Changes in bcea29f: add EE

				CD79B.md
			
          @@ -18,6 +18,10 @@ This and other common mutations primarily occur in the immunoreceptor tyrosine-b

          +## Experimental Evidence

          +

          +Driver mutations affecting this gene in DLBCL have been experimentally demonstrated to cause a gain of function (GOF).[@davisChronicActiveBcellreceptor2010]

          +

           ## Relevance tier by entity

           [[include:table1_CD79B.md]]

				CDKN2A.md
			
          @@ -11,6 +11,10 @@ nocite: |

           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.[@spinaGeneticsNodalMarginal2016] 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*). 

          +## Experimental Evidence

          +

          +Driver mutations affecting this gene in DLBCL have been experimentally demonstrated to cause a reduction or loss of function (LOF).[@kannengiesserFunctionalStructuralGenetic2009]

          +

           ## Relevance tier by entity

           [[include:table1_CDKN2A.md]]

				CIITA.md
			
          @@ -11,6 +11,10 @@ nocite: |

           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.[@mottokGenomicAlterationsCIITA2015]  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.[@morinFrequentMutationHistonemodifying2011] 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.

          +## Experimental Evidence

          +

          +Driver mutations affecting this gene in DLBCL have been experimentally demonstrated to cause a reduction or loss of function (LOF).[@mottokGenomicAlterationsCIITA2015]

          +

           ## Relevance tier by entity

           [[include:table1_CIITA.md]]

				CTSS.md
			
          @@ -9,6 +9,10 @@ nocite: |

          +## Experimental Evidence

          +

          +Driver mutations affecting this gene in FL have been experimentally demonstrated to cause a gain of function (GOF).[@dheillyCathepsinRegulatesAntigen2020]

          +

           ## Relevance tier by entity

           [[include:table1_CTSS.md]]

				CXCR4.md
			
          @@ -15,6 +15,10 @@ Mutations in this gene were first described in DLBCL in 2012 [@khodabakhshiRecur

          +## Experimental Evidence

          +

          +Driver mutations affecting this gene in DLBCL have been experimentally demonstrated to cause a reduction or loss of function (LOF).[@zmajkovicovaGenotypephenotypeCorrelationsWHIM2022]

          +

           ## Relevance tier by entity

           [[include:table1_CXCR4.md]]

				DDX3X.md
			
          @@ -12,6 +12,10 @@ Mutations in the DDX3X gene, which encodes an RNA helicase involved in various a

           These mutations are predominantly loss-of-function (LOF) mutations, affecting the helicase domain of the protein. Missense mutations are predominantly found in male patients and rarely in females, hence showing a sex-specific pattern.[@gongSequentialInverseDysregulation2021]

          +## Experimental Evidence

          +

          +Driver mutations affecting this gene in DLBCL/BL have been experimentally demonstrated to cause a reduction or loss of function (LOF).[@gongSequentialInverseDysregulation2021]

          +

           ## Relevance tier by entity

           [[include:table1_DDX3X]]

				EBF1.md
			
          @@ -13,6 +13,10 @@ EBF1 is a critical transcription factor in early B-cell development, regulating 

          +## Experimental Evidence

          +

          +Driver mutations affecting this gene in DLBCL/FL have been experimentally demonstrated to cause a reduction or loss of function (LOF).[@ramirez-komoSpontaneousLossLineage2017]

          +

           ## Relevance tier by entity

           [[include:table1_EBF1.md]]

				ETV6.md
			
          @@ -16,6 +16,10 @@ Coding and non-coding mutations in this gene are associated with the MCD genetic

          +## Experimental Evidence

          +

          +Driver mutations affecting this gene in DLBCL have been experimentally demonstrated to cause a reduction or loss of function (LOF).[@wangETV6MutationCohort2014]

          +

           ## Relevance tier by entity

           [[include:table1_ETV6.md]]

				FAS.md
			
          @@ -15,6 +15,10 @@ thereby allowing malignant cells to evade immune surveillance.[@rysFasMutationsN

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

          +## Experimental Evidence

          +

          +Driver mutations affecting this gene in FL/DLBCL have been experimentally demonstrated to cause a reduction or loss of function (LOF).[@wangFasFADDDeathDomain2010]

          +

           ## Relevance tier by entity

           [[include:table1_FAS.md]]

				FBXO11.md
			
          @@ -13,6 +13,10 @@ This gene has some recurrent sites of mutations (hot spots). Mutations lead to s

           These mutations present a potential novel target for therapeutic intervention, particularly through strategies aimed at degrading BCL6 or inhibiting its function.

          +## Experimental Evidence

          +

          +Driver mutations affecting this gene in DLBCL/BL have been experimentally demonstrated to cause a reduction or loss of function (LOF).[@duanFBXO11TargetsBCL62011]

          +

           ## Relevance tier by entity

           [[include:table1_FBXO11]]

				FBXW7.md
			
          @@ -14,6 +14,10 @@ The most commonly observed mutations in those cancers are the hot spots R465 and

           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. 

          +## Experimental Evidence

          +

          +Driver mutations affecting this gene in DLBCL have been experimentally demonstrated to cause a reduction or loss of function (LOF).[@saffieFBXW7TriggersDegradation2020]

          +

           ## Relevance tier by entity

           [[include:table1_FBXW7.md]]

				FOXO1.md
			
          @@ -11,6 +11,10 @@ nocite: |

           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.[@trinhAnalysisFOXO1Mutations]  These mutations are common in DLBCL, BL and, to a lesser extent, FL.[@schmitzBurkittLymphomaPathogenesis2012; @morinFrequentMutationHistonemodifying2011] FOXO1 mutations can contribute to resistance to certain therapies, such as anti-CD20-based immunotherapies, by repressing MS4A1 (CD20) expression.[@pyrzynskaFOXO1PromotesResistance2018] 

          +## Experimental Evidence

          +

          +Driver mutations affecting this gene in FL/DLBCL/BL have been experimentally demonstrated to cause a gain of function (GOF).[@trinhAnalysisFOXO1Mutations]

          +

           ## Relevance tier by entity

           [[include:table1_FOXO1.md]]

				GNA13.md
			
          @@ -12,6 +12,10 @@ Mutations in GNA13, which encodes a G protein alpha subunit involved in multiple

          +## Experimental Evidence

          +

          +Driver mutations affecting this gene in BL/FL/DLBCL have been experimentally demonstrated to cause a reduction or loss of function (LOF).[@muppidiLossSignalingGa132014; @ohayreInactivatingMutationsGNA132016]

          +

           ## Relevance tier by entity

           [[include:table1_GNA13]]

				GNAI2.md
			
          @@ -13,6 +13,10 @@ Mutations in the GNAI2 gene, which encodes the G protein alpha subunit involved 

           Mutations were first described in DLBCL in 2013 by Morin et al[@morinMutationalStructuralAnalysis2013] and in BL in 2019 by Grande et al.[@grandeGenomewideDiscoverySomatic2019]

          +## Experimental Evidence

          +

          +Driver mutations affecting this gene in DLBCL have been experimentally demonstrated to cause a gain of function (GOF).[@muppidiLossSignalingGa132014]

          +

           ## Relevance tier by entity

           [[include:table1_GNAI2]]

				HLA-A.md
			
          @@ -12,6 +12,10 @@ Mutations in the HLA-B gene have been associated with a loss of cell surface exp

            The mutation pattern in DLBCL implies the preferential accumulation of *inactivating mutations*. Different analytical strategies relating to the mapping of sequencing data and subtracting common germline variants can complicate the detection of mutations in this and other HLA genes. Likely owing to this, the rate of mutations is highly variable across studies and the true mutation rate has not been firmly established. 

