HAEM5:Primary cutaneous gamma/delta T-cell lymphoma

Haematolymphoid Tumours (WHO Classification, 5th ed.)

(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 HUGO-approved gene names and symbols (italicized when appropriate), 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 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 Author_Instructions and FAQs as well as contact your Associate Editor or Technical Support.)

Primary Author(s)*

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WHO Classification of Disease

Structure	Disease
Book	Haematolymphoid Tumours (5th ed.)
Category	T-cell and NK-cell lymphoid proliferations and lymphomas
Family	Mature T-cell and NK-cell neoplasms
Type	Primary cutaneous T-cell lymphoid proliferations and lymphomas
Subtype(s)	Primary cutaneous gamma/delta T-cell lymphoma

Related Terminology

Acceptable	N/A
Not Recommended	N/A

Gene Rearrangements

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Gene / Fusion	Partner Gene (for fusion)	Genetic Alteration & Molecular Pathogenesis	Tumour Suppressor / Oncogene / Other	Prevalence (common>20%, recurrent 5-20% or rare <5%)	D / P / T	Established clinical significance per guidelines?	Clinical relevance / Other notes
CDKN2A	—	Homozygous or biallelic deletion → loss of p16^INK4A/p14^ARF function (cell‑cycle control)	Tumour suppressor	Common (>20%) (~61% in cohort) (PubMed)	P	No	High‐frequency deletion, suggests aggressive biology and may be a prognostic marker
ARID1A	—	Deletion/truncating mutation → loss of chromatin‑remodelling function	Tumour suppressor	Recurrent (5‑20%) (~28%) (PMC)	Other / P	No	Indicates involvement of epigenetic/chromatin pathways in PCGDTCL
FAS	—	Focal or biallelic deletion → loss of apoptosis signalling via FAS‑FASL pathway	Tumour suppressor / apoptotic regulator	Recurrent (5‑20%) (~22%) (PMC)	Other / P	No	Loss of FAS may contribute to immune‐escape of malignant γδ T‑cells
PDCD1	—	Deletion → loss of PD‑1 (immune‐checkpoint) regulatory function	Tumour suppressor / immune‑regulator	Recurrent (5‑20%) (~22%) (PMC)	Other / P	No	Suggests immune‐escape mechanism; potential implications for checkpoint therapy though unproven
STAT5B	—	Activating missense (e.g., N642H) → constitutive STAT5B signalling (JAK/STAT pathway)	Oncogene	Recurrent (5‑20%) (JAK/STAT mutations ~21%) (PubMed)	T / P	No	JAK/STAT pathway dependency; early data suggest JAK‐inhibitor sensitivity in analogous T‑cell neoplasms; investigational in PCGDTCL
STAT3	—	Activating missense → constitutive STAT3 signalling (JAK/STAT cascade)	Oncogene	Rare (<5%) to Recurrent (~5‑20%) (PubMed)	T / P	No	Part of JAK/STAT alterations; less frequent than STAT5B in PCGDTCL
JAK3	—	Activating mutation (e.g., R657W) → JAK3 tyrosine kinase activation (JAK/STAT pathway)	Oncogene	Rare (<5%) (PMC)	T	No	Supports JAK/STAT pathway involvement; therapeutic relevance remains investigational in this disease
KRAS	—	Activating hotspot mutations (e.g., G12D, Q61H) → RAS/MAPK pathway activation	Oncogene	Recurrent (5‑20%) (PubMed)	T / P	No	MAPK pathway potentially targetable; mutations associated with poorer outcome in the cohort studied
NRAS	—	Activating hotspot mutation → RAS/MAPK pathway activation	Oncogene	Rare (<5%) to Recurrent (~5‑20%) (PMC)	T / P	No	Part of same pathway as KRAS though less common
MYC	—	Activating missense mutation (e.g., P74L) → MYC pathway up‑regulation	Oncogene	Rare (<5%) (PMC)	P / T	No	MYC pathway involvement may contribute to more aggressive phenotype; direct targeting not yet established
MYCN	—	Activating mutation (e.g., G34R) → MYCN pathway activation	Oncogene	Rare (<5%) (PMC)	P / T	No	Highlights involvement of MYC family beyond MYC itself in PCGDTCL
Arm‑level chromosomal alterations (e.g., 9p, 18q deletions; 1q, 7q,15q gains)	—	Copy number loss or gain → altered gene dosage of tumour suppressors/oncogenes	Other / chromosomal alteration	Recurrent (5‑20%) (9p del ~22%, 18q del ~22%; 1q/7q/15q gains ~33‑39%) (PMC)	D / P	No	These structural changes suggest genomic instability and aggressive biology; may help risk stratification though not diagnostic per se
Fusion: FYN :: (probable partner TRAF3IP2)	TRAF3IP2	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 (PubMed)	Oncogene / Other	Rare (<5%) (single case reported)	T	No	Very recently described; may represent novel driver/target; further cases needed
Fusion: PCM1 :: JAK2	PCM1	Fusion → juxtaposition of dimerization domain of PCM1 with kinase domain of JAK2 → constitutive JAK2 activation	Oncogene	Rare (<5%) (single documented PCGDTCL case) (PubMed)	T	No	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
Fusion: TBL1XR1 :: TP63	TBL1XR1	Fusion → truncation/overexpression of ΔNp63 form → oncogenic p63 signalling	Oncogene / Other	Rare (<5%) (same single case) (PubMed)	P / T	No	Associated with aggressive behaviour in T‑cell lymphomas; in the reported PCGDTCL case contributed to aggressive course and JAK inhibitor resistance

