oncology|volume=128|issue=2|pages=293–302|doi=10.1007/s11060-016-2109-x|issn=1573-7373|pmid=26994902}}</ref>.  
Put your text here
 
==Links==
<br />
(use the "Link" icon that looks like two overlapping circles at the top of the 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 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>
==References==
==References==
(use the "Cite" icon at the top of the page) <span style="color:#0070C0">(''Instructions: Add each reference into the text above by clicking on where you want to insert the reference, selecting the “Cite” icon at the top of the page, and using the “Automatic” tab option to search such as 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>
[[Category:CNS5]]
==Notes==
[[Category:DISEASE]]
<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|''Associate Editor'']] 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.
[[Category:Diseases D]]
 
<references />
Prior Author(s):

Latest revision as of 22:00, 7 July 2025


Central Nervous System Tumours (WHO Classification, 5th ed.)


Primary Author(s)*

Laveniya Satgunaseelan, MBBS BMedSc FRCPA, Royal Prince Alfred Hospital

WHO Classification of Disease

Structure Disease
Book Central Nervous System Tumours (5th ed.)
Category Gliomas, glioneuronal tumours, and neuronal tumours
Family Gliomas, glioneuronal tumours, and neuronal tumours
Type Glioneuronal and neuronal tumours
Subtype(s) Diffuse leptomeningeal glioneuronal tumour

Related Terminology

Acceptable N/A
Not Recommended Disseminated oligodendroglioma-like leptomeningeal neoplasm; primary leptomeningeal oligodendrogliomatosis

Gene Rearrangements

Driver Gene Fusion(s) and Common Partner Genes Molecular Pathogenesis Typical Chromosomal Alteration(s) Prevalence -Common >20%, Recurrent 5-20% or Rare <5% (Disease) Diagnostic, Prognostic, and Therapeutic Significance - D, P, T Established Clinical Significance Per Guidelines - Yes or No (Source) Clinical Relevance Details/Other Notes
BRAF KIAA1549::BRAF Tandem duplication at chr7q34 - duplication and insertion of ~2Mb fragment resulting in fusion of 5’ of KIAA1549 with 3’ of BRAF t(7;7)(q34;q34) Common (72%; WHO) D, T Yes (WHO) Case report evidence of efficacy of BRAF inhibitors in DLGNT case harboring KIAA1549::BRAF fusion[1]
NTRK1/2/3 Fusion partner not specified (PMID: 29766299) Downstream activation of MAPK/ERK signalling pathway in CNS tumors Not specified Rare D,T Yes (WHO) 3 cases with NTRK1/2/3 fusions[2]
RAF1 TRIM33:RAF1 Downstream activation of MAPK/ERK signalling pathway in CNS tumors t(1;3)(p13;p25) Rare D Yes (WHO) 1 case with TRIM33::RAF1 fusion[3]


Individual Region Genomic Gain/Loss/LOH

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 Established Clinical Significance Per Guidelines - Yes or No (Source) Clinical Relevance Details/Other Notes
1p Loss Complete arm loss (PMIDs: 22941225, 29766299) Chr1p Unknown D Yes (WHO) Prevalence common, between 59% (by FISH; PMIDs: 22596013, 17184079, 19486008, 22941225, 25720745) and 100% (by CNV calling from DNA methylation array data[4]).
1q Gain Complete arm gain (PMIDs: 29766299, 30465258) Chr1q Unknown D Yes (WHO) Prevalence common, between 56% and 63% (by CNV calling from DNA methylation array data[5][6])

Found in all cases of DLGNT methylation class (MC)-2[7]

Characteristic Chromosomal or Other Global Mutational Patterns

Chromosomal Pattern Molecular Pathogenesis Prevalence -

Common >20%, Recurrent 5-20% or Rare <5% (Disease)

Diagnostic, Prognostic, and Therapeutic Significance - D, P, T Established Clinical Significance Per Guidelines - Yes or No (Source) Clinical Relevance Details/Other Notes
Co-deletion of 1p and 19q Unknown Recurrent to common D Yes (WHO) Prevalence between 18% and 33%[8][9]

Gene Mutations (SNV/INDEL)

Gene Genetic Alteration Tumor Suppressor Gene, Oncogene, Other Prevalence -

Common >20%, Recurrent 5-20% or Rare <5% (Disease)