          +## Experimental Evidence

          +

          +Driver mutations affecting this gene in DLBCL have been experimentally demonstrated to cause a reduction or loss of function (LOF).[@fangazioGeneticMechanismsHLAI2021]

          +

           ## Relevance tier by entity

           [[include:table1_HLA-A.md]]

				HLA-B.md
			
          @@ -12,6 +12,10 @@ Mutations in the HLA-B gene have been associated with a loss of cell surface exp

           The mutation pattern in DLBCL implies the preferential accumulation of *inactivating mutations*. Different analytical strategies relating to the mapping of sequencing data and subtracting common germline variants can complicate the detection of mutations in this and other HLA genes. Likely owing to this, the rate of mutations is highly variable across studies and the true mutation rate has not been firmly established. 

          +## Experimental Evidence

          +

          +Driver mutations affecting this gene in DLBCL have been experimentally demonstrated to cause a reduction or loss of function (LOF).[@fangazioGeneticMechanismsHLAI2021]

          +

           ## Relevance tier by entity

           [[include:table1_HLA-B.md]]

				HLA-C.md
			
          @@ -13,6 +13,10 @@ The mutation pattern in DLBCL implies the preferential accumulation of *inactiva

          +## Experimental Evidence

          +

          +Driver mutations affecting this gene in DLBCL have been experimentally demonstrated to cause a reduction or loss of function (LOF).[@fangazioGeneticMechanismsHLAI2021]

          +

           ## Relevance tier by entity

           [[include:table1_HLA-C.md]]

				IKZF3.md
			
          @@ -11,6 +11,10 @@ nocite: |

           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 

          +## Experimental Evidence

          +

          +Driver mutations affecting this gene in DLBCL have been experimentally demonstrated to cause a gain of function (GOF).[@lazarianHotspotMutationTranscription2021]

          +

           ## Relevance tier by entity

           [[include:table1_IKZF3.md]]

				IL4R.md
			
          @@ -11,6 +11,10 @@ nocite: |

           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.[@viganoSomaticIL4RMutations2018; @dunsCharacterizationDLBCLPMBL2021] In DLBCL, IL4R mutations are more rare and tend to occur within the GCB subgroup.[@dunsCharacterizationDLBCLPMBL2021]

          +## Experimental Evidence

          +

          +Driver mutations affecting this gene in DLBCL have been experimentally demonstrated to cause a gain of function (GOF).[@viganoSomaticIL4RMutations2018]

          +

           ## Relevance tier by entity

           [[include:table1_IL4R.md]]

				IRF8.md
			
          @@ -15,6 +15,10 @@ There is preliminary evidence that IRF8 mutations contribute to immune evasion b

           These are crucial for processing and presentation of self antigens.

          +## Experimental Evidence

          +

          +Driver mutations affecting this gene in DLBCL/FL have been experimentally demonstrated to cause a reduction or loss of function (LOF).[@qiuIRF8mutantCellLymphoma2024]

          +

           ## Relevance tier by entity

           [[include:table1_IRF8.md]]

				ITPKB.md
			
          @@ -11,6 +11,10 @@ nocite: |

           The ITPKB gene encodes inositol-trisphosphate 3-kinase B, an enzyme involved in the regulation of intracellular calcium levels and PI3K/Akt signaling pathways. Mutations in ITPKB have been linked to various B-cell lymphomas, including DLBCL, PMBCL and, less commonly, FL.[@reichelFlowSortingExome2015;  @schmitzGeneticsPathogenesisDiffuse2018] ITPKB 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. These mutations are associated with the **BN2** genetic subgroup of DLBCL. The mutation pattern in ITPKB implies selection for loss-of-function mutations. 

          +## Experimental Evidence

          +

          +Driver mutations affecting this gene in DLBCL have been experimentally demonstrated to cause a reduction or loss of function (LOF).[@tiacciPervasiveMutationsJAKSTAT2018]

          +

           ## Relevance tier by entity

           [[include:table1_ITPKB.md]]

				KLHL14.md
			
          @@ -11,6 +11,10 @@ nocite: |

           KLHL14 (Kelch-like family member 14) is a gene that has been identified as playing a role in B-cell lymphomas, particularly diffuse large B-cell lymphoma (DLBCL).[@zhangGeneticHeterogeneityDiffuse2013] KLHL14 has been identified as a recurrent target of somatic mutations in ABC DLBCLs. These mutations are a feature of the MCD genetic subgroup of DLBCL. The gene encodes a protein involved in the ubiquitin-proteasome system, and its inactivation leads to increased cell proliferation and survival, suggesting its role as a tumor suppressor.[@schmitzGeneticsPathogenesisDiffuse2018] KLHL14 loss has been shown to BCR-dependent NF-κB activation and cell survival in DLBCL.[@schmitzGeneticsPathogenesisDiffuse2018] This gene has some mutation hotspots but the patter of mutation overall is consistent with its role as a tumor suppressor gene.

          +## Experimental Evidence

          +

          +Driver mutations affecting this gene in DLBCL have been experimentally demonstrated to cause a reduction or loss of function (LOF).[@choiRegulationCellReceptordependent2020]

          +

           ## Relevance tier by entity

           [[include:table1_KLHL14.md]]

				KLHL6.md
			
          @@ -12,6 +12,10 @@ KLHL6 mutations appear to be relatively common in DLBCL, FL and possibly BL.[@mo

           KLHL6 is considered a tumor suppressor gene in DLBCL with mutations tending to disrupt its interaction with cullin3, leading to the loss of its ligase activity.[@choiLossKLHL6Promotes2018] 

          +## Experimental Evidence

          +

          +Driver mutations affecting this gene in DLBCL/FL have been experimentally demonstrated to cause a reduction or loss of function (LOF).[@choiLossKLHL6Promotes2018]

          +

           ## Relevance tier by entity

           [[include:table1_KLHL6.md]]

				KMT2D.md
			
          @@ -17,6 +17,10 @@ First identified as mutated in DLBCL and FL in 2011 by Morin et al.[@morinFreque

           Mutations were later described in MCL in 2013 by Bea et al.[@beaLandscapeSomaticMutations2013] KMT2D mutations were later reported in BL by Grande et al.[@grandeGenomewideDiscoverySomatic2019]

          +## Experimental Evidence

          +

          +Driver mutations affecting this gene in BL/DLBCL/FL have been experimentally demonstrated to cause a reduction or loss of function (LOF).[@zhangDisruptionKMT2DPerturbs2015]

          +

           ## Relevance tier by entity

           [[include:table1_KMT2D]]

				KRAS.md
			
          @@ -11,6 +11,10 @@ nocite: |

           KRAS mutations are rare but occur in some cases of DLBCL.[@lohrDiscoveryPrioritizationSomatic2012] These often affect the most common KRAS hotspot sites that are mutated in other solid cancers (G12 and G13).

