Compendium of Cancer Genome Aberrations

HAEM5:Primary cutaneous gamma/delta T-cell lymphoma: Difference between revisions

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{{DISPLAYTITLE:Primary cutaneous gamma/delta T-cell lymphoma}}
[[HAEM5:Table_of_Contents|Haematolymphoid Tumours (WHO Classification, 5th ed.)]]
[[HAEM5:Table_of_Contents|Haematolymphoid 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)*==


 
Mahzad Azimpouran, MD; Sumire Kitahara, MD; Cedars-Sinai, Los Angeles, CA
Put your text here<span style="color:#0070C0"> (''<span class="blue-text">EXAMPLE:</span>'' Jane Smith, PhD) </span>
==WHO Classification of Disease==
==WHO Classification of Disease==


Line 32: Line 26:
|}
|}


==WHO Essential and Desirable Genetic Diagnostic Criteria==
<span style="color:#0070C0">(''Instructions: The table will have the diagnostic criteria from the WHO book <u>autocompleted</u>; remove any <u>non</u>-genetics related criteria. If applicable, add text about other classification'' ''systems that define this entity and specify how the genetics-related criteria differ.'')</span>
{| class="wikitable"
|+
|WHO Essential Criteria (Genetics)*
|
|-
|WHO Desirable Criteria (Genetics)*
|
|-
|Other Classification
|
|}
<nowiki>*</nowiki>Note: These are only the genetic/genomic criteria. Additional diagnostic criteria can be found in the [https://tumourclassification.iarc.who.int/home <u>WHO Classification of Tumours</u>].
==Related Terminology==
==Related Terminology==
<span style="color:#0070C0">(''Instructions: The table will have the related terminology from the WHO <u>autocompleted</u>.)''</span>
 
{| class="wikitable"
{| class="wikitable"
|+
|Acceptable
|Acceptable
|
|N/A
|-
|-
|Not Recommended
|Not Recommended
|
|N/A
|}
|}


==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>
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
Line 67: Line 45:
!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)
|'''Arm‑level chromosomal alterations (e.g., 9p,  18q deletions; 1q, 7q,15q gains)'''
|<span class="blue-text">EXAMPLE:</span> Common (CML)
|—
|<span class="blue-text">EXAMPLE:</span> D, P, T
|Copy number loss or gain → altered gene dosage of tumour  suppressors/oncogenes
|<span class="blue-text">EXAMPLE:</span> Yes (WHO, NCCN)
|Other / chromosomal alteration
|<span class="blue-text">EXAMPLE:</span>
|Recurrent (5‑20%) (9p del ~22%, 18q del ~22%; 1q/7q/15q  gains ~33‑39%)  
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).
|D / P
|No
|These structural changes suggest genomic instability and  aggressive biology; may help risk stratification though not diagnostic per se<ref name=":0">{{Cite journal|last=Daniels|first=Jay|last2=Doukas|first2=Peter G.|last3=Escala|first3=Maria E. Martinez|last4=Ringbloom|first4=Kimberly G.|last5=Shih|first5=David J. H.|last6=Yang|first6=Jingyi|last7=Tegtmeyer|first7=Kyle|last8=Park|first8=Joonhee|last9=Thomas|first9=Jane J.|date=2020-04-14|title=Cellular origins and genetic landscape of cutaneous gamma delta T cell lymphomas|url=https://pubmed.ncbi.nlm.nih.gov/32286303|journal=Nature Communications|volume=11|issue=1|pages=1806|doi=10.1038/s41467-020-15572-7|issn=2041-1723|pmc=7156460|pmid=32286303}}</ref>
|-
|-
|<span class="blue-text">EXAMPLE:</span> ''CIC''
|'''Fusion: FYN :: (probable partner TRAF3IP2)'''
|<span class="blue-text">EXAMPLE:</span> ''CIC::DUX4''
|TRAF3IP2
|<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''.
|Structural alteration – deletion/exon8 deletion → (in  other T‑cell lymphomas) FYN::TRAF3IP2 fusion leading to SRC‑family kinase  activation; in this PCGDTCL case FYN exon8 deletion noted
|<span class="blue-text">EXAMPLE:</span> t(4;19)(q25;q13)
|Oncogene / Other
|<span class="blue-text">EXAMPLE:</span> Common (CIC-rearranged sarcoma)
|Rare (<5%) (single case reported)
|<span class="blue-text">EXAMPLE:</span> D
|T
|
|No
|<span class="blue-text">EXAMPLE:</span>
|Very recently described; may represent novel  driver/target; further cases needed<ref>{{Cite journal|last=Azimpouran|first=Mahzad|last2=Bui|first2=Chau M.|last3=Balzer|first3=Bonnie|last4=Kitahara|first4=Sumire|date=2024-12-01|title=Rapidly Progressive Primary Cutaneous Gamma Delta T-Cell Lymphoma With FYN Gene Alteration|url=https://pubmed.ncbi.nlm.nih.gov/39412302|journal=The American Journal of Dermatopathology|volume=46|issue=12|pages=e120–e123|doi=10.1097/DAD.0000000000002856|issn=1533-0311|pmid=39412302}}</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).
|-
|-
|<span class="blue-text">EXAMPLE:</span> ''ALK''
|'''Fusion: PCM1 :: JAK2'''
|<span class="blue-text">EXAMPLE:</span> ''ELM4::ALK''
|PCM1
 