Diagnostic, Prognostic, and Therapeutic Significance - D, P, T   Established Clinical Significance Per Guidelines - Yes or No (Source) Clinical Relevance Details/Other Notes
BRAF p.V600E (activating mutation) Oncogene


Rare D, T Yes (WHO, NCCN) Rare reports of DLGNTs harboring BRAF p.V600E mutations\[10][11], including abstracts detailing efficacy of BRAF inhibtors in BRAF-mutant DLGNT[12][13])


PIK3CA p.E545A Oncogene


Rare Nil No Case report of co-occurring PIK3CA variant[14]
TERT Activating mutations in promoter region Oncogene Rare Nil No Point mutations described include C228T and C228A[15]

Note: A more extensive list of mutations can be found in cBioportal, COSMIC, and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.

Epigenomic Alterations

On methylation profiling of a large series of DLGNTs, two methylation classes have been defined - DLGNT methylation class (MC)-1 and DLGNT methylation class (MC)-2. All cases of DLGNT-MC-2 exhibited gain of chr1q, with 1p/19q codeletion more common in DLGNT-MC-1[16].

Genes and Main Pathways Involved

Gene; Genetic Alteration Pathway Pathophysiologic Outcome
BRAF, FGFR1; Activating mutations MAPK signaling Increased cell growth and proliferation
FGFR1, PIK3CA; Activating mutations PI3K–Akt signaling pathway Increased cell growth, proliferation, survival and motility

Genetic Diagnostic Testing Methods

-         Fusion detection via targeted NGS (RNA or DNA panels) or FISH

-         Chromosomal alterations can be detected by FISH, SNP array, methylation array or NGS

-         Methylation profiling via CNS tumor classifiers for DLGNT-MCs

Familial Forms

One case of DLGNT in which a germline mutation in RAF1 has been documented[17].