          +## Experimental Evidence

          +

          +Driver mutations affecting this gene in DLBCL have been experimentally demonstrated to cause a gain of function (GOF).[@scheffzekRasRasGAPComplexStructural1997]

          +

           ## Relevance tier by entity

           [[include:table1_KRAS.md]]

				MAP2K1.md
			
          @@ -8,6 +8,10 @@ nocite: |

           [[_TOC_]]

          +## Experimental Evidence

          +

          +Driver mutations affecting this gene in FL have been experimentally demonstrated to cause a gain of function (GOF).[@schmidtMutationsMAP2K1Are2017]

          +

           ## Relevance tier by entity

           [[include:table1_MAP2K1.md]]

				MGA.md
			
          @@ -11,6 +11,10 @@ nocite: |

           MGA acts as a transcriptional repressor and interacts with MYC, a well-known oncogene. Mutations in MGA have been described in DLBCL.[@jalladesExomeSequencingIdentifies2017] One study suggested MGA mutations were more common in DLBCLs in patients of African ancestry.[@reddyGeneticFunctionalDrivers2017] The mutation pattern in MGA is consistent with a role as a tumour suppressor gene. 

          +## Experimental Evidence

          +

          +Driver mutations affecting this gene in DLBCL have been experimentally demonstrated to cause a reduction or loss of function (LOF).[@depaoliMGASuppressorMYC2013]

          +

           ## Relevance tier by entity

           [[include:table1_MGA.md]]

				MIR142.md
			
          @@ -8,6 +8,10 @@ nocite: |

           [[_TOC_]]

          +## Experimental Evidence

          +

          +Driver mutations affecting this gene in DLBCL have been experimentally demonstrated to cause a reduction or loss of function (LOF).[@trissalMIR142LossofFunctionMutations2018]

          +

           ## Relevance tier by entity

           [[include:table1_MIR142.md]]

				MS4A1.md
			
          @@ -14,6 +14,10 @@ which complicates the interpretation of mutations at this locus.

           In relapsed DLBCLs, MS4A1 is sometimes mutated and these mutations have been shown to reduce CD20 expression.[@rushtonGeneticEvolutionaryPatterns2020]

          +## Experimental Evidence

          +

          +Driver mutations affecting this gene in DLBCL have been experimentally demonstrated to cause a reduction or loss of function (LOF).[@rushtonGeneticEvolutionaryPatterns2020]

          +

           ## Relevance tier by entity

           [[include:table1_MS4A1.md]]

				MTOR.md
			
          @@ -14,6 +14,10 @@ Although mutations in MTOR have been reported in DLBCL and some BL, their role i

          +## Experimental Evidence

          +

          +Driver mutations affecting this gene in DLBCL have been experimentally demonstrated to cause a gain of function (GOF).[@grabinerDiverseArrayCancerassociated2014]

          +

           ## Relevance tier by entity

           [[include:table1_MTOR.md]]

				MYC.md
			
          @@ -11,6 +11,10 @@ nocite: |

           MYC 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.

          +## Experimental Evidence

          +

          +Driver mutations affecting this gene in DLBCL/FL/BL have been experimentally demonstrated to cause a gain of function (GOF).[@freieGermlinePointMutation2024]

          +

           ## Relevance tier by entity

           [[include:table1_MYC]]

				MYD88.md
			
          @@ -8,6 +8,10 @@ nocite: |

           [[_TOC_]]

          +## Experimental Evidence

          +

          +Driver mutations affecting this gene in DLBCL have been experimentally demonstrated to cause a gain of function (GOF).[@ngoOncogenicallyActiveMYD882011]

          +

           ## Relevance tier by entity

           [[include:table1_MYD88.md]]

				NFKBIA.md
			
          @@ -11,6 +11,10 @@ nocite: |

           NFKBIA encodes IκBα, an inhibitor of NF-κB, which regulates the NF-κB signaling pathway by preventing the translocation of NF-κB to the nucleus. Mutations in NFKBIA can disrupt this regulation, leading to constitutive activation of NF-κB signaling, which has an important role in a subset of DLBCLs. Mutations and deletions in NFKBIA are observed in DLBCL and are associated with constitutive activation of the NF-κB pathway. These mutations often occur in the ABC subtype and are associated with the **ST2** genetic subgroup of DLBCL.[@wienandGenomicAnalysesFlowsorted2019]

          +## Experimental Evidence

          +

          +Driver mutations affecting this gene in DLBCL have been experimentally demonstrated to cause a reduction or loss of function (LOF).[@jungnickelClonalDeleteriousMutations2000]

          +

           ## Relevance tier by entity

           [[include:table1_NFKBIA.md]]

				NFKBIE.md
			
          @@ -12,6 +12,10 @@ NFKBIE encodes IκBε, a negative regulator of NF-κB. Mutations in NFKBIE can d

          +## Experimental Evidence

          +

          +Driver mutations affecting this gene in DLBCL have been experimentally demonstrated to cause a reduction or loss of function (LOF).[@mansouriFunctionalLossIkBe2015]

          +

           ## Relevance tier by entity

           [[include:table1_NFKBIE.md]]

				NFKBIZ.md
			
          @@ -11,6 +11,10 @@ nocite: |

           The NFKBIZ gene is a significant player in NF-κB signaling, with mutations leading to its deregulation. This pathway is critical in the pathogenesis of ABC DLBCL. NFKBIZ 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 predominant cluster of mutations in NFKBIZ is in the 3' UTR and not a consequence of aSHM. NFKBIZ 3' UTR mutations confer a selective growth advantage in DLBCL cells by stabilizing NFKBIZ mRNA, resulting in increased protein levels.[@arthurGenomewideDiscoverySomatic2018] 

          +## Experimental Evidence

          +

          +Driver mutations affecting this gene in DLBCL have been experimentally demonstrated to cause a gain of function (GOF).[@arthurGenomewideDiscoverySomatic2018]

          +

           ## Relevance tier by entity

           [[include:table1_NFKBIZ.md]]

