KMT2C.md
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# KMT2C
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## Overview
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-This gene has been reported to be recurrently mutated in DLBCL. The rate of mutations in KMT2C (MLL3) varies across published cohorts. In the initial study describing these mutations, it was suggested to be mutated in >15% of DLBCLs.<sup>1</sup> The actual rate of mutations may be much lower,<sup>2</sup> potentially due to the existence of germline variants in some studies.<sup>3</sup>
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+This gene has been reported to be recurrently mutated in DLBCL. The rate of mutations in KMT2C (MLL3) varies across published cohorts. In the initial study describing these mutations, it was suggested to be mutated in >15% of DLBCLs.<sup>1</sup> The actual rate of mutations may be much lower,<sup>2</sup> potentially due to the existence of germline variants in some studies.<sup>3</sup> A more recent study suggested KMT2C mutations were more common in DLBCLs in patients of African ancestry.<sup>4</sup> Although KMT2C mutations have been described as a feature of MCL in a single study, this pattern was not reproduced in other cohorts.<sup>5</sup>
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## Relevance tier by entity
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1. *Zhang J, Grubor V, Love CL, Banerjee A, Richards KL, Mieczkowski PA, Dunphy C, Choi W, Au WY, Srivastava G, Lugar PL, Rizzieri DA, Lagoo AS, Bernal-Mizrachi L, Mann KP, Flowers C, Naresh K, Evens A, Gordon LI, Czader M, Gill JI, Hsi ED, Liu Q, Fan A, Walsh K, Jima D, Smith LL, Johnson AJ, Byrd JC, Luftig MA, Ni T, Zhu J, Chadburn A, Levy S, Dunson D, Dave SS. Genetic heterogeneity of diffuse large B-cell lymphoma. Proc Natl Acad Sci U S A. 2013 Jan 22;110(4):1398-403. doi: 10.1073/pnas.1205299110. Epub 2013 Jan 4. PMID: 23292937; PMCID: PMC3557051.*
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2. *Reddy A, Zhang J, Davis NS, Moffitt AB, Love CL, Waldrop A, Leppa S, Pasanen A, Meriranta L, Karjalainen-Lindsberg ML, Nørgaard P, Pedersen M, Gang AO, Høgdall E, Heavican TB, Lone W, Iqbal J, Qin Q, Li G, Kim SY, Healy J, Richards KL, Fedoriw Y, Bernal-Mizrachi L, Koff JL, Staton AD, Flowers CR, Paltiel O, Goldschmidt N, Calaminici M, Clear A, Gribben J, Nguyen E, Czader MB, Ondrejka SL, Collie A, Hsi ED, Tse E, Au-Yeung RKH, Kwong YL, Srivastava G, Choi WWL, Evens AM, Pilichowska M, Sengar M, Reddy N, Li S, Chadburn A, Gordon LI, Jaffe ES, Levy S, Rempel R, Tzeng T, Happ LE, Dave T, Rajagopalan D, Datta J, Dunson DB, Dave SS. Genetic and Functional Drivers of Diffuse Large B Cell Lymphoma. Cell. 2017 Oct 5;171(2):481-494.e15. doi: 10.1016/j.cell.2017.09.027. PMID: 28985567; PMCID: PMC5659841.*
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3. *https://pubpeer.com/publications/C1086AC68FD7082E3811E097EA4EA0*
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+4. *Lee MJ, Koff JL, Switchenko JM, Jhaney CI, Harkins RA, Patel SP, Dave SS, Flowers CR. Genome-defined African ancestry is associated with distinct mutations and worse survival in patients with diffuse large B-cell lymphoma. Cancer. 2020 Aug 1;126(15):3493-3503. doi: 10.1002/cncr.32866. Epub 2020 May 29. PMID: 32469082; PMCID: PMC7494053.*
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+5. *Zhang J, Jima D, Moffitt AB, Liu Q, Czader M, Hsi ED, Fedoriw Y, Dunphy CH, Richards KL, Gill JI, Sun Z, Love C, Scotland P, Lock E, Levy S, Hsu DS, Dunson D, Dave SS. The genomic landscape of mantle cell lymphoma is related to the epigenetically determined chromatin state of normal B cells. Blood. 2014 May 8;123(19):2988-96. doi: 10.1182/blood-2013-07-517177. Epub 2014 Mar 28. PMID: 24682267; PMCID: PMC4014841.*
KMT2D.md
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# KMT2D
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+## Overview
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+KMT2D (also known as MLL2) encodes a histone H3K4 methyltransferase, playing a crucial role in germinal center B cell development and function. Mutations in KMT2D are among the most common mutations in FL and are also common in DLBCL.<sup>1</sup> KMT2D mutations are recurrent but less common in BL and MCL and many other B-cell neoplasms. Mutations typically cause loss of KMT2D function, leading to diminished H3K4 methylation, impacting gene expression that favours lymphomagenesis. KMT2D mutations are associated with poor prognosis in DLBCL.<sup>2,3</sup>