|Fusion → juxtaposition of dimerization domain of PCM1  with kinase domain of JAK2 → constitutive JAK2 activation
 
|Oncogene
Other fusion partners include ''KIF5B, NPM1, STRN, TFG, TPM3, CLTC, KLC1''
|Rare (<5%) (single documented PCGDTCL case)
|<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.
|T
|<span class="blue-text">EXAMPLE:</span> N/A
|No
|<span class="blue-text">EXAMPLE:</span> Rare (Lung adenocarcinoma)
|Known in other T‑cell and myeloid neoplasms; in PCGDTCL  this double‐hit  case had PCM1::JAK2 + TBL1XR1::TP63 fusion; patient refractory to JAK  inhibitor<ref name=":2">{{Cite journal|last=Fadl|first=Amr|last2=Bennani|first2=N. Nora|last3=Comfere|first3=Nneka|last4=Durani|first4=Urshila|last5=Greipp|first5=Patricia T.|last6=Feldman|first6=Andrew L.|date=2023-09|title=Primary cutaneous gamma/delta T-cell lymphoma with simultaneous JAK2 and TP63 rearrangements: a new double-hit?|url=https://pubmed.ncbi.nlm.nih.gov/37308177|journal=Histopathology|volume=83|issue=3|pages=492–495|doi=10.1111/his.14973|issn=1365-2559|pmc=10524708|pmid=37308177}}</ref>
|<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> ''ABL1''
|'''Fusion: TBL1XR1 :: TP63'''
|<span class="blue-text">EXAMPLE:</span> N/A
|TBL1XR1
|<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.
|Fusion → truncation/overexpression of ΔNp63 form →  oncogenic p63 signalling
|<span class="blue-text">EXAMPLE:</span> N/A
|Oncogene / Other
|<span class="blue-text">EXAMPLE:</span> Recurrent (IDH-wildtype Glioblastoma)
|Rare (<5%) (same single case) (
|<span class="blue-text">EXAMPLE:</span> D, P, T
|P / T
|
|No
|
|Associated with aggressive behaviour in T‑cell lymphomas;  in the reported PCGDTCL case contributed to aggressive course and JAK  inhibitor resistance<ref name=":2" />
|-
|
|
|
|
|
|
|
|
|}
|}
==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>
 