				NOTCH1.md
			
          @@ -13,6 +13,10 @@ The relevance of NOTCH1 mutations in various malignancies has been well establis

          +## Experimental Evidence

          +

          +Driver mutations affecting this gene in DLBCL have been experimentally demonstrated to cause a gain of function (GOF).[@ryanCellRegulomeLinks2017]

          +

           ## Relevance tier by entity

           [[include:table1_NOTCH1.md]]

				NOTCH2.md
			
          @@ -9,6 +9,10 @@ nocite: |

          +## Experimental Evidence

          +

          +Driver mutations affecting this gene in DLBCL have been experimentally demonstrated to cause a gain of function (GOF).[@leeGainoffunctionMutationsCopy2009]

          +

           ## Relevance tier by entity

           [[include:table1_NOTCH2.md]]

				P2RY8.md
			
          @@ -13,6 +13,10 @@ P2RY8 encodes a G protein–coupled receptor that is expressed on germinal cente

           Downstream signaling through Galpha13 (encoded by GNA13) and S1PR2 is distrupted by mutations of one of these genes in GC lymphomas including the GCB subgroup of DLBCL and BL.[@muppidiLossSignalingGa132014] 

          +## Experimental Evidence

          +

          +Driver mutations affecting this gene in BL/DLBCL have been experimentally demonstrated to cause a reduction or loss of function (LOF).[@muppidiLossSignalingGa132014]

          +

           ## Relevance tier by entity

           [[include:table1_P2RY8.md]]

				PIM1.md
			
          @@ -3,6 +3,10 @@ bibliography: 'morinlab.bib'

           csl: 'NLM.csl'

           link-citations: true

           nocite: |

          +## Experimental Evidence

          +

          +Driver mutations affecting this gene in FL/DLBCL have been experimentally demonstrated to cause a gain of function (GOF).[@kuoRolePIM1Ibrutinibresistant2016]

          +

             @dunsCharacterizationDLBCLPMBL2021, @burkhardtClinicalRelevanceMolecular2022, @pasqualucciHypermutationMultipleProtooncogenes2001

           ---

           [[_TOC_]]

          @@ -11,6 +15,10 @@ nocite: |

           PIM1 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.

          +## Experimental Evidence

          +

          +Driver mutations affecting this gene in FL/DLBCL have been experimentally demonstrated to cause a gain of function (GOF).[@kuoRolePIM1Ibrutinibresistant2016]

          +

           ## Relevance tier by entity

           [[include:table1_PIM1.md]]

          @@ -59,7 +67,15 @@ PIM1 is one of [a number of genes](https://github.com/morinlab/LLMPP/wiki/ashm) 

           ## Expression

           ![](images/gene_expression/PIM1_by_pathology.svg)

           <!-- ORIGIN: pasqualucciHypermutationMultipleProtooncogenes2001a -->

          +## Experimental Evidence

          +

          +Driver mutations affecting this gene in FL/DLBCL have been experimentally demonstrated to cause a gain of function (GOF).[@kuoRolePIM1Ibrutinibresistant2016]

          +

           <!-- BL: burkhardtClinicalRelevanceMolecular2022b -->

          +## Experimental Evidence

          +

          +Driver mutations affecting this gene in FL/DLBCL have been experimentally demonstrated to cause a gain of function (GOF).[@kuoRolePIM1Ibrutinibresistant2016]

          +

           <!-- BL: burkhardtClinicalRelevanceMolecular2022b -->

           <!-- DLBCL: pasqualucciHypermutationMultipleProtooncogenes2001a -->

				POU2AF1.md
			
          @@ -11,6 +11,10 @@ nocite: |

           POU2AF1 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.

          +## Experimental Evidence

          +

          +Driver mutations affecting this gene in DLBCL have been experimentally demonstrated to cause a reduction or loss of function (LOF).[@gonzalez-rinconUnravelingTransformationFollicular2019]

          +

           ## Relevance tier by entity

           [[include:table1_POU2AF1.md]]

				POU2F2.md
			
          @@ -8,6 +8,10 @@ nocite: |

           [[_TOC_]]

          +## Experimental Evidence

          +

          +Driver mutations affecting this gene in FL/DLBCL have been experimentally demonstrated to cause a reduction or loss of function (LOF).[@hodsonRegulationNormalBcell2016]

          +

           ## Relevance tier by entity

           [[include:table1_POU2F2.md]]

				PRDM1.md
			
          @@ -8,6 +8,10 @@ nocite: |

           [[_TOC_]]

          +## Experimental Evidence

          +

          +Driver mutations affecting this gene in DLBCL have been experimentally demonstrated to cause a reduction or loss of function (LOF).[@pasqualucciInactivationPRDM1BLIMP12006]

          +

           ## Relevance tier by entity

           [[include:table1_PRDM1.md]]

				PTEN.md
			
          @@ -8,6 +8,10 @@ nocite: |

           [[_TOC_]]

          +## Experimental Evidence

          +

          +Driver mutations affecting this gene in BL/DLBCL have been experimentally demonstrated to cause a reduction or loss of function (LOF).[@pfeiferPTENLossDefines2013]

          +

           ## Relevance tier by entity

           [[include:table1_PTEN.md]]

				PTPN6.md
			
          @@ -8,6 +8,10 @@ nocite: |

           [[_TOC_]]

          +## Experimental Evidence

          +

          +Driver mutations affecting this gene in DLBCL have been experimentally demonstrated to cause a reduction or loss of function (LOF).[@demosthenousLossFunctionMutations2015]

          +

           ## Relevance tier by entity

           [[include:table1_PTPN6.md]]

				RB1.md
			
          @@ -9,6 +9,10 @@ nocite: |

          +## Experimental Evidence

          +

          +Driver mutations affecting this gene in DLBCL have been experimentally demonstrated to cause a reduction or loss of function (LOF).[@pinyolInactivationRB1Mantlecell2007]

          +

           ## Relevance tier by entity

           [[include:table1_RB1.md]]

				RFX7.md
			
          @@ -12,6 +12,10 @@ nocite: |

           First described as mutated in BL in 2009 by Grande et al.[@grandeGenomewideDiscoverySomatic2019]

          +## Experimental Evidence

          +

          +Driver mutations affecting this gene in DLBCL/BL have been experimentally demonstrated to cause a reduction or loss of function (LOF).[@weberPiggyBacTransposonTools2019]

          +

           ## Relevance tier by entity

           [[include:table1_RFX7.md]]

				RHOA.md
			
          @@ -8,6 +8,10 @@ nocite: |

           [[_TOC_]]

          +## Experimental Evidence

          +

          +Driver mutations affecting this gene in DLBCL/BL have been experimentally demonstrated to cause a reduction or loss of function (LOF).[@ohayreInactivatingMutationsGNA132016]

          +

           ## Relevance tier by entity

           [[include:table1_RHOA.md]]

				RRAGC.md
			
          @@ -8,6 +8,10 @@ nocite: |

           [[_TOC_]]

          +## Experimental Evidence

          +

          +Driver mutations affecting this gene in DLBCL/FL have been experimentally demonstrated to cause a gain of function (GOF).[@okosunRecurrentMTORC1activatingRRAGC2016]

          +

           ## Relevance tier by entity

           [[include:table1_RRAGC.md]]

				S1PR2.md
			
          @@ -11,6 +11,10 @@ nocite: |

           S1PR2 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.

