Merge branch 'master' of github.com:morinlab/LLMPP.wiki

-Mutations were first described in DLBCL in 2013 by Morin et al.¹ Subsequent exome and genome-wide studies of DLBCL did not reproduce this observation.

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-Mutations in this gene were first described in DLBCL in 2021 by Hübschmann et al.¹

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-Mutations in this gene were first described in DLBCL in 2021 by Hübschmann et al.¹

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-Mutations in this gene were first described in MZL by Braggio et al,^{[@braggioGenomicAnalysisMarginal2012]} then in MCL by Bea et al.^{[@beaLandscapeSomaticMutations2013]} ATM mutations were later described in DLBCL by Reddy et al.^{[@reddyGeneticFunctionalDrivers2017]}

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-Mutations in this gene were first described in DLBCL in 2021 by Hübschmann et al.^{[@hubschmannMutationalMechanismsShaping2021]}

-Mutations in this gene were first described in DLBCL in 2017 by Reddy et al.^{[@reddyGeneticFunctionalDrivers2017]} Subsequent exome and genome-wide studies of DLBCL did not reproduce this observation.

-BCOR acts as a co-repressor of BCL6, and mutations in BCOR could impair its binding affinity to BCL6 and other partners. Overall, protein-altering mutations in BCOR seem to be rare in DLBCL and MCL.^{[@jalladesExomeSequencingIdentifies2017],[@nadeuGenomicEpigenomicInsights2020]} One study reported a much higher prevalence of a hot spot mutation in BCOR but this result has not been reproduced.^{[@jalladesExomeSequencingIdentifies2017]}

-BIRC6, as a negative regulator of non-canonical NF-κB signaling, is implicated in lymphomagenesis. Mutations in the BIRC6 have been found in DLBCL and grey zone lymphoma (GZL).^{[@sarkozyMutationalLandscapeGray2021],[@reddyGeneticFunctionalDrivers2017]}

-# BLK

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-Mutations in this gene were first described in DLBCL in 2017 by Reddy et al.^{[@reddyGeneticFunctionalDrivers2017]} Subsequent exome and genome-wide studies of DLBCL did not reproduce this observation.

-*Q36H* Conditional knock-in mouse models expressing the BTG1 Q36H mutation in B cells have shown that these mutations lead to earlier onset of lymphoma, shorter survival, and dysplastic B cell infiltration into non-lymphoid organs. These findings reinforce the role of BTG1 mutations in enhancing lymphoma aggressiveness.³

-*L26P, G66D, and I115V* Have each been shown to be unable to rescue wild-type BTG1 activity in a xenotransplantation model, suggesting that they impair BTG1 function.²

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-One study reported BTK mutations in approximately 7% of FL and 11% of transformed FL cases.^{[@krysiakRecurrentSomaticMutations2017]} Another showed these mutations were more common, and typically co-occur in tumours with BCL2 translocations. Despite the known role of certain BTK mutations in acquired resistance to BTK inhibitors, these mutations were found in BTK inhibitor-naïve patients.^{[@albuquerqueEnhancingKnowledgeDiscovery2017]} These mutations often occur in treatment-naive patients and lead to inactivation of the BTK protein through destabilization or by altering key residues involved in enzymatic activity.^{[@krysiakRecurrentSomaticMutations2017]} The mutation pattern in DLBCL and FL implies the preferential accumulation of *inactivating mutations*^{[@huFollicularLymphomaassociatedBTK2021; @schejbelInactivatingBTKMutations2022]}. No notable hot spots have been described in this gene in the context of the cancers listed below.

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-Mutations in this gene were first described in DLBCL in 2021 by Hübschmann et al.¹

-Mutations in this gene were first described in DLBCL in 2017 by Reddy et al.¹

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-Mutations in this gene were first described in DLBCL in 2017 by Reddy et al.¹ Subsequent exome and genome-wide studies of DLBCL did not reproduce this observation.

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-Mutations in this gene were first described in DLBCL in 2017 by Reddy et al.¹ Subsequent exome and genome-wide studies of DLBCL did not reproduce this observation.

