Buchumschlag

Mutational mechanisms shaping the coding and noncoding genome of germinal center derived B-cell lymphomas

B cells have the unique property to somatically alter their immunoglobulin (IG) genes by V(D)J recombination, somatic hypermutation (SHM) and class-switch recombination (CSR). Aberrant targeting of these mechanisms is implicated in lymphomagenesis, but the mutational processes are poorly understood....

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Hauptverfasser: Hübschmann, Daniel (VerfasserIn) , Kleinheinz, Kortine (VerfasserIn) , Wagener, Rabea (VerfasserIn) , Bernhart, Stephan H. (VerfasserIn) , López, Cristina (VerfasserIn) , Toprak, Umut (VerfasserIn) , Sungalee, Stéphanie (VerfasserIn) , Ishaque, Naveed (VerfasserIn) , Kretzmer, Helene (VerfasserIn) , Kreuz, Markus (VerfasserIn) , Waszak, Sebastian Martin (VerfasserIn) , Paramasivam, Nagarajan (VerfasserIn) , Ammerpohl, Ole (VerfasserIn) , Aukema, Sietse M. (VerfasserIn) , Beekman, Renée (VerfasserIn) , Bergmann, Anke K. (VerfasserIn) , Bieg, Matthias (VerfasserIn) , Binder, Hans (VerfasserIn) , Borkhardt, Arndt (VerfasserIn) , Borst, Christoph (VerfasserIn) , Brors, Benedikt (VerfasserIn) , Bruns, Philipp (VerfasserIn) , Carrillo de Santa Pau, Enrique (VerfasserIn) , Claviez, Alexander (VerfasserIn) , Doose, Gero (VerfasserIn) , Haake, Andrea (VerfasserIn) , Karsch, Dennis (VerfasserIn) , Haas, Siegfried (VerfasserIn) , Hansmann, Martin-Leo (VerfasserIn) , Hoell, Jessica I. (VerfasserIn) , Hovestadt, Volker (VerfasserIn) , Huang, Bingding (VerfasserIn) , Hummel, Michael (VerfasserIn) , Jäger-Schmidt, Christina (VerfasserIn) , Kerssemakers, Jules (VerfasserIn) , Korbel, Jan Oliver (VerfasserIn) , Kube, Dieter (VerfasserIn) , Lawerenz, Christian (VerfasserIn) , Lenze, Dido (VerfasserIn) , Martens, Joost H. A. (VerfasserIn) , Ott, German (VerfasserIn) , Radlwimmer, Bernhard (VerfasserIn) , Reisinger, Eva (VerfasserIn) , Richter, Julia (VerfasserIn) , Rico, Daniel (VerfasserIn) , Rosenstiel, Philip (VerfasserIn) , Rosenwald, Andreas (VerfasserIn) , Schillhabel, Markus (VerfasserIn) , Stilgenbauer, Stephan (VerfasserIn) , Stadler, Peter F. (VerfasserIn) , Martín-Subero, José I. (VerfasserIn) , Szczepanowski, Monika (VerfasserIn) , Warsow, Gregor (VerfasserIn) , Weniger, Marc A. (VerfasserIn) , Zapatka, Marc (VerfasserIn) , Valencia, Alfonso (VerfasserIn) , Stunnenberg, Hendrik G. (VerfasserIn) , Lichter, Peter (VerfasserIn) , Möller, Peter (VerfasserIn) , Loeffler, Markus (VerfasserIn) , Eils, Roland (VerfasserIn) , Klapper, Wolfram (VerfasserIn) , Hoffmann, Steve (VerfasserIn) , Trümper, Lorenz (VerfasserIn) , Küppers, Ralf (VerfasserIn) , Schlesner, Matthias (VerfasserIn) , Siebert, Reiner (VerfasserIn)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: 5 May 2021
In: Leukemia
Year: 2021, Jahrgang: 35, Heft: 7, Pages: 2002-2016
ISSN:1476-5551
DOI:10.1038/s41375-021-01251-z
Online-Zugang:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1038/s41375-021-01251-z
Verlag, lizenzpflichtig, Volltext: https://www.nature.com/articles/s41375-021-01251-z
Volltext
Verfasserangaben:Daniel Hübschmann et al.