{| 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
|-
|1p
|Loss
|1p36.11
|ARID1A
|P
|No
|Deleted in ~28% of cases. Indicates epigenetic/chromatin modifier pathway involvement<ref name=":0" />
|-
|1q
|Gain (arm‐level  amplification)
|1q (approx chr1:144,000,000‑249,000,000)
|Multiple genes on 1q (unspecified)
|P / T
|No
|Amplification in ~33% of cases. Potential gene dosage effect; specific driver gene not yet defined<ref name=":0" />
|-
|2q
|Loss
|2q37.3
|PDCD1
|P
|No
|Deletion in ~22% of cases. Immune checkpoint gene loss; potential therapeutic‑escape mechanism<ref name=":0" />
|-
|7q
|Gain (arm‐level)
|7q (approx chr7:100,000,000‑159,000,000)
|Multiple genes on 7q (unspecified)
|P
|No
|Amplification in ~39% of cases. Suggests MAPK/other pathway involvement but specific gene not yet defined.
|-
|-
|<span class="blue-text">EXAMPLE:</span>
|9p
7
|Loss (deletion)
|<span class="blue-text">EXAMPLE:</span> Loss
|9p21.3 (~ chr9:21,900,000‑22,200,000)
|<span class="blue-text">EXAMPLE:</span>
|CDKN2A, CDKN2B
chr7
|P
|<span class="blue-text">EXAMPLE:</span>
|No
Unknown
|High‐frequency  homozygous or biallelic deletion (~61% of cases; 45% biallelic) in PCGDTCL. (PMC) Suggests aggressive biology, prognostic marker candidate<ref name=":0" />
|<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>
|10q
8
|Loss
|<span class="blue-text">EXAMPLE:</span> Gain
|10q24.1
|<span class="blue-text">EXAMPLE:</span>
|FAS
chr8
|P
|<span class="blue-text">EXAMPLE:</span>
|No
Unknown
|Deletion in ~22% of cases. Loss of apoptosis regulator; may contribute to immune‑escape<ref name=":0" />
|<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>
|15q
17
|Gain (arm‐level)
|<span class="blue-text">EXAMPLE:</span> Amp
|15q (approx chr15:30,000,000‑102,000,000)
|<span class="blue-text">EXAMPLE:</span>
|Multiple genes on 15q (unspecified)
17q12; chr17:39,700,064-39,728,658 [hg38; 28.6 kb]
|P
|<span class="blue-text">EXAMPLE:</span>
|No
''ERBB2''
|Amplification in ~33% of cases.  Likely reflects tumour evolution rather than diagnostic biomarker<ref name=":0" />
|<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.
|-
|-
|
|18q
|
|Loss
|
|18q (arm level; no precise minimal region specified)
|
|Putative tumour suppressors (unspecified)
|
|P
|
|No
|
|Recurrent deletion ~22% in PCGDTCL cohort. May reflect genomic instability and poor outcome<ref name=":0" />
|}
|}
==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>
 