          +## Experimental Evidence

          +

          +Driver mutations affecting this gene in DLBCL have been experimentally demonstrated to cause a reduction or loss of function (LOF).[@muppidiLossSignalingGa132014]

          +

           ## Relevance tier by entity

           [[include:table1_S1PR2.md]]

				SETD1B.md
			
          @@ -8,6 +8,10 @@ nocite: |

           [[_TOC_]]

          +## Experimental Evidence

          +

          +Driver mutations affecting this gene in DLBCL have been experimentally demonstrated to cause a reduction or loss of function (LOF).[@]

          +

           ## Relevance tier by entity

           [[include:table1_SETD1B.md]]

				SF3B1.md
			
          @@ -9,6 +9,10 @@ nocite: |

          +## Experimental Evidence

          +

          +Driver mutations affecting this gene in DLBCL have been experimentally demonstrated to cause a new function (NEO).[@cazzolaBiologicClinicalSignificance2013]

          +

           ## Relevance tier by entity

           [[include:table1_SF3B1.md]]

				SGK1.md
			
          @@ -8,6 +8,10 @@ nocite: |

           [[_TOC_]]

          +## Experimental Evidence

          +

          +Driver mutations affecting this gene in FL/DLBCL have been experimentally demonstrated to cause a gain of function (GOF).[@gaoSGK1MutationsDLBCL2021]

          +

           ## Relevance tier by entity

           [[include:table1_SGK1.md]]

				SMARCA4.md
			
          @@ -14,6 +14,10 @@ Overall, components of SWI/SNF have been identified as an emerging theme in germ

          +## Experimental Evidence

          +

          +Driver mutations affecting this gene in DLBCL/FL/BL have been experimentally demonstrated to cause a reduction or loss of function (LOF).[@fernandoFunctionalCharacterizationSMARCA42020]

          +

           ## Relevance tier by entity

           [[include:table1_SMARCA4.md]]

				SOCS1.md
			
          @@ -8,6 +8,10 @@ nocite: |

           [[_TOC_]]

          +## Experimental Evidence

          +

          +Driver mutations affecting this gene in FL/DLBCL have been experimentally demonstrated to cause a reduction or loss of function (LOF).[@melznerBiallelicMutationSOCS12005]

          +

           ## Relevance tier by entity

           [[include:table1_SOCS1.md]]

				STAT3.md
			
          @@ -10,6 +10,10 @@ nocite: |

          +## Experimental Evidence

          +

          +Driver mutations affecting this gene in DLBCL have been experimentally demonstrated to cause a gain of function (GOF).[@huNovelMissenseM206K2013]

          +

           ## Relevance tier by entity

           [[include:table1_STAT3.md]]

				STAT6.md
			
          @@ -13,6 +13,10 @@ nocite: |

           The STAT6 gene, which encodes a transcription factor involved in the JAK-STAT signaling pathway, plays a significant role in the pathogenesis of various lymphomas, including diffuse large B-cell lymphoma (DLBCL). Below is a summary of the common mutations in the STAT6 gene identified in DLBCL. Mutations in the DNA binding domain of STAT6 are common in PMBCL and more rare in DLBCL. 

          +## Experimental Evidence

          +

          +Driver mutations affecting this gene in DLBCL/FL have been experimentally demonstrated to cause a gain of function (GOF).[@mentzPARP14NovelTarget2022]

          +

           ## Relevance tier by entity

           [[include:table1_STAT6.md]]

				TBL1XR1.md
			
          @@ -8,6 +8,10 @@ nocite: |

           [[_TOC_]]

          +## Experimental Evidence

          +

          +Driver mutations affecting this gene in FL/DLBCL have been experimentally demonstrated to cause a reduction or loss of function (LOF).[@venturuttiTBL1XR1MutationsDrive2020]

          +

           ## Relevance tier by entity

           [[include:table1_TBL1XR1.md]]

				TCF3.md
			
          @@ -9,6 +9,10 @@ nocite: |

           [[_TOC_]]

          +## Experimental Evidence

          +

          +Driver mutations affecting this gene in BL have been experimentally demonstrated to cause a gain of function (GOF).[@schmitzBurkittLymphomaPathogenesis2012]

          +

           ## Relevance tier by entity

           [[include:table1_TCF3.md]]

				TET2.md
			
          @@ -9,6 +9,10 @@ nocite: |

          +## Experimental Evidence

          +

          +Driver mutations affecting this gene in DLBCL have been experimentally demonstrated to cause a reduction or loss of function (LOF).[@asmarGenomewideProfilingIdentifies2013]

          +

           ## Relevance tier by entity

           [[include:table1_TET2.md]]

				TFAP4.md
			
          @@ -12,6 +12,10 @@ nocite: |

           Mutations in BL were first described by Grande et al.[@grandeGenomewideDiscoverySomatic2019]

          +## Experimental Evidence

          +

          +Driver mutations affecting this gene in BL have been experimentally demonstrated to cause a reduction or loss of function (LOF).[@toncUnexpectedSuppressionTumorigenesis2021]

          +

           ## Relevance tier by entity

           [[include:table1_TFAP4.md]]

				TMEM30A.md
			
          @@ -8,6 +8,10 @@ nocite: |

           [[_TOC_]]

          +## Experimental Evidence

          +

          +Driver mutations affecting this gene in DLBCL have been experimentally demonstrated to cause a reduction or loss of function (LOF).[@ennishiTMEM30ALossoffunctionMutations2020]

          +

           ## Relevance tier by entity

           [[include:table1_TMEM30A.md]]

				TNFAIP3.md
			
          @@ -8,6 +8,10 @@ nocite: |

           [[_TOC_]]

          +## Experimental Evidence

          +

          +Driver mutations affecting this gene in FL/DLBCL have been experimentally demonstrated to cause a reduction or loss of function (LOF).[@compagnoMutationsMultipleGenes2009]

          +

           ## Relevance tier by entity

           [[include:table1_TNFAIP3.md]]

				TNFRSF14.md
			
          @@ -10,6 +10,10 @@ nocite: |

          +## Experimental Evidence

          +

          +Driver mutations affecting this gene in DLBCL have been experimentally demonstrated to cause a reduction or loss of function (LOF).[@]

          +

           ## Relevance tier by entity

           [[include:table1_TNFRSF14.md]]