-CD36 is a transmembrane glycoprotein involved in fatty acid metabolism, glucose intolerance, and immune responses. It is expressed on various cell types, including platelets, monocytes, and some lymphocytes. One study showed higher rates of CD36 mutations in FL relative to DLBCLs.¹

-Mutations at Y196 enhance B-cell receptor (BCR) signaling by preventing the negative regulatory feedback provided by Lyn kinase, a feedback inhibitor of BCR signaling. This results in continuous activation of the NF-κB pathway, promoting tumor cell survival and proliferation.^{[@kimCD79BMYD88Mutations2014]}

-Mutations in this gene were first described in DLBCL in 2013 by Morin et al^{[@morinMutationalStructuralAnalysis2013]}, in BL in 2019 by Panea et al^{[@paneaWholeGenomeLandscape2019]} and in FL in 2023 by Russler-Germain et al.^{[@russler-germainMutationsAssociatedProgression2023]}

-Mutations in this gene were first described in FL in 2021 by Hübschmann et al.^{[@hubschmannMutationalMechanismsShaping2021]}

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-Mutations in this gene were first described in BL in 2012 by Love et al¹ and subsequently in DLBCL by Reddy et al.² Subsequent exome and genome-wide studies of DLBCL and BL did not reproduce these observations.

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-Although CDKN2A aberrations are common in DLBCL, this gene is predominantly affected by copy number alterations. One study found that deletions of the CDKN2A locus occur in about one-third of DLBCL patients.¹ The mutation pattern in DLBCL and FL implies the preferential accumulation of *inactivating mutations*. This gene has some recurrent sites of mutations (hotspots) with the most common mutation causing a truncation at codon 80 (R80*).

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-Mutations in this gene were first described in DLBCL in 2017 by Reddy et al.¹ Subsequent exome and genome-wide studies of DLBCL did not reproduce this observation.

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-Mutations in this gene were first described in DLBCL in 2017 by Reddy et al.¹ Subsequent exome and genome-wide studies of DLBCL did not reproduce this observation.

-CIITA encodes the major histocompatibility complex (MHC) class II transactivator. CIITA mutations are frequent in PMBCL. These mutations often include structural genomic rearrangements, missense, nonsense, and frameshift mutations. In PMBCL, these mutations are thought to contribute to loss of MHC expression.¹ Although loss of CIITA and MHC Class II Expression is commonly observed in DLBCL, the role of mutations and methylation affecting this locus remains unclear.² CIITA is one of [a number of genes](https://github.com/morinlab/LLMPP/wiki/ashm) affected by aberrant somatic hypermutation in B-cell lymphomas, which complicates the interpretation of mutations at this locus.

-Mutations in this gene were first described in DLBCL in 2021 by Hübschmann et al.¹

-Mutations in this gene were first described in DLBCL in 2013 by Morin et al.¹

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-Mutations in this gene were first described in FL in 2021 by Hübschmann et al.¹

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-### BL

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-This gene has some recurrent sites of mutations (hot spots). The mutation pattern in DLBCL and FL implies the preferential accumulation of *inactivating mutations* however the pattern is notable. These mutations often result in truncations affecting the DAZAP1 C-terminus, which are predicted to alter protein sub-cellular localization and disrupt protein-protein interactions.¹

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-Mutations in this gene were first described in DLBCL in 2017 by Reddy et al.¹ Subsequent exome and genome-wide studies of DLBCL did not reproduce this observation.

-Mutations in this gene were first described in FL in 2021 by Hübschmann et al.¹

-Mutations in this gene were first described in DLBCL in 2021 by Hübschmann et al.¹

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-Mutations in this gene were first described in DLBCL and FL in 2021 by Hübschmann et al.¹

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-EBF1 is a critical transcription factor in early B-cell development, regulating the expression of key genes involved in B-cell differentiation, survival, and function. EBF1 is essential for proper B-cell receptor (BCR) signaling.^{[@gyoryTranscriptionFactorEbf12012]} Mutations in EBF1 can impair BCR signaling pathways, affecting B-cell survival and proliferation.¹ EBF1 is one of [a number of genes](https://github.com/morinlab/LLMPP/wiki/ashm) affected by aberrant somatic hypermutation in B-cell lymphomas, which complicates the interpretation of mutations at this locus. This gene has some recurrent sites of mutations (hot spots) but the mutation pattern in DLBCL and FL implies the preferential accumulation of *inactivating mutations*.