{| 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
|-
|'''Arm‑level somatic copy‑number variation  (SCNV)''' (average ~4 arm‑level events per case; median ~166.5  SCNVs per sample)<ref name=":0" />
|Reflects genomic instability; multiple gains and losses  of whole chromosome arms likely contribute to oncogenesis and progression by  altering gene dosage of multiple oncogenes/tumour suppressors simultaneously.  (PMC)
|'''Common''' (>20%) — nearly all  cases show multiple arm‑level events (median 4 per sample) (PMC)
|P
|No
|High genomic complexity may explain aggressive behaviour  and poor response to therapy. Could impact prognosis or treatment resistance  but not yet in guidelines.
|-
|-
|<span class="blue-text">EXAMPLE:</span>
|'''High burden of somatic copy‑number variants  (SCNVs) relative to single‐nucleotide  variants (SNVs)''' (e.g., median ~166.5 SCNVs per sample) <ref name=":0" />
Co-deletion of 1p and 18q
|Suggests that structural genomic alterations dominate the  mutational landscape, perhaps more so than classical hotspot SNVs, indicating  a biology driven by large‑scale genomic disruption rather than just point  mutations.
|<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).
|'''Common''' (>20%)
|<span class="blue-text">EXAMPLE:</span> Common (Oligodendroglioma)
|P
|<span class="blue-text">EXAMPLE:</span> D, P
|No
|
|Recognising this pattern may guide expectation of  complexity, but this is not currently used clinically for diagnosis or  treatment.
|
|-
|-
|<span class="blue-text">EXAMPLE:</span>
|'''Distinct cell‑of‑origin signature: Vδ1 vs Vδ2  subtype''' (epidermal/dermal Vδ1 vs panniculitic Vδ2) <ref name=":0" />
Microsatellite instability - hypermutated
|Different tissue compartments (epidermis/dermis vs  subcutaneous) correspond to distinct γδ T‑cell subsets (Vδ1 vs Vδ2). The cell‑of‑origin  influences mutational signatures (eg UV signature in Vδ1) and clinical  phenotype (Vδ2 more aggressive)<ref name=":0" />
|
|'''Recurrent''' (5‑20%) — this  pattern applies in a subset of cases defined by tissue involvement and TCR  subtype.
|<span class="blue-text">EXAMPLE:</span> Common (Endometrial carcinoma)
|D / P
|<span class="blue-text">EXAMPLE:</span> P, T
|No
|
|This dichotomy may help stratify patients clinically (Vδ2  subtype worse prognosis) but is not currently part of formal diagnostic or  therapeutic guidelines.
|
|-
|-
|
|'''Ultraviolet (UV) mutational signature in Vδ1  subtype''' <ref name=":0" />
|
|The epidermal/dermal Vδ1 γδ T‑cell lymphomas exhibit a UV  signature in their mutation spectrum, likely reflecting skin localization and  UV exposure contributing to oncogenesis.
|
|'''Recurrent''' (5‑20%) — seen in  Vδ1 cases but not all.
|
|P
|
|No
|
|Could suggest etiology and may influence prognosis;  though not yet used for therapy selection.
|-
|'''Frequent deletions of 9p21.3 (CDKN2A region)'''  (part of the SCNV pattern) <ref name=":0" />
|Loss of CDKN2A/p14^ARF leads to cell‑cycle deregulation,  loss of tumour suppressor control: a hallmark of many aggressive lymphomas
|'''Common''' (>20%) (approx 61% of  cases)
|P
|No
|Among the most prevalent genomic events in PCGDTCL —  potential prognostic marker though not yet guideline‑endorsed.
|-
|'''Multiple gains of oncogenic arms (e.g., 1q,  7q, 15q) and corresponding losses (eg 18q)''' <ref name=":0" />
|Gains may increase dosage of oncogenes; losses may reduce  tumour suppressor dosage—together contributing to malignant phenotype
|'''Recurrent''' (5‑20%) for specific  arm‑level changes (e.g., 1q gain ~33%, 7q ~39%, 15q ~33%)
|P
|No
|These arm‑level events indicate complexity; may correlate  with poorer prognosis; not yet actionable in therapy.
|-
|'''TCR chain repertoire restriction / non‑random  Vγ or Vδ usage''' (eg Vγ3Vδ2 in panniculitic cases) <ref name=":0" />
|Suggests antigen‑driven or tissue‐resident γδ T‑cell  proliferation; highlights non‑random selection of malignant clones
|'''Recurrent''' (5‑20%) in defined  subtypes
|D
|No
|Might help refine subclassification of PCGDTCL; not  currently used in routine diagnostic algorithms.
|}
|}
==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>
 