				TP53.md
			
          @@ -9,6 +9,10 @@ nocite: |

          +## Experimental Evidence

          +

          +Driver mutations affecting this gene in BL/FL/DLBCL have been experimentally demonstrated to cause a reduction or loss of function (LOF).[@katoUnderstandingFunctionstructureFunctionmutation2003]

          +

           ## Relevance tier by entity

           [[include:table1_TP53.md]]

				VMA21.md
			
          @@ -7,6 +7,10 @@ nocite: |

           ---

           [[_TOC_]]

          +## Experimental Evidence

          +

          +Driver mutations affecting this gene in FL have been experimentally demonstrated to cause a reduction or loss of function (LOF).[@wangFollicularLymphomaassociatedMutations2022]

          +

           ## Relevance tier by entity

           [[include:table1_VMA21.md]]

				XPO1.md
			
          @@ -9,6 +9,10 @@ nocite: |

           [[_TOC_]]

          +## Experimental Evidence

          +

          +Driver mutations affecting this gene in DLBCL have been experimentally demonstrated to cause a new function (NEO).[@miloudiXPO1E571KMutationModifies2020]

          +

           ## Relevance tier by entity

           [[include:table1_XPO1.md]]

...	...	@@ -18,6 +18,10 @@ This and other common mutations primarily occur in the immunoreceptor tyrosine-b
18	18
19	19
20	20
	21	+## Experimental Evidence
	22	+
	23	+Driver mutations affecting this gene in DLBCL have been experimentally demonstrated to cause a gain of function (GOF).[@davisChronicActiveBcellreceptor2010]
	24	+
21	25	## Relevance tier by entity
22	26
23	27	[[include:table1_CD79B.md]]

...	...	@@ -11,6 +11,10 @@ nocite: \|
11	11	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.[@spinaGeneticsNodalMarginal2016] 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*).
12	12
13	13
	14	+## Experimental Evidence
	15	+
	16	+Driver mutations affecting this gene in DLBCL have been experimentally demonstrated to cause a reduction or loss of function (LOF).[@kannengiesserFunctionalStructuralGenetic2009]
	17	+
14	18	## Relevance tier by entity
15	19
16	20	[[include:table1_CDKN2A.md]]

...	...	@@ -11,6 +11,10 @@ nocite: \|
11	11	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.[@mottokGenomicAlterationsCIITA2015] 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.[@morinFrequentMutationHistonemodifying2011] 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.
12	12
13	13
	14	+## Experimental Evidence
	15	+
	16	+Driver mutations affecting this gene in DLBCL have been experimentally demonstrated to cause a reduction or loss of function (LOF).[@mottokGenomicAlterationsCIITA2015]
	17	+
14	18	## Relevance tier by entity
15	19
16	20	[[include:table1_CIITA.md]]

...	...	@@ -9,6 +9,10 @@ nocite: \|
9	9
10	10
11	11
	12	+## Experimental Evidence
	13	+
	14	+Driver mutations affecting this gene in FL have been experimentally demonstrated to cause a gain of function (GOF).[@dheillyCathepsinRegulatesAntigen2020]
	15	+
12	16	## Relevance tier by entity
13	17
14	18	[[include:table1_CTSS.md]]

...	...	@@ -15,6 +15,10 @@ Mutations in this gene were first described in DLBCL in 2012 [@khodabakhshiRecur
15	15
16	16
17	17
	18	+## Experimental Evidence
	19	+
	20	+Driver mutations affecting this gene in DLBCL have been experimentally demonstrated to cause a reduction or loss of function (LOF).[@zmajkovicovaGenotypephenotypeCorrelationsWHIM2022]
	21	+
18	22	## Relevance tier by entity
19	23
20	24	[[include:table1_CXCR4.md]]

...	...	@@ -12,6 +12,10 @@ Mutations in the DDX3X gene, which encodes an RNA helicase involved in various a
12	12	These mutations are predominantly loss-of-function (LOF) mutations, affecting the helicase domain of the protein. Missense mutations are predominantly found in male patients and rarely in females, hence showing a sex-specific pattern.[@gongSequentialInverseDysregulation2021]
13	13
14	14
	15	+## Experimental Evidence
	16	+
	17	+Driver mutations affecting this gene in DLBCL/BL have been experimentally demonstrated to cause a reduction or loss of function (LOF).[@gongSequentialInverseDysregulation2021]
	18	+
15	19	## Relevance tier by entity
16	20
17	21	[[include:table1_DDX3X]]

...	...	@@ -13,6 +13,10 @@ EBF1 is a critical transcription factor in early B-cell development, regulating
13	13
14	14
15	15
	16	+## Experimental Evidence
	17	+
	18	+Driver mutations affecting this gene in DLBCL/FL have been experimentally demonstrated to cause a reduction or loss of function (LOF).[@ramirez-komoSpontaneousLossLineage2017]
	19	+
16	20	## Relevance tier by entity
17	21
18	22	[[include:table1_EBF1.md]]

...	...	@@ -16,6 +16,10 @@ Coding and non-coding mutations in this gene are associated with the MCD genetic
16	16
17	17
18	18
	19	+## Experimental Evidence
	20	+
	21	+Driver mutations affecting this gene in DLBCL have been experimentally demonstrated to cause a reduction or loss of function (LOF).[@wangETV6MutationCohort2014]
	22	+
19	23	## Relevance tier by entity
20	24
21	25	[[include:table1_ETV6.md]]

...	...	@@ -15,6 +15,10 @@ thereby allowing malignant cells to evade immune surveillance.[@rysFasMutationsN
15	15	In mouse models, Fas mutations led to a significantly shorter lymphoma-specific survival and reduced sensitivity to chemotherapy.[@rysFasMutationsNonHodgkins2019]
16	16
17	17
	18	+## Experimental Evidence
	19	+
	20	+Driver mutations affecting this gene in FL/DLBCL have been experimentally demonstrated to cause a reduction or loss of function (LOF).[@wangFasFADDDeathDomain2010]
	21	+
18	22	## Relevance tier by entity
19	23
20	24	[[include:table1_FAS.md]]

...	...	@@ -13,6 +13,10 @@ This gene has some recurrent sites of mutations (hot spots). Mutations lead to s
13	13	These mutations present a potential novel target for therapeutic intervention, particularly through strategies aimed at degrading BCL6 or inhibiting its function.
14	14
15	15
	16	+## Experimental Evidence
	17	+
	18	+Driver mutations affecting this gene in DLBCL/BL have been experimentally demonstrated to cause a reduction or loss of function (LOF).[@duanFBXO11TargetsBCL62011]
	19	+
16	20	## Relevance tier by entity
17	21
18	22	[[include:table1_FBXO11]]