References

  1. ↑ Valiakhmetova, Andge; et al. (2020-12-04). "LGG-26. DIFFUSE LEPTOMENINGEAL GLIONEURONAL TUMOR (DLGNT) IN CHILDREN: DIFFERENT CLINICAL PRESENTATIONS AND OUTCOMES". Neuro-Oncology. 22 (Supplement_3): iii371–iii371. doi:10.1093/neuonc/noaa222.408. ISSN 1522-8517. PMC 7715974 Check |pmc= value (help).
  2. ↑ Deng, Maximilian Y.; et al. (2018-08). "Molecularly defined diffuse leptomeningeal glioneuronal tumor (DLGNT) comprises two subgroups with distinct clinical and genetic features". Acta Neuropathologica. 136 (2): 239–253. doi:10.1007/s00401-018-1865-4. ISSN 1432-0533. PMID 29766299. Check date values in: |date= (help)
  3. ↑ Deng, Maximilian Y.; et al. (2018-08). "Molecularly defined diffuse leptomeningeal glioneuronal tumor (DLGNT) comprises two subgroups with distinct clinical and genetic features". Acta Neuropathologica. 136 (2): 239–253. doi:10.1007/s00401-018-1865-4. ISSN 1432-0533. PMID 29766299. Check date values in: |date= (help)
  4. ↑ Deng, Maximilian Y.; et al. (2018-08). "Molecularly defined diffuse leptomeningeal glioneuronal tumor (DLGNT) comprises two subgroups with distinct clinical and genetic features". Acta Neuropathologica. 136 (2): 239–253. doi:10.1007/s00401-018-1865-4. ISSN 1432-0533. PMID 29766299. Check date values in: |date= (help)
  5. ↑ Deng, Maximilian Y.; et al. (2018-08). "Molecularly defined diffuse leptomeningeal glioneuronal tumor (DLGNT) comprises two subgroups with distinct clinical and genetic features". Acta Neuropathologica. 136 (2): 239–253. doi:10.1007/s00401-018-1865-4. ISSN 1432-0533. PMID 29766299. Check date values in: |date= (help)
  6. ↑ Chiang, Jason; et al. (2019-01). "Chromosome arm 1q gain is an adverse prognostic factor in localized and diffuse leptomeningeal glioneuronal tumors with BRAF gene fusion and 1p deletion". Acta Neuropathologica. 137 (1): 179–181. doi:10.1007/s00401-018-1940-x. ISSN 1432-0533. PMID 30465258. Check date values in: |date= (help)
  7. ↑ Deng, Maximilian Y.; et al. (2018-08). "Molecularly defined diffuse leptomeningeal glioneuronal tumor (DLGNT) comprises two subgroups with distinct clinical and genetic features". Acta Neuropathologica. 136 (2): 239–253. doi:10.1007/s00401-018-1865-4. ISSN 1432-0533. PMID 29766299. Check date values in: |date= (help)
  8. ↑ Rodriguez, Fausto J.; et al. (2015-04). "High rate of concurrent BRAF-KIAA1549 gene fusion and 1p deletion in disseminated oligodendroglioma-like leptomeningeal neoplasms (DOLN)". Acta Neuropathologica. 129 (4): 609–610. doi:10.1007/s00401-015-1400-9. ISSN 1432-0533. PMC 4696044. PMID 25720745. Check date values in: |date= (help)
  9. ↑ Deng, Maximilian Y.; et al. (2018-08). "Molecularly defined diffuse leptomeningeal glioneuronal tumor (DLGNT) comprises two subgroups with distinct clinical and genetic features". Acta Neuropathologica. 136 (2): 239–253. doi:10.1007/s00401-018-1865-4. ISSN 1432-0533. PMID 29766299. Check date values in: |date= (help)
  10. ↑ Dodgshun, Andrew J.; et al. (2016-06). "Disseminated glioneuronal tumors occurring in childhood: treatment outcomes and BRAF alterations including V600E mutation". Journal of Neuro-Oncology. 128 (2): 293–302. doi:10.1007/s11060-016-2109-x. ISSN 1573-7373. PMID 26994902. Check date values in: |date= (help)
  11. ↑ Appay, Romain; et al. (2020-06-30). "Diffuse leptomeningeal glioneuronal tumor: a double misnomer? A report of two cases". Acta Neuropathologica Communications. 8 (1): 95. doi:10.1186/s40478-020-00978-7. ISSN 2051-5960. PMC 7325675 Check |pmc= value (help). PMID 32605662 Check |pmid= value (help).
  12. ↑ Valiakhmetova, Andge; et al. (2020-12-04). "LGG-26. DIFFUSE LEPTOMENINGEAL GLIONEURONAL TUMOR (DLGNT) IN CHILDREN: DIFFERENT CLINICAL PRESENTATIONS AND OUTCOMES". Neuro-Oncology. 22 (Supplement_3): iii371–iii371. doi:10.1093/neuonc/noaa222.408. ISSN 1522-8517. PMC 7715974 Check |pmc= value (help).
  13. ↑ Aung, Le Le (2020-12-01). "HGG-06. REMARKABLE RESPONSE TO BRAF INHIBITOR IN AN INFANT WITH DISSEMINATED DIFFUSE LEPTOMENINGEAL GLIONEURONAL TUMOR (DLGNT)". Neuro-Oncology. 22 (Supplement_3): iii345. doi:10.1093/neuonc/noaa222.297. ISSN 1522-8517. PMC 7715114 Check |pmc= value (help).
  14. ↑ Appay, Romain; et al. (2020-06-30). "Diffuse leptomeningeal glioneuronal tumor: a double misnomer? A report of two cases". Acta Neuropathologica Communications. 8 (1): 95. doi:10.1186/s40478-020-00978-7. ISSN 2051-5960. PMC 7325675 Check |pmc= value (help). PMID 32605662 Check |pmid= value (help).
  15. ↑ Deng, Maximilian Y.; et al. (2018-08). "Molecularly defined diffuse leptomeningeal glioneuronal tumor (DLGNT) comprises two subgroups with distinct clinical and genetic features". Acta Neuropathologica. 136 (2): 239–253. doi:10.1007/s00401-018-1865-4. ISSN 1432-0533. PMID 29766299. Check date values in: |date= (help)
  16. ↑ Deng, Maximilian Y.; et al. (2018-08). "Molecularly defined diffuse leptomeningeal glioneuronal tumor (DLGNT) comprises two subgroups with distinct clinical and genetic features". Acta Neuropathologica. 136 (2): 239–253. doi:10.1007/s00401-018-1865-4. ISSN 1432-0533. PMID 29766299. Check date values in: |date= (help)
  17. ↑ Dodgshun, Andrew J.; et al. (2016-06). "Disseminated glioneuronal tumors occurring in childhood: treatment outcomes and BRAF alterations including V600E mutation". Journal of Neuro-Oncology. 128 (2): 293–302. doi:10.1007/s11060-016-2109-x. ISSN 1573-7373. PMID 26994902. Check date values in: |date= (help)
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