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-### BL²

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-FAS encodes a cell surface receptor involved in the induction of apoptosis. FAS mutations are common in DLBCL and may be more frequent in primary gastric DLBCL.^{[@wohlfartFASCD95Mutations2004],[@schollMutationsRegionFAS2007]}

-Mutations also occur in FL at a lower rate.^{[@morinFrequentMutationHistonemodifying2011]} Although reported in one BL study,^{[[@paneaWholeGenomeLandscape2019]} overall the evidence for FAS mutations in BL remains sparse.

-thereby allowing malignant cells to evade immune surveillance.^{[@rysFasMutationsNonHodgkins2019]}

-In mouse models, Fas mutations led to a significantly shorter lymphoma-specific survival and reduced sensitivity to chemotherapy.^{[@rysFasMutationsNonHodgkins2019]}

-|Entity|Tier|Description|

-|:------:|:----:|--------------------------------------|

-||1|high-confidence MZL gene[@spinaGeneticsNodalMarginal2016]|

-||1|high-confidence PMBL/cHL/GZL gene[@]|

-Overall, these mutations are relatively rare in DLBCL and occur more frequently in other solid tumors as well as T-cell acute lymphocytic leukemia.^{[@akhoondiFBXW7HCDC4General2007]}

-The most commonly observed mutations in those cancers are the hot spots R465 and R479.^{[@akhoondiFBXW7HCDC4General2007]}

-In leukemias, FBXW7 mutations enhance the activity of leukemia-initiating cells by stabilizing oncogenic MYC.^{[@kingUbiquitinLigaseFBXW72013]} Whether they have this role in DLBCL remains to be determined.

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-Mutations in the FOXO1 gene, which encodes a member of the forkhead family of transcription factors, play a significant role in diffuse large B-cell lymphoma (DLBCL). Mutations primarily occur in the first exon, with significant portions affecting the N-terminal region and the Forkhead DNA binding domain.¹ These mutations are common in DLBCL, BL and, to a lesser extent, FL.^2,3 FOXO1 mutations can contribute to resistance to certain therapies, such as anti-CD20-based immunotherapies, by repressing MS4A1 (CD20) expression.⁴

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-**[See below ](#representative-mutations) or [the study page ](papers/paneaWholeGenomeLandscape2019.md#tier-2) for more information**

-### BL¹

-Mutations in this gene were first described in DLBCL and FL in 2021 by Hübschmann et al.¹

-Mutations in this gene were first described in DLBCL in 2021 by Hübschmann et al.¹

-Mutations in GNA13, which encodes a G protein alpha subunit involved in multiple signaling pathways, have been identified as significant contributors to the pathogenesis of germinal centre-derived B-cell lymphomas, including diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma (BL).¹ This gene has some recurrent sites of mutations (hot spots). Overall, mutations are often loss-of-function in nature, disrupting the normal activity of GNA13. GNA13 regulates B-cell homing and growth suppression within the germinal center niche and its loss of function promotes lymphoma development.²

-Mutations in the GNAI2 gene, which encodes the G protein alpha subunit involved in signal transduction, have been identified as significant contributors to the pathogenesis of B-cell lymphomas, including BL, DLBCL and, to a lesser extent, FL.¹ Mutations in GNAI2, along with GNA13 and other small GTPases, affect the signaling pathways that regulate B-cell homing. These mutations are thought to cause aberrant localization and function of B-cells within lymphoid tissues.¹ The functional role of these mutations has not been studied as extensively as those in GNA13 and further work is needed to elucidate the specific role of these mutations in lymphomagenesis.

-Mutations were first described in DLBCL in 2013 by Morin et al¹ and in BL in 2019 by Grande et al.²

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-GRHPR is one of [a number of genes](https://github.com/morinlab/LLMPP/wiki/ashm) affected by aberrant somatic hypermutation in B-cell lymphomas, which complicates the interpretation of mutations at this locus. The mutation pattern in DLBCL implies the preferential accumulation of *inactivating mutations*. Coding and non-coding mutations in GRHPR are a feature of the MCD genetic subgroup of DLBCL.¹ Further research is needed to elucidate the specific role of GRHPR mutations in DLBCL.