...	...	@@ -14,6 +14,10 @@ The most commonly observed mutations in those cancers are the hot spots R465 and
14	14	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.
15	15
16	16
	17	+## Experimental Evidence
	18	+
	19	+Driver mutations affecting this gene in DLBCL have been experimentally demonstrated to cause a reduction or loss of function (LOF).[@saffieFBXW7TriggersDegradation2020]
	20	+
17	21	## Relevance tier by entity
18	22
19	23	[[include:table1_FBXW7.md]]

...	...	@@ -11,6 +11,10 @@ nocite: \|
11	11	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.[@trinhAnalysisFOXO1Mutations] These mutations are common in DLBCL, BL and, to a lesser extent, FL.[@schmitzBurkittLymphomaPathogenesis2012; @morinFrequentMutationHistonemodifying2011] FOXO1 mutations can contribute to resistance to certain therapies, such as anti-CD20-based immunotherapies, by repressing MS4A1 (CD20) expression.[@pyrzynskaFOXO1PromotesResistance2018]
12	12
13	13
	14	+## Experimental Evidence
	15	+
	16	+Driver mutations affecting this gene in FL/DLBCL/BL have been experimentally demonstrated to cause a gain of function (GOF).[@trinhAnalysisFOXO1Mutations]
	17	+
14	18	## Relevance tier by entity
15	19
16	20	[[include:table1_FOXO1.md]]

...	...	@@ -12,6 +12,10 @@ Mutations in GNA13, which encodes a G protein alpha subunit involved in multiple
12	12
13	13
14	14
	15	+## Experimental Evidence
	16	+
	17	+Driver mutations affecting this gene in BL/FL/DLBCL have been experimentally demonstrated to cause a reduction or loss of function (LOF).[@muppidiLossSignalingGa132014; @ohayreInactivatingMutationsGNA132016]
	18	+
15	19	## Relevance tier by entity
16	20
17	21	[[include:table1_GNA13]]

...	...	@@ -13,6 +13,10 @@ Mutations in the GNAI2 gene, which encodes the G protein alpha subunit involved
13	13	Mutations were first described in DLBCL in 2013 by Morin et al[@morinMutationalStructuralAnalysis2013] and in BL in 2019 by Grande et al.[@grandeGenomewideDiscoverySomatic2019]
14	14
15	15
	16	+## Experimental Evidence
	17	+
	18	+Driver mutations affecting this gene in DLBCL have been experimentally demonstrated to cause a gain of function (GOF).[@muppidiLossSignalingGa132014]
	19	+
16	20	## Relevance tier by entity
17	21
18	22	[[include:table1_GNAI2]]

...	...	@@ -12,6 +12,10 @@ Mutations in the HLA-B gene have been associated with a loss of cell surface exp
12	12	The mutation pattern in DLBCL implies the preferential accumulation of inactivating mutations. Different analytical strategies relating to the mapping of sequencing data and subtracting common germline variants can complicate the detection of mutations in this and other HLA genes. Likely owing to this, the rate of mutations is highly variable across studies and the true mutation rate has not been firmly established.
13	13
14	14
	15	+## Experimental Evidence
	16	+
	17	+Driver mutations affecting this gene in DLBCL have been experimentally demonstrated to cause a reduction or loss of function (LOF).[@fangazioGeneticMechanismsHLAI2021]
	18	+
15	19	## Relevance tier by entity
16	20
17	21	[[include:table1_HLA-A.md]]

...	...	@@ -13,6 +13,10 @@ The mutation pattern in DLBCL implies the preferential accumulation of *inactiva
13	13
14	14
15	15
	16	+## Experimental Evidence
	17	+
	18	+Driver mutations affecting this gene in DLBCL have been experimentally demonstrated to cause a reduction or loss of function (LOF).[@fangazioGeneticMechanismsHLAI2021]
	19	+
16	20	## Relevance tier by entity
17	21
18	22	[[include:table1_HLA-C.md]]

...	...	@@ -11,6 +11,10 @@ nocite: \|
11	11	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
12	12
13	13
	14	+## Experimental Evidence
	15	+
	16	+Driver mutations affecting this gene in DLBCL have been experimentally demonstrated to cause a gain of function (GOF).[@lazarianHotspotMutationTranscription2021]
	17	+
14	18	## Relevance tier by entity
15	19
16	20	[[include:table1_IKZF3.md]]

...	...	@@ -11,6 +11,10 @@ nocite: \|
11	11	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.[@viganoSomaticIL4RMutations2018; @dunsCharacterizationDLBCLPMBL2021] In DLBCL, IL4R mutations are more rare and tend to occur within the GCB subgroup.[@dunsCharacterizationDLBCLPMBL2021]
12	12
13	13
	14	+## Experimental Evidence
	15	+
	16	+Driver mutations affecting this gene in DLBCL have been experimentally demonstrated to cause a gain of function (GOF).[@viganoSomaticIL4RMutations2018]
	17	+
14	18	## Relevance tier by entity
15	19
16	20	[[include:table1_IL4R.md]]

...	...	@@ -15,6 +15,10 @@ There is preliminary evidence that IRF8 mutations contribute to immune evasion b
15	15	These are crucial for processing and presentation of self antigens.
16	16
17	17
	18	+## Experimental Evidence
	19	+
	20	+Driver mutations affecting this gene in DLBCL/FL have been experimentally demonstrated to cause a reduction or loss of function (LOF).[@qiuIRF8mutantCellLymphoma2024]
	21	+
18	22	## Relevance tier by entity
19	23
20	24	[[include:table1_IRF8.md]]

...	...	@@ -11,6 +11,10 @@ nocite: \|
11	11	The ITPKB gene encodes inositol-trisphosphate 3-kinase B, an enzyme involved in the regulation of intracellular calcium levels and PI3K/Akt signaling pathways. Mutations in ITPKB have been linked to various B-cell lymphomas, including DLBCL, PMBCL and, less commonly, FL.[@reichelFlowSortingExome2015; @schmitzGeneticsPathogenesisDiffuse2018] ITPKB 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. These mutations are associated with the BN2 genetic subgroup of DLBCL. The mutation pattern in ITPKB implies selection for loss-of-function mutations.
12	12
13	13
	14	+## Experimental Evidence
	15	+
	16	+Driver mutations affecting this gene in DLBCL have been experimentally demonstrated to cause a reduction or loss of function (LOF).[@tiacciPervasiveMutationsJAKSTAT2018]
	17	+
14	18	## Relevance tier by entity
15	19
16	20	[[include:table1_ITPKB.md]]