{| 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
|-
|'''STAT5B'''
|Activating missense (e.g., p.N642H) → constitutive  downstream STAT5 signalling
|Oncogene
|Recurrent (~5‑20 %) — e.g., in the 2020 genomic study:  JAK/STAT mutations ~21 % of cases<ref name=":0" />
|T / P: Therapeutic potential (JAK/STAT inhibition);  Prognostic implication (pathway addiction/resistance)
|No
|Mutant STAT5B (especially N642H) shown to induce T‑cell  neoplasia in models; in PCGDTCL JAK/STAT addiction shown clinically <ref name=":1">{{Cite journal|last=Küçük|first=Can|last2=Jiang|first2=Bei|last3=Hu|first3=Xiaozhou|last4=Zhang|first4=Wenyan|last5=Chan|first5=John K. C.|last6=Xiao|first6=Wenming|last7=Lack|first7=Nathan|last8=Alkan|first8=Can|last9=Williams|first9=John C.|date=2015-01-14|title=Activating mutations of STAT5B and STAT3 in lymphomas derived from γδ-T or NK cells|url=https://pubmed.ncbi.nlm.nih.gov/25586472|journal=Nature Communications|volume=6|pages=6025|doi=10.1038/ncomms7025|issn=2041-1723|pmc=7743911|pmid=25586472}}</ref><ref name=":3">{{Cite journal|last=Zhang|first=Yue|last2=Yescas|first2=Julia A.|last3=Tefft|first3=Kristy|last4=Ng|first4=Spencer|last5=Qiu|first5=Kevin|last6=Wang|first6=Erica B.|last7=Akhtar|first7=Shifa|last8=Walker|first8=Addie|last9=Welborn|first9=Macartney|date=2025-04-15|title=Addiction of primary cutaneous γδ T cell lymphomas to JAK/STAT signaling|url=https://pubmed.ncbi.nlm.nih.gov/40231467|journal=The Journal of Clinical Investigation|volume=135|issue=8|pages=e180417|doi=10.1172/JCI180417|issn=1558-8238|pmc=11996904|pmid=40231467}}</ref>
|-
|'''STAT3'''
|Activating missense (SH2 domain) → constitutive STAT3  signalling
|Oncogene
|Rare (<5 %) to Recurrent (≈5‑10 %) (in NK/γδ‑T  lymphomas earlier)
|T / P
|No
|Less frequent than STAT5B in PCGDTCL; part of JAK/STAT pathway involvement<ref name=":0" /><ref name=":1" />
|-
|'''JAK3'''
|Activating mutation (e.g., p.R657W) → JAK3 tyrosine  kinase activation
|Oncogene
|Rare (<5 %) (noted in the Daniels et al. cohort)
|T
|No
|Supports JAK/STAT involvement; one case report showed  response to JAK inhibition<ref name=":3" />
|-
|'''KRAS'''
|Activating hotspot mutations (e.g., G12D, Q61H, D119N) →  RAS/MAPK activation
|Oncogene
|Recurrent (~5‑20 %) — “KRAS was the most frequently  mutated oncogene” <ref name=":0" />
|T / P
|No
|MAPK pathway appears relevant; patients with MAPK‑pathway  driver mutations had worse survival in the cohort<ref name=":0" />
|-
|-
|<span class="blue-text">EXAMPLE:</span>''EGFR''
|'''NRAS'''
 
|Activating hotspot mutation → RAS/MAPK activation
<br />
|Oncogene
|<span class="blue-text">EXAMPLE:</span> Exon 18-21 activating mutations
|Rare (<5 %) to Recurrent (~5‑10 %)  
|<span class="blue-text">EXAMPLE:</span> Oncogene
|T / P
|<span class="blue-text">EXAMPLE:</span> Common (lung cancer)
|No
|<span class="blue-text">EXAMPLE:</span> T
|Part of the same RAS/MAPK pathway as KRAS; less common.
|<span class="blue-text">EXAMPLE:</span> Yes (NCCN)
|<span class="blue-text">EXAMPLE:</span> Exons 18, 19, and 21 mutations are targetable for therapy. Exon 20 T790M variants cause resistance to first generation TKI therapy and are targetable by second and third generation TKIs (add references).
|-
|-
|<span class="blue-text">EXAMPLE:</span> ''TP53''; Variable LOF mutations
|'''MAPK1'''
<br />
|Activating mutation → MAPK1 signalling activation
|<span class="blue-text">EXAMPLE:</span> Variable LOF mutations
|Oncogene
|<span class="blue-text">EXAMPLE:</span> Tumor Supressor Gene
|Rare (<5 %)
|<span class="blue-text">EXAMPLE:</span> Common (breast cancer)
|T
|<span class="blue-text">EXAMPLE:</span> P
|No
|
|Also in MAPK pathway; limited data in PCGDTCL<ref name=":0" /><ref name=":1" />
|<span class="blue-text">EXAMPLE:</span> >90% are somatic; rare germline alterations associated with Li-Fraumeni syndrome (add reference). Denotes a poor prognosis in breast cancer.
|-
|-
|<span class="blue-text">EXAMPLE:</span> ''BRAF''; Activating mutations
|'''MYC'''
|<span class="blue-text">EXAMPLE:</span> Activating mutations
|Activating missense mutation (e.g., p.P74L) → MYC pathway  up‑regulation
|<span class="blue-text">EXAMPLE:</span> Oncogene
|Oncogene
|<span class="blue-text">EXAMPLE:</span> Common (melanoma)
|Rare (<5 %)
|<span class="blue-text">EXAMPLE:</span> T
|P / T
|
|No
|
|MYC pathway involvement may contribute to the aggressive  phenotype; direct targeting not yet established<ref name=":0" />
|-
|-
|
|'''MYCN'''
|
|Activating mutation (e.g., p.G34R) → MYCN pathway  activation
|
|Oncogene
|
|Rare (<5 %)
|
|P / T
|
|No
|
|Highlights involvement of MYC‑family beyond MYC itself in  this disease<ref name=":0" />
|}Note: A more extensive list of mutations can be found in [https://www.cbioportal.org/ <u>cBioportal</u>], [https://cancer.sanger.ac.uk/cosmic <u>COSMIC</u>], and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.
|}Note: A more extensive list of mutations can be found in [https://www.cbioportal.org/ <u>cBioportal</u>], [https://cancer.sanger.ac.uk/cosmic <u>COSMIC</u>], and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.
==Epigenomic Alterations==
==Epigenomic Alterations==
Put your text here
N/A
==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>
 