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-This is one of several genes that encode linker histone proteins that are recurrently mutated in DLBCL and FL.^1,2 Mutations are often found in the globular domain of the protein, which is critical for its interaction with DNA and other histone proteins.

-This is one of several genes that encode linker histone proteins that are recurrently mutated in DLBCL and FL.^1,2 Mutations are often found in the globular domain of the protein, which is critical for its interaction with DNA and other histone proteins.

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-**[See below ](#representative-mutations) or [the study page ](papers/paneaWholeGenomeLandscape2019.md#tier-2) for more information**

-This is one of several genes that encode linker histone proteins that are recurrently mutated in DLBCL and FL.^1,2 Mutations are often found in the globular domain of the protein, which is critical for its interaction with DNA and other histone proteins.

-Mutations in this gene were first described in DLBCL in 2013 by Morin et al.³ Mutations were subsequently reported in FL in 2017 by Krysiak et al⁴ and in BL by Grande et al.⁵

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-**[See below ](#representative-mutations) or [the study page ](papers/paneaWholeGenomeLandscape2019.md#tier-2) for more information**

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-**[See below ](#representative-mutations) or [the study page ](papers/paneaWholeGenomeLandscape2019.md#tier-2) for more information**

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-**[See below ](#representative-mutations) or [the study page ](papers/paneaWholeGenomeLandscape2019.md#tier-2) for more information**

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-**[See below ](#representative-mutations) or [the study page ](papers/paneaWholeGenomeLandscape2019.md#tier-2) for more information**

-Mutations in this gene were first described in DLBCL and FL in 2021 by Hübschmann et al.¹

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-HVCN1, a voltage-gated proton channel, has been identified as recurrently mutated in follicular lymphoma and mutations also appear in some DLBCL.¹ HVCN1 mutations disrupt its normal function, affecting B-cell receptor (BCR) signaling pathways.¹ This gene has some recurrent sites of mutations (hot spots) but the function of these mutations is not well understood. The mutation pattern in DLBCL and FL implies the preferential accumulation of *inactivating mutations*.

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-Mutations in this gene were first described in DLBCL and FL in 2021 by Hübschmann et al.¹

-IKZF3 (IKAROS family zinc finger 3, also known as AIOLOS) is a transcription factor involved in regulating B-cell development and function. Mutations in IKZF3 can lead to transcriptional dysregulation and contribute to the pathogenesis of B-cell neoplasms. IKZF3 is one of [a number of genes](https://github.com/morinlab/LLMPP/wiki/ashm) affected by aberrant somatic hypermutation in B-cell lymphomas, which complicates the interpretation of mutations at this locus. IKZF3 has multiple hot spot mutations in DLBCL. The most common, L162R, has been identified as a driver in CLL. In that context, it alters DNA binding specificity and causes hyperactivation of B-cell receptor (BCR) signaling and overexpression of NF-κB target genes.^{[@lazarianHotspotMutationTranscription2021]} While primarily studied in CLL, the functional effects of IKZF3 mutations could have implications for other B-cell malignancies, including DLBCL

-Mutations in IL4R have been identified in various types of B-cell lymphomas, particularly primary mediastinal large B-cell lymphoma (PMBCL) and DLBCL. IL4R is one of [a number of genes](https://github.com/morinlab/LLMPP/wiki/ashm) affected by aberrant somatic hypermutation in B-cell lymphomas, which complicates the interpretation of mutations at this locus. IL4R mutations are found in approximately 24.2% of primary PMBCL cases. These mutations are commonly single nucleotide variants in exon 8, resulting in the I242N amino acid change. This leads to constitutive activation of the JAK-STAT signaling pathway and upregulation of downstream cytokine expression profiles and B cell-specific antigens.^1,2 In DLBCL, IL4R mutations are more rare and tend to occur within the GCB subgroup.²

-Mutations in this gene were first described in DLBCL and FL in 2021 by Hübschmann et al.¹