...	...	@@ -11,6 +11,10 @@ nocite: \|
11	11	KLHL14 (Kelch-like family member 14) is a gene that has been identified as playing a role in B-cell lymphomas, particularly diffuse large B-cell lymphoma (DLBCL).[@zhangGeneticHeterogeneityDiffuse2013] KLHL14 has been identified as a recurrent target of somatic mutations in ABC DLBCLs. These mutations are a feature of the MCD genetic subgroup of DLBCL. The gene encodes a protein involved in the ubiquitin-proteasome system, and its inactivation leads to increased cell proliferation and survival, suggesting its role as a tumor suppressor.[@schmitzGeneticsPathogenesisDiffuse2018] KLHL14 loss has been shown to BCR-dependent NF-κB activation and cell survival in DLBCL.[@schmitzGeneticsPathogenesisDiffuse2018] This gene has some mutation hotspots but the patter of mutation overall is consistent with its role as a tumor suppressor gene.
12	12
13	13
	14	+## Experimental Evidence
	15	+
	16	+Driver mutations affecting this gene in DLBCL have been experimentally demonstrated to cause a reduction or loss of function (LOF).[@choiRegulationCellReceptordependent2020]
	17	+
14	18	## Relevance tier by entity
15	19
16	20	[[include:table1_KLHL14.md]]

...	...	@@ -12,6 +12,10 @@ KLHL6 mutations appear to be relatively common in DLBCL, FL and possibly BL.[@mo
12	12	KLHL6 is considered a tumor suppressor gene in DLBCL with mutations tending to disrupt its interaction with cullin3, leading to the loss of its ligase activity.[@choiLossKLHL6Promotes2018]
13	13
14	14
	15	+## Experimental Evidence
	16	+
	17	+Driver mutations affecting this gene in DLBCL/FL have been experimentally demonstrated to cause a reduction or loss of function (LOF).[@choiLossKLHL6Promotes2018]
	18	+
15	19	## Relevance tier by entity
16	20
17	21	[[include:table1_KLHL6.md]]

...	...	@@ -17,6 +17,10 @@ First identified as mutated in DLBCL and FL in 2011 by Morin et al.[@morinFreque
17	17	Mutations were later described in MCL in 2013 by Bea et al.[@beaLandscapeSomaticMutations2013] KMT2D mutations were later reported in BL by Grande et al.[@grandeGenomewideDiscoverySomatic2019]
18	18
19	19
	20	+## Experimental Evidence
	21	+
	22	+Driver mutations affecting this gene in BL/DLBCL/FL have been experimentally demonstrated to cause a reduction or loss of function (LOF).[@zhangDisruptionKMT2DPerturbs2015]
	23	+
20	24	## Relevance tier by entity
21	25
22	26	[[include:table1_KMT2D]]

...	...	@@ -11,6 +11,10 @@ nocite: \|
11	11	KRAS mutations are rare but occur in some cases of DLBCL.[@lohrDiscoveryPrioritizationSomatic2012] These often affect the most common KRAS hotspot sites that are mutated in other solid cancers (G12 and G13).
12	12
13	13
	14	+## Experimental Evidence
	15	+
	16	+Driver mutations affecting this gene in DLBCL have been experimentally demonstrated to cause a gain of function (GOF).[@scheffzekRasRasGAPComplexStructural1997]
	17	+
14	18	## Relevance tier by entity
15	19
16	20	[[include:table1_KRAS.md]]

...	...	@@ -8,6 +8,10 @@ nocite: \|
8	8	[[_TOC_]]
9	9
10	10
	11	+## Experimental Evidence
	12	+
	13	+Driver mutations affecting this gene in FL have been experimentally demonstrated to cause a gain of function (GOF).[@schmidtMutationsMAP2K1Are2017]
	14	+
11	15	## Relevance tier by entity
12	16
13	17	[[include:table1_MAP2K1.md]]

...	...	@@ -11,6 +11,10 @@ nocite: \|
11	11	MGA acts as a transcriptional repressor and interacts with MYC, a well-known oncogene. Mutations in MGA have been described in DLBCL.[@jalladesExomeSequencingIdentifies2017] One study suggested MGA mutations were more common in DLBCLs in patients of African ancestry.[@reddyGeneticFunctionalDrivers2017] The mutation pattern in MGA is consistent with a role as a tumour suppressor gene.
12	12
13	13
	14	+## Experimental Evidence
	15	+
	16	+Driver mutations affecting this gene in DLBCL have been experimentally demonstrated to cause a reduction or loss of function (LOF).[@depaoliMGASuppressorMYC2013]
	17	+
14	18	## Relevance tier by entity
15	19
16	20	[[include:table1_MGA.md]]

...	...	@@ -14,6 +14,10 @@ which complicates the interpretation of mutations at this locus.
14	14	In relapsed DLBCLs, MS4A1 is sometimes mutated and these mutations have been shown to reduce CD20 expression.[@rushtonGeneticEvolutionaryPatterns2020]
15	15
16	16
	17	+## Experimental Evidence
	18	+
	19	+Driver mutations affecting this gene in DLBCL have been experimentally demonstrated to cause a reduction or loss of function (LOF).[@rushtonGeneticEvolutionaryPatterns2020]
	20	+
17	21	## Relevance tier by entity
18	22
19	23	[[include:table1_MS4A1.md]]

...	...	@@ -14,6 +14,10 @@ Although mutations in MTOR have been reported in DLBCL and some BL, their role i
14	14
15	15
16	16
	17	+## Experimental Evidence
	18	+
	19	+Driver mutations affecting this gene in DLBCL have been experimentally demonstrated to cause a gain of function (GOF).[@grabinerDiverseArrayCancerassociated2014]
	20	+
17	21	## Relevance tier by entity
18	22
19	23	[[include:table1_MTOR.md]]

...	...	@@ -11,6 +11,10 @@ nocite: \|
11	11	MYC 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.
12	12
13	13
	14	+## Experimental Evidence
	15	+
	16	+Driver mutations affecting this gene in DLBCL/FL/BL have been experimentally demonstrated to cause a gain of function (GOF).[@freieGermlinePointMutation2024]
	17	+
14	18	## Relevance tier by entity
15	19
16	20	[[include:table1_MYC]]

...	...	@@ -11,6 +11,10 @@ nocite: \|
11	11	NFKBIA encodes IκBα, an inhibitor of NF-κB, which regulates the NF-κB signaling pathway by preventing the translocation of NF-κB to the nucleus. Mutations in NFKBIA can disrupt this regulation, leading to constitutive activation of NF-κB signaling, which has an important role in a subset of DLBCLs. Mutations and deletions in NFKBIA are observed in DLBCL and are associated with constitutive activation of the NF-κB pathway. These mutations often occur in the ABC subtype and are associated with the ST2 genetic subgroup of DLBCL.[@wienandGenomicAnalysesFlowsorted2019]
12	12
13	13
	14	+## Experimental Evidence
	15	+
	16	+Driver mutations affecting this gene in DLBCL have been experimentally demonstrated to cause a reduction or loss of function (LOF).[@jungnickelClonalDeleteriousMutations2000]
	17	+
14	18	## Relevance tier by entity
15	19
16	20	[[include:table1_NFKBIA.md]]