{| 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
|DNMT3A (DNA methyltransferase)
|<span class="blue-text">EXAMPLE:</span> MAPK signaling
|Loss‑of‑function mutations or deletions → reduced de novo  DNA methylation; “epigenetic writer” defect (DNA methylation pathway)<ref name=":4">{{Cite journal|last=Zhang|first=Ping|last2=Zhang|first2=Mingzhi|date=2020-11-07|title=Epigenetic alterations and advancement of treatment in peripheral T-cell lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/33160401|journal=Clinical Epigenetics|volume=12|issue=1|pages=169|doi=10.1186/s13148-020-00962-x|issn=1868-7083|pmc=7648940|pmid=33160401}}</ref>
|<span class="blue-text">EXAMPLE:</span> Increased cell growth and proliferation
|Deregulation of gene silencing; tumour suppressor genes  may remain unmethylated or aberrantly methylated → genomic instability,  aberrant T‑cell differentiation/activation
|-
|-
|<span class="blue-text">EXAMPLE:</span> ''CDKN2A''; Inactivating mutations
|TET2 (methylcytosine dioxygenase)
|<span class="blue-text">EXAMPLE:</span> Cell cycle regulation
|Loss‑of‑function mutations → failure of DNA 5‑mC → 5‑hmC  demethylation (“epigenetic eraser” defect)<ref name=":4" />
|<span class="blue-text">EXAMPLE:</span> Unregulated cell division
|Aberrant hypermethylation or demethylation patterns;  influences T‑cell development and malignant transformation (e.g., in T‑fh  lymphomas)
|-
|-
|<span class="blue-text">EXAMPLE:</span> ''KMT2C'' and ''ARID1A''; Inactivating mutations
|IDH2 (metabolic enzyme altering epigenome)
|<span class="blue-text">EXAMPLE:</span> Histone modification, chromatin remodeling
|Gain‑of‑function mutation (e.g., R172) → produces 2‑hydroxyglutarate  → inhibits TET family → epigenetic dysregulation<ref name=":4" />
|<span class="blue-text">EXAMPLE:</span> Abnormal gene expression program
|Oncometabolite‑driven methylation changes, impaired  differentiation, proliferation of malignant T cells
|-
|-
|
|ARID1A (SWI/SNF chromatin‑remodeller)
|
|Loss‑of‑function mutation/deletion → impaired nucleosome  remodelling, altered chromatin accessibility (“chromatin remodeller”)<ref name=":4" />
|
|Reduced tumour‑suppressor gene expression due to  chromatin compaction; may influence immune microenvironment and genomic  instability
|-
|KMT2D / KMT2A (H3K4 methyltransferases)
|Loss‑of‑function mutations (“histone‑writer” defect) →  decreased H3K4 methylation (activating mark)<ref name=":5">{{Cite journal|last=Ahmed|first=Nada|last2=Feldman|first2=Andrew L.|date=2020-02|title=Targeting epigenetic regulators in the treatment of T-cell lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/31903826|journal=Expert Review of Hematology|volume=13|issue=2|pages=127–139|doi=10.1080/17474086.2020.1711732|issn=1747-4094|pmc=7110907|pmid=31903826}}</ref>
|Impaired activation of gene expression programs  (differentiation, apoptosis) → contributes to malignant transformation
|-
|KDM6A (H3K27 demethylase)
|Loss‑of‑function → accumulation of H3K27me3 (repressive  histone mark) (“histone‑eraser” defect)<ref name=":5" />
|Further chromatin repression of tumour‑suppressor genes;  may enhance survival of malignant T cells
|-
|EZH2 (PRC2 complex methyltransferase)
|Overexpression/gain of function → increased H3K27me3  (“histone‑writer” overactivity) <ref name=":4" />
|Enhanced silencing of differentiation/apoptosis genes;  contributes to aggressive lymphoma phenotypes
|-
|CREBBP / EP300 (histone acetyl‑transferases)
|Loss‑of‑function mutations (“histone‑writer” defect) →  reduced histone acetylation and gene activation<ref name=":5" />
|Diminished transcriptional activation of tumour‑suppressor/immune  genes; may drive malignant progression
|-
|DNA methylation of specific tumour‑suppressor loci (e.g.,  CDKN2A promoter; FAS promoter)
|Hypermethylation of promoter CpG islands → silencing of tumor suppressor / apoptosis‑initiator genes<ref>{{Cite journal|last=Hara|first=Natsumi|last2=Sawada|first2=Yu|date=2022-03-24|title=Epigenetics of Cutaneous T-Cell Lymphomas|url=https://pubmed.ncbi.nlm.nih.gov/35408897|journal=International Journal of Molecular Sciences|volume=23|issue=7|pages=3538|doi=10.3390/ijms23073538|issn=1422-0067|pmc=8998216|pmid=35408897}}</ref>
|Loss of cell‑cycle control or apoptosis leads to  malignant T‑cell survival/proliferation
|}
|}
==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>
 