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
EXAMPLE: ABL1	EXAMPLE: BCR::ABL1	EXAMPLE: The pathogenic derivative is the der(22) resulting in fusion of 5’ BCR and 3’ABL1.	EXAMPLE: t(9;22)(q34;q11.2)	EXAMPLE: Common (CML)	EXAMPLE: D, P, T	EXAMPLE: Yes (WHO, NCCN)	EXAMPLE: 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).
EXAMPLE: CIC	EXAMPLE: CIC::DUX4	EXAMPLE: 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.	EXAMPLE: t(4;19)(q25;q13)	EXAMPLE: Common (CIC-rearranged sarcoma)	EXAMPLE: D		EXAMPLE: 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).
EXAMPLE: ALK	EXAMPLE: ELM4::ALK Other fusion partners include KIF5B, NPM1, STRN, TFG, TPM3, CLTC, KLC1	EXAMPLE: 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.	EXAMPLE: N/A	EXAMPLE: Rare (Lung adenocarcinoma)	EXAMPLE: T		EXAMPLE: Both balanced and unbalanced forms are observed by FISH (add references).
EXAMPLE: ABL1	EXAMPLE: N/A	EXAMPLE: 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.	EXAMPLE: N/A	EXAMPLE: Recurrent (IDH-wildtype Glioblastoma)	EXAMPLE: D, P, T

Individual Region Genomic Gain/Loss/LOH

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Chr #	Gain / Loss / Amp / LOH	Minimal Region Cytoband and/or Approximate Genomic Coordinates [Genome build GRCh38/hg38 if available]	Relevant Gene(s)	D / P / T (Diagnostic / Prognostic / Therapeutic)	Established clinical significance per guidelines? (Yes/No; source)	Clinical relevance / Notes
9p	Loss (deletion)	9p21.3 (~ chr9:21,900,000‑22,200,000)	CDKN2A, CDKN2B	P	No	High‐frequency homozygous or biallelic deletion (~61% of cases; 45% biallelic) in PCGDTCL. (PMC) Suggests aggressive biology, prognostic marker candidate.
18q	Loss	18q (arm level; no precise minimal region specified)	Putative tumour suppressors (unspecified)	P	No	Recurrent deletion ~22% in PCGDTCL cohort. (PMC) May reflect genomic instability and poor outcome.
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. (PMC) Potential gene dosage effect; specific driver gene not yet defined.
15q	Gain (arm‐level)	15q (approx chr15:30,000,000‑102,000,000)	Multiple genes on 15q (unspecified)	P	No	Amplification in ~33% of cases. (PMC) Likely reflects tumour evolution rather than diagnostic biomarker.
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. (PMC) Suggests MAPK/other pathway involvement but specific gene not yet defined.
Focal deletion: CDKN2A	Loss (homozygous/biallelic)	within 9p21.3, CDKN2A region	CDKN2A	P	No	From GISTIC analysis: CDKN2A deletion in 61% of samples, 45% biallelic. (PMC) Key focal region in PCGDTCL.
Focal deletion: ARID1A	Loss	unspecified (del/trunc)	ARID1A	P	No	Deleted in ~28% of cases. (PMC) Indicates epigenetic/chromatin modifier pathway involvement.
Focal deletion: FAS	Loss	unspecified (biallelic)	FAS	P	No	Deletion in ~22% of cases. (PMC) Loss of apoptosis regulator; may contribute to immune‑escape.
Focal deletion: PDCD1	Loss	unspecified	PDCD1	P	No	Deletion in ~22% of cases. (PMC) Immune checkpoint gene loss; potential therapeutic‑escape mechanism.

