HAEM5:Primary cutaneous gamma/delta T-cell lymphoma: Difference between revisions
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|No | |No | ||
|MYC pathway involvement may contribute to the aggressive phenotype; direct targeting not yet established | |MYC pathway involvement may contribute to the aggressive phenotype; direct targeting not yet established<ref name=":0" /> | ||
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|'''MYCN''' | |'''MYCN''' | ||
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|P / T | |P / T | ||
|No | |No | ||
|Highlights involvement of MYC‑family beyond MYC itself in this disease | |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== | ||
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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)<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> | ||
|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 | ||
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|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)<ref name=":4" /> | ||
|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) | ||
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|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<ref name=":4" /> | ||
|Oncometabolite‑driven methylation changes, impaired differentiation, proliferation of malignant T cells | |Oncometabolite‑driven methylation changes, impaired differentiation, proliferation of malignant T cells | ||
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|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”)<ref name=":4" /> | ||
|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 | ||
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|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)<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 | |Impaired activation of gene expression programs (differentiation, apoptosis) → contributes to malignant transformation | ||
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|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)<ref name=":5" /> | ||
|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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|EZH2 (PRC2 complex methyltransferase) | |EZH2 (PRC2 complex methyltransferase) | ||
|Overexpression/gain of function → increased H3K27me3 (“histone‑writer” overactivity) | |Overexpression/gain of function → increased H3K27me3 (“histone‑writer” overactivity) <ref name=":4" /> | ||
|Enhanced silencing of differentiation/apoptosis genes; contributes to aggressive lymphoma phenotypes | |Enhanced silencing of differentiation/apoptosis genes; contributes to aggressive lymphoma phenotypes | ||
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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<ref name=":5" /> | ||
|Diminished transcriptional activation of tumour‑suppressor/immune genes; may drive malignant progression | |Diminished transcriptional activation of tumour‑suppressor/immune genes; may drive malignant progression | ||
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|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<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 | |Loss of cell‑cycle control or apoptosis leads to malignant T‑cell survival/proliferation | ||
|} | |} | ||