{| class="wikitable"
|'''Method'''
|'''Description'''
|'''Type of Alteration Detected'''
|'''Advantages'''
|'''Limitations'''
|'''Clinical Use in PCGDTCL'''
|-
|'''Next-Generation Sequencing (NGS)'''
|High-throughput sequencing of targeted gene panels,  whole-exome, or whole-genome sequencing
|SNVs, INDELs, copy number variants (CNVs), some fusions  (if RNA-seq included)
|Comprehensive mutation detection; scalable; can detect  multiple variants simultaneously
|Requires high-quality DNA/RNA; bioinformatics expertise  needed; cost-intensive
|Main tool for mutational profiling in PCGDTCL; used in  research and increasingly in clinical labs
|-
|'''Targeted Gene Panels (amplicon or hybrid  capture-based)'''
|Sequencing of a defined set of genes known to be relevant
|SNVs, INDELs, limited CNVs, hotspot fusions (if included)
|Faster, cheaper than WES/WGS; focused on clinically  relevant genes
|May miss novel or unexpected mutations; limited to panel  content
|Often used clinically to screen for mutations in  JAK/STAT, RAS pathways in PCGDTCL
|-
|'''Fluorescence In Situ Hybridization (FISH)'''
|DNA probes hybridize to metaphase or interphase  chromosomes
|Structural chromosomal alterations, gene fusions,  amplifications, deletions
|Visualizes gene rearrangements and copy number changes;  established clinical use
|Limited to known targets; low resolution; labor-intensive
|Used to detect known translocations or gene  amplifications (e.g., MYC) in lymphoma diagnosis
|-
|'''Array Comparative Genomic Hybridization  (aCGH) / SNP Arrays'''
|Genome-wide detection of copy number alterations and LOH
|Copy number gains, losses, LOH (Loss of heterozygosity)
|Genome-wide coverage; detects submicroscopic CNVs
|Cannot detect balanced translocations or point mutations;  resolution depends on array density
|Useful for detecting large chromosomal alterations in  lymphoma samples
|-
|'''RNA Sequencing (RNA-Seq)'''
|Sequencing of transcriptome
|Gene fusions, splice variants, expression levels
|Detects novel and known fusions; measures gene  expression; alternative splicing
|RNA quality sensitive; bioinformatics expertise needed
|Research use for identifying novel fusion partners or  expression signatures in PCGDTCL
|-
|'''Sanger Sequencing'''
|Chain termination sequencing of PCR-amplified regions
|SNVs and small indels
|Gold standard for validation; high accuracy
|Low throughput; not suitable for large panels
|Used to confirm NGS-identified mutations
|-
|'''Digital Droplet PCR (ddPCR) / qPCR'''
|Highly sensitive quantification of known mutations or  gene rearrangements
|Known point mutations, copy number changes
|Very sensitive, quantitative; fast turnaround
|Limited to known mutations; not comprehensive
|Useful for monitoring known mutations (e.g., STAT5B  N642H) in minimal residual disease (MRD) or treatment response
|-
|'''Immunohistochemistry (IHC)'''  (surrogate genetic marker)
|Antibody staining of protein expression
|Protein expression reflecting genetic alterations (e.g.,  pSTAT5B, MYC)
|Widely available; easy to implement
|Indirect; may not perfectly correlate with mutation  status
|Supportive role in diagnosis and prognosis, not  definitive genetic test
|}
 
