HAEM5:Primary cutaneous gamma/delta T-cell lymphoma: Difference between revisions
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|Activating missense (SH2 domain) → constitutive STAT3 signalling | |Activating missense (SH2 domain) → constitutive STAT3 signalling | ||
|Oncogene | |Oncogene | ||
|Rare (<5 %) to Recurrent (≈5‑10 %) (in NK/γδ‑T lymphomas earlier | |Rare (<5 %) to Recurrent (≈5‑10 %) (in NK/γδ‑T lymphomas earlier) | ||
|T / P | |T / P | ||
|No | |No | ||
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|Activating mutation (e.g., p.R657W) → JAK3 tyrosine kinase activation | |Activating mutation (e.g., p.R657W) → JAK3 tyrosine kinase activation | ||
|Oncogene | |Oncogene | ||
|Rare (<5 %) (noted in the Daniels et al. cohort | |Rare (<5 %) (noted in the Daniels et al. cohort) | ||
|T | |T | ||
|No | |No | ||
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|Activating hotspot mutations (e.g., G12D, Q61H, D119N) → RAS/MAPK activation | |Activating hotspot mutations (e.g., G12D, Q61H, D119N) → RAS/MAPK activation | ||
|Oncogene | |Oncogene | ||
|Recurrent (~5‑20 %) — “KRAS was the most frequently mutated oncogene” | |Recurrent (~5‑20 %) — “KRAS was the most frequently mutated oncogene” <ref name=":0" /> | ||
|T / P | |T / P | ||
|No | |No | ||
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|Activating hotspot mutation → RAS/MAPK activation | |Activating hotspot mutation → RAS/MAPK activation | ||
|Oncogene | |Oncogene | ||
|Rare (<5 %) to Recurrent (~5‑10 % | |Rare (<5 %) to Recurrent (~5‑10 %) | ||
|T / P | |T / P | ||
|No | |No | ||
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|Activating mutation → MAPK1 signalling activation | |Activating mutation → MAPK1 signalling activation | ||
|Oncogene | |Oncogene | ||
|Rare (<5 % | |Rare (<5 %) | ||
|T | |T | ||
|No | |No | ||
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|Activating missense mutation (e.g., p.P74L) → MYC pathway up‑regulation | |Activating missense mutation (e.g., p.P74L) → MYC pathway up‑regulation | ||
|Oncogene | |Oncogene | ||
|Rare (<5 % | |Rare (<5 %) | ||
|P / T | |P / T | ||
|No | |No | ||
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|Activating mutation (e.g., p.G34R) → MYCN pathway activation | |Activating mutation (e.g., p.G34R) → MYCN pathway activation | ||
|Oncogene | |Oncogene | ||
|Rare (<5 % | |Rare (<5 %) | ||
|P / T | |P / T | ||
|No | |No | ||
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|DNMT3A (DNA methyltransferase) | |DNMT3A (DNA methyltransferase) | ||
|Loss‑of‑function mutations or deletions → reduced de novo DNA methylation; “epigenetic writer” defect (DNA methylation pathway | |Loss‑of‑function mutations or deletions → reduced de novo DNA methylation; “epigenetic writer” defect (DNA methylation pathway) | ||
|Deregulation of gene silencing; tumour suppressor genes may remain unmethylated or aberrantly methylated → genomic instability, aberrant T‑cell differentiation/activation | |Deregulation of gene silencing; tumour suppressor genes may remain unmethylated or aberrantly methylated → genomic instability, aberrant T‑cell differentiation/activation | ||
|- | |- | ||
|TET2 (methylcytosine dioxygenase) | |TET2 (methylcytosine dioxygenase) | ||
|Loss‑of‑function mutations → failure of DNA 5‑mC → 5‑hmC demethylation (“epigenetic eraser” defect | |Loss‑of‑function mutations → failure of DNA 5‑mC → 5‑hmC demethylation (“epigenetic eraser” defect) | ||
|Aberrant hypermethylation or demethylation patterns; influences T‑cell development and malignant transformation (e.g., in T‑fh lymphomas) | |Aberrant hypermethylation or demethylation patterns; influences T‑cell development and malignant transformation (e.g., in T‑fh lymphomas) | ||
|- | |- | ||
|IDH2 (metabolic enzyme altering epigenome) | |IDH2 (metabolic enzyme altering epigenome) | ||
|Gain‑of‑function mutation (e.g., R172) → produces 2‑hydroxyglutarate → inhibits TET family → epigenetic dysregulation | |Gain‑of‑function mutation (e.g., R172) → produces 2‑hydroxyglutarate → inhibits TET family → epigenetic dysregulation | ||
|Oncometabolite‑driven methylation changes, impaired differentiation, proliferation of malignant T cells | |Oncometabolite‑driven methylation changes, impaired differentiation, proliferation of malignant T cells | ||
|- | |- | ||
|ARID1A (SWI/SNF chromatin‑remodeller) | |ARID1A (SWI/SNF chromatin‑remodeller) | ||
|Loss‑of‑function mutation/deletion → impaired nucleosome remodelling, altered chromatin accessibility (“chromatin remodeller” | |Loss‑of‑function mutation/deletion → impaired nucleosome remodelling, altered chromatin accessibility (“chromatin remodeller”) | ||
|Reduced tumour‑suppressor gene expression due to chromatin compaction; may influence immune microenvironment and genomic instability | |Reduced tumour‑suppressor gene expression due to chromatin compaction; may influence immune microenvironment and genomic instability | ||
|- | |- | ||
|KMT2D / KMT2A (H3K4 methyltransferases) | |KMT2D / KMT2A (H3K4 methyltransferases) | ||
|Loss‑of‑function mutations (“histone‑writer” defect) → decreased H3K4 methylation (activating mark | |Loss‑of‑function mutations (“histone‑writer” defect) → decreased H3K4 methylation (activating mark) | ||
|Impaired activation of gene expression programs (differentiation, apoptosis) → contributes to malignant transformation | |Impaired activation of gene expression programs (differentiation, apoptosis) → contributes to malignant transformation | ||
|- | |- | ||
|KDM6A (H3K27 demethylase) | |KDM6A (H3K27 demethylase) | ||
|Loss‑of‑function → accumulation of H3K27me3 (repressive histone mark) (“histone‑eraser” defect | |Loss‑of‑function → accumulation of H3K27me3 (repressive histone mark) (“histone‑eraser” defect) | ||
|Further chromatin repression of tumour‑suppressor genes; may enhance survival of malignant T cells | |Further chromatin repression of tumour‑suppressor genes; may enhance survival of malignant T cells | ||
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|CREBBP / EP300 (histone acetyl‑transferases) | |CREBBP / EP300 (histone acetyl‑transferases) | ||
|Loss‑of‑function mutations (“histone‑writer” defect) → reduced histone acetylation and gene activation | |Loss‑of‑function mutations (“histone‑writer” defect) → reduced histone acetylation and gene activation | ||
|Diminished transcriptional activation of tumour‑suppressor/immune genes; may drive malignant progression | |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) | |DNA methylation of specific tumour‑suppressor loci (e.g., CDKN2A promoter; FAS promoter) | ||
|Hypermethylation of promoter CpG islands → silencing of | |Hypermethylation of promoter CpG islands → silencing of tumor suppressor / apoptosis‑initiator genes | ||
|Loss of cell‑cycle control or apoptosis leads to malignant T‑cell survival/proliferation | |Loss of cell‑cycle control or apoptosis leads to malignant T‑cell survival/proliferation | ||
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