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
EXAMPLE: 7	EXAMPLE: Loss	EXAMPLE: chr7	EXAMPLE: Unknown	EXAMPLE: D, P	EXAMPLE: No	EXAMPLE: 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).
EXAMPLE: 8	EXAMPLE: Gain	EXAMPLE: chr8	EXAMPLE: Unknown	EXAMPLE: D, P		EXAMPLE: Common recurrent secondary finding for t(8;21) (add references).
EXAMPLE: 17	EXAMPLE: Amp	EXAMPLE: 17q12; chr17:39,700,064-39,728,658 [hg38; 28.6 kb]	EXAMPLE: ERBB2	EXAMPLE: D, P, T		EXAMPLE: Amplification of ERBB2 is associated with HER2 overexpression in HER2 positive breast cancer (add references). Add criteria for how amplification is defined.

Characteristic Chromosomal or Other Global Mutational Patterns

Put your text here and fill in the table (Instructions: 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.)

Chromosomal/Global Pattern	Molecular Pathogenesis / Explanation	Prevalence (common>20%, recurrent 5-20% or rare <5%)	D / P / T	Established Clinical Significance per Guidelines? (Yes/No; Source)	Clinical Relevance / Other Notes
Arm‑level somatic copy‑number variation (SCNV) (average ~4 arm‑level events per case; median ~166.5 SCNVs per sample) (PMC)	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.
High burden of somatic copy‑number variants (SCNVs) relative to single‐nucleotide variants (SNVs) (e.g., median ~166.5 SCNVs per sample) (PMC)	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.	Common (>20%)	P	No	Recognising this pattern may guide expectation of complexity, but this is not currently used clinically for diagnosis or treatment.
Distinct cell‑of‑origin signature: Vδ1 vs Vδ2 subtype (epidermal/dermal Vδ1 vs panniculitic Vδ2) (PMC)	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). (PMC)	Recurrent (5‑20%) — this pattern applies in a subset of cases defined by tissue involvement and TCR subtype.	D / P	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 (PMC)	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) (PMC)	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) (PubMed)	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) (PMC)	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%) (PubMed)	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) (PMC)	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.

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
EXAMPLE: Co-deletion of 1p and 18q	EXAMPLE: See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).	EXAMPLE: Common (Oligodendroglioma)	EXAMPLE: D, P
EXAMPLE: Microsatellite instability - hypermutated		EXAMPLE: Common (Endometrial carcinoma)	EXAMPLE: P, T

Gene Mutations (SNV/INDEL)

Put your text here and fill in the table (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.)