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## Relevance tier by entity
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|Entity|Tier|Description |
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|:------:|:----:|--------------------------|
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-|BL |1 |high-confidence BL gene |
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-|DLBCL |1 |high-confidence DLBCL gene|
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|FL |1 |high-confidence FL gene |
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+|DLBCL |1 |high-confidence DLBCL gene|
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+|BL |1 |high-confidence BL gene |
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|MCL |1 |high-confidence MCL gene |
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## Mutation incidence in large patient cohorts (GAMBL reanalysis)
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|Entity|source |frequency (%)|
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|:------:|:---------------------:|:-------------:|
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-|BL |GAMBL genomes+capture|11.32 |
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-|BL |Thomas cohort |14.00 |
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-|BL |Panea cohort |15.80 |
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+|FL |GAMBL genomes |67.67 |
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|DLBCL |GAMBL genomes |33.46 |
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|DLBCL |Schmitz cohort |34.47 |
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|DLBCL |Reddy cohort |22.32 |
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|DLBCL |Chapuy cohort |26.07 |
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-|FL |GAMBL genomes |67.67 |
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+|BL |GAMBL genomes+capture|11.32 |
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+|BL |Thomas cohort |14.00 |
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+|BL |Panea cohort |15.80 |
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|MCL |GAMBL genomes |16.59 |
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## Mutation pattern and selective pressure estimates
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## References
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1. *Morin RD, Mendez-Lago M, Mungall AJ, Goya R, Mungall KL, Corbett RD, Johnson NA, Severson TM, Chiu R, Field M, Jackman S, Krzywinski M, Scott DW, Trinh DL, Tamura-Wells J, Li S, Firme MR, Rogic S, Griffith M, Chan S, Yakovenko O, Meyer IM, Zhao EY, Smailus D, Moksa M, Chittaranjan S, Rimsza L, Brooks-Wilson A, Spinelli JJ, Ben-Neriah S, Meissner B, Woolcock B, Boyle M, McDonald H, Tam A, Zhao Y, Delaney A, Zeng T, Tse K, Butterfield Y, Birol I, Holt R, Schein J, Horsman DE, Moore R, Jones SJ, Connors JM, Hirst M, Gascoyne RD, Marra MA. Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma. Nature. 2011 Jul 27;476(7360):298-303. doi: 10.1038/nature10351. PMID: 21796119; PMCID: PMC3210554.*
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+2. *You, H., Xu-Monette, Z., Wei, L., Nunns, H., Nagy, M., Bhagat, G., Fang, X., Zhu, F., Visco, C., Tzankov, A., Dybkaer, K., Chiu, A., Tam, W., Zu, Y., Hsi, E., Hagemeister, F., Huh, J., Ponzoni, M., Ferreri, A., Møller, M., Parsons, B., Krieken, J., Piris, M., Winter, J., Li, Y., Au, Q., Xu, B., Albitar, M., & Young, K. (2021). Genomic complexity is associated with epigenetic regulator mutations and poor prognosis in diffuse large B-cell lymphoma. Oncoimmunology, 10. https://doi.org/10.1080/2162402X.2021.1928365.*
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+3. *Rushton CK, Arthur SE, Alcaide M, Cheung M, Jiang A, Coyle KM, Cleary KLS, Thomas N, Hilton LK, Michaud N, Daigle S, Davidson J, Bushell K, Yu S, Rys RN, Jain M, Shepherd L, Marra MA, Kuruvilla J, Crump M, Mann K, Assouline S, Connors JM, Steidl C, Cragg MS, Scott DW, Johnson NA, Morin RD. Genetic and evolutionary patterns of treatment resistance in relapsed B-cell lymphoma. Blood Adv. 2020 Jul 14;4(13):2886-2898. doi: 10.1182/bloodadvances.2020001696. PMID: 32589730; PMCID: PMC7362366.*
KRAS.md
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# KRAS
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+## Overview
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+KRAS mutations are rare but occur in some cases of DLBCL.<sup>1</sup> These often affect the most common KRAS hotspot sites that are mutated in other solid cancers (G12 and G13).