==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>
There are currently '''no well-established familial or hereditary forms''' described in the literature.
==Additional Information==
==Additional Information==
Put your text here
N/A
==Links==
==Links==


Put a link here or anywhere appropriate in this page <span style="color:#0070C0">(''Instructions: Highlight the text to which you want to add a link in this section or elsewhere, select the "Link" icon at the top of the wiki page, and search the name of the internal page to which you want to link this text, or enter an external internet address by including the "<nowiki>http://www</nowiki>." portion.'')</span>
N/A


==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 where you want to insert the reference, selecting the “Cite” icon at the top of the wiki page, and using the “Automatic” tab option to search by PMID to select the reference to insert. If a PMID is not available, such as for a book, please use the “Cite” icon, select “Manual” and then “Basic Form”, and include the entire reference. To insert the same reference again later in the page, select the “Cite” icon and “Re-use” to find the reference; DO NOT insert the same reference twice using the “Automatic” tab as it will be treated as two separate references. The reference list in this section will be automatically generated and sorted''</span><span style="color:#0070C0">''.''</span><span style="color:#0070C0">)</span>
<references />
==Notes==
<nowiki>*</nowiki>''Citation of this Page'': Azimpouran M, Kitahara S. “Primary cutaneous gamma/delta T-cell lymphoma”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated {{REVISIONMONTH}}/{{REVISIONDAY}}/{{REVISIONYEAR}}, <nowiki>https://ccga.io/index.php/HAEM5:Primary_cutaneous_gamma/delta_T-cell_lymphoma</nowiki>.
 


==Notes==
<nowiki>*</nowiki>Primary authors will typically be those that initially create and complete the content of a page.  If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the [[Leadership|''<u>Associate Editor</u>'']] or other CCGA representative.  When pages have a major update, the new author will be acknowledged at the beginning of the page, and those who contributed previously will be acknowledged below as a prior author.
<nowiki>*</nowiki>Primary authors will typically be those that initially create and complete the content of a page.  If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the [[Leadership|''<u>Associate Editor</u>'']] or other CCGA representative.  When pages have a major update, the new author will be acknowledged at the beginning of the page, and those who contributed previously will be acknowledged below as a prior author.


Prior Author(s):   
Prior Author(s): N/A  
 
[[Category:HAEM5]]
       
[[Category:DISEASE]]
<nowiki>*</nowiki>''Citation of this Page'': “Primary cutaneous gamma/delta T-cell lymphoma”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated {{REVISIONMONTH}}/{{REVISIONDAY}}/{{REVISIONYEAR}}, <nowiki>https://ccga.io/index.php/HAEM5:Primary_cutaneous_gamma/delta_T-cell_lymphoma</nowiki>.
[[Category:Diseases P]]
[[Category:HAEM5]][[Category:DISEASE]][[Category:Diseases P]]
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