Gene	Genetic Alteration (SNV/INDEL) + presumed mechanism	Tumour Suppressor / Oncogene / Other	Prevalence in PCGDTCL*	D / P / T (Diagnostic / Prognostic / Therapeutic)	Established Clinical Significance per Guidelines?	Clinical Relevance / 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. (PMC)	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 (JCI 2025) (Ovid)
STAT3	Activating missense (SH2 domain) → constitutive STAT3 signalling	Oncogene	Rare (<5 %) to Recurrent (≈5‑10 %) (in NK/γδ‑T lymphomas earlier) (PubMed)	T / P	No	Less frequent than STAT5B in PCGDTCL; part of JAK/STAT pathway involvement.
JAK3	Activating mutation (e.g., p.R657W) → JAK3 tyrosine kinase activation	Oncogene	Rare (<5 %) (noted in the Daniels et al. cohort) (PMC)	T	No	Supports JAK/STAT involvement; one case report showed response to JAK inhibition. (JCI)
KRAS	Activating hotspot mutations (e.g., G12D, Q61H, D119N) → RAS/MAPK activation	Oncogene	Recurrent (~5‑20 %) — “KRAS was the most frequently mutated oncogene” in Daniels et al. (PMC)	T / P	No	MAPK pathway appears relevant; patients with MAPK‑pathway driver mutations had worse survival in the cohort. (PubMed)
NRAS	Activating hotspot mutation → RAS/MAPK activation	Oncogene	Rare (<5 %) to Recurrent (~5‑10 %) (PMC)	T / P	No	Part of the same RAS/MAPK pathway as KRAS; less common.
MAPK1	Activating mutation → MAPK1 signalling activation	Oncogene	Rare (<5 %) (PMC)	T	No	Also in MAPK pathway; limited data in PCGDTCL.
MYC	Activating missense mutation (e.g., p.P74L) → MYC pathway up‑regulation	Oncogene	Rare (<5 %) (PMC)	P / T	No	MYC pathway involvement may contribute to the aggressive phenotype; direct targeting not yet established.
MYCN	Activating mutation (e.g., p.G34R) → MYCN pathway activation	Oncogene	Rare (<5 %) (PMC)	P / T	No	Highlights involvement of MYC‑family beyond MYC itself in this disease.

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
EXAMPLE:EGFR	EXAMPLE: Exon 18-21 activating mutations	EXAMPLE: Oncogene	EXAMPLE: Common (lung cancer)	EXAMPLE: T	EXAMPLE: Yes (NCCN)	EXAMPLE: 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).
EXAMPLE: TP53; Variable LOF mutations	EXAMPLE: Variable LOF mutations	EXAMPLE: Tumor Supressor Gene	EXAMPLE: Common (breast cancer)	EXAMPLE: P		EXAMPLE: >90% are somatic; rare germline alterations associated with Li-Fraumeni syndrome (add reference). Denotes a poor prognosis in breast cancer.
EXAMPLE: BRAF; Activating mutations	EXAMPLE: Activating mutations	EXAMPLE: Oncogene	EXAMPLE: Common (melanoma)	EXAMPLE: T

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

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Genes and Main Pathways Involved

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Gene	Alteration / Pathway	Pathophysiologic Outcome
DNMT3A (DNA methyltransferase)	Loss‑of‑function mutations or deletions → reduced de novo DNA methylation; “epigenetic writer” defect (DNA methylation pathway) (BioMed Central)	Deregulation of gene silencing; tumour suppressor genes may remain unmethylated or aberrantly methylated → genomic instability, aberrant T‑cell differentiation/activation
TET2 (methylcytosine dioxygenase)	Loss‑of‑function mutations → failure of DNA 5‑mC → 5‑hmC demethylation (“epigenetic eraser” defect) (BioMed Central)	Aberrant hypermethylation or demethylation patterns; influences T‑cell development and malignant transformation (e.g., in T‑fh lymphomas)
IDH2 (metabolic enzyme altering epigenome)	Gain‑of‑function mutation (e.g., R172) → produces 2‑hydroxyglutarate → inhibits TET family → epigenetic dysregulation (BioMed Central)	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”) (PMC)	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) (PMC)	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) (PMC)	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) (PMC)	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 (PMC)	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 tumour suppressor / apoptosis‑initiator genes (PMC)	Loss of cell‑cycle control or apoptosis leads to malignant T‑cell survival/proliferation

Gene; Genetic Alteration	Pathway	Pathophysiologic Outcome
EXAMPLE: BRAF and MAP2K1; Activating mutations	EXAMPLE: MAPK signaling	EXAMPLE: Increased cell growth and proliferation
EXAMPLE: CDKN2A; Inactivating mutations	EXAMPLE: Cell cycle regulation	EXAMPLE: Unregulated cell division
EXAMPLE: KMT2C and ARID1A; Inactivating mutations	EXAMPLE: Histone modification, chromatin remodeling	EXAMPLE: Abnormal gene expression program

Genetic Diagnostic Testing Methods

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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

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There are currently no well-established familial or hereditary forms described in the literature.

Additional Information

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Links

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References

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Notes

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Prior Author(s):

*Citation of this Page: “Primary cutaneous gamma/delta T-cell lymphoma”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 10/20/2025, https://ccga.io/index.php/HAEM5:Primary_cutaneous_gamma/delta_T-cell_lymphoma.