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## Relevance tier by entity
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View all variants in GenomePaint [hg19](https://morinlab.github.io/LLMPP/GAMBL/KRAS.html) or [hg38](https://morinlab.github.io/LLMPP/GAMBL/KRAS_hg38.html)
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![image](images/proteinpaint/KRAS.svg)
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+
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+## References
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+1. Lohr JG, Stojanov P, Lawrence MS, Auclair D, Chapuy B, Sougnez C, Cruz-Gordillo P, Knoechel B, Asmann YW, Slager SL, Novak AJ, Dogan A, Ansell SM, Link BK, Zou L, Gould J, Saksena G, Stransky N, Rangel-Escareño C, Fernandez-Lopez JC, Hidalgo-Miranda A, Melendez-Zajgla J, Hernández-Lemus E, Schwarz-Cruz y Celis A, Imaz-Rosshandler I, Ojesina AI, Jung J, Pedamallu CS, Lander ES, Habermann TM, Cerhan JR, Shipp MA, Getz G, Golub TR. Discovery and prioritization of somatic mutations in diffuse large B-cell lymphoma (DLBCL) by whole-exome sequencing. Proc Natl Acad Sci U S A. 2012 Mar 6;109(10):3879-84. doi: 10.1073/pnas.1121343109. Epub 2012 Feb 17. PMID: 22343534; PMCID: PMC3309757.
LCOR.md
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# LCOR
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+## Overview
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+LCOR (Ligand Dependent Nuclear Receptor Corepressor) is involved in the regulation of gene expression by acting as a corepressor for various nuclear receptors and transcription factors. It influences chromatin structure and gene transcription, which can impact cell growth and differentiation. Although recurrently mutated in DLBCL, owing to different annotations of this gene and C10orf12 in hg19 and hg38, there is some confusion about the mutation rate.
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## Relevance tier by entity
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|Entity|Tier|Description |
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|:------:|:----:|--------------------------------------|
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-|BL |2 |relevance in BL not firmly established|
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|DLBCL |1 |high-confidence DLBCL gene |
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+|BL |2 |relevance in BL not firmly established|
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## Mutation incidence in large patient cohorts (GAMBL reanalysis)
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|Entity|source |frequency (%)|
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|:------:|:---------------------:|:-------------:|
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-|BL |GAMBL genomes+capture|3.46 |
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-|BL |Thomas cohort |0.00 |
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-|BL |Panea cohort | NA |
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|DLBCL |GAMBL genomes |6.31 |
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|DLBCL |Schmitz cohort |0.43 |
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|DLBCL |Reddy cohort |0.50 |
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|DLBCL |Chapuy cohort |0.43 |
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+|BL |GAMBL genomes+capture|3.46 |
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+|BL |Thomas cohort |0.00 |
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+|BL |Panea cohort | NA |
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## Mutation pattern and selective pressure estimates
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