MARC

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520 |a B cells have the unique property to somatically alter their immunoglobulin (IG) genes by V(D)J recombination, somatic hypermutation (SHM) and class-switch recombination (CSR). Aberrant targeting of these mechanisms is implicated in lymphomagenesis, but the mutational processes are poorly understood. By performing whole genome and transcriptome sequencing of 181 germinal center derived B-cell lymphomas (gcBCL) we identified distinct mutational signatures linked to SHM and CSR. We show that not only SHM, but presumably also CSR causes off-target mutations in non-IG genes. Kataegis clusters with high mutational density mainly affected early replicating regions and were enriched for SHM- and CSR-mediated off-target mutations. Moreover, they often co-occurred in loci physically interacting in the nucleus, suggesting that mutation hotspots promote increased mutation targeting of spatially co-localized loci (termed hypermutation by proxy). Only around 1% of somatic small variants were in protein coding sequences, but in about half of the driver genes, a contribution of B-cell specific mutational processes to their mutations was found. The B-cell-specific mutational processes contribute to both lymphoma initiation and intratumoral heterogeneity. Overall, we demonstrate that mutational processes involved in the development of gcBCL are more complex than previously appreciated, and that B cell-specific mutational processes contribute via diverse mechanisms to lymphomagenesis. 
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JSO |a {"note":["Affiliations: Daniel Hübschmann, Kortine Kleinheinz, Rabea Wagener, Stephan H. Bernhart, Cristina López, Umut H. Toprak, Stephanie Sungalee, Naveed Ishaque, Helene Kretzmer, Markus Kreuz, Sebastian M. Waszak, Nagarajan Paramasivam, Ole Ammerpohl, Sietse M. Aukema, Renée Beekman, Anke K. Bergmann, Matthias Bieg, Hans Binder, Arndt Borkhardt, Christoph Borst, Benedikt Brors, Philipp Bruns, Enrique Carrillo de Santa Pau, Alexander Claviez, Gero Doose, Andrea Haake, Dennis Karsch, Siegfried Haas, Martin-Leo Hansmann, Jessica I. Hoell, Volker Hovestadt, Bingding Huang, Michael Hummel, Christina Jäger-Schmidt, Jules N.A. Kerssemakers, Jan O. Korbel, Dieter Kube, Chris Lawerenz, Dido Lenze, Joost H.A. Martens, German Ott, Bernhard Radlwimmer, Eva Reisinger, Julia Richter, Daniel Rico, Philip Rosenstiel, Andreas Rosenwald, Markus Schillhabel, Stephan Stilgenbauer, Peter F. Stadler, José I. Martín-Subero, Monika Szczepanowski, Gregor Warsow, Marc A. Weniger, Marc Zapatka, Alfonso Valencia, Hendrik G. Stunnenberg, Peter Lichter, Peter Möller, Markus Loeffler, Roland Eils, Wolfram Klapper, Steve Hoffmann, Lorenz Trümper, ICGC MMML-Seq consortium, ICGC DE-Mining consortium, BLUEPRINT consortium, Ralf Küppers, Matthias Schlesner, Reiner Siebert","Gesehen am 03.02.2022"],"relHost":[{"note":["Gesehen am 15.03.04"],"part":{"year":"2021","pages":"2002-2016","text":"35(2021), 7, Seite 2002-2016","volume":"35","extent":"15","issue":"7"},"id":{"zdb":["2008023-2"],"issn":["1476-5551"],"eki":["32046699X"]},"physDesc":[{"extent":"Online-Ressource"}],"title":[{"title_sort":"Leukemia","subtitle":"normal and malignant hemopoiesis ; a peer-reviewed journal","title":"Leukemia"}],"origin":[{"publisher":"Springer Nature ; Stockton Press ; Nature Publ. Group","dateIssuedDisp":"1997-","dateIssuedKey":"1997","publisherPlace":"London ; Basingstoke [u.a.] ; Basingstoke"}],"type":{"bibl":"periodical","media":"Online-Ressource"},"pubHistory":["Nachgewiesen 11.1997 -"],"language":["eng"],"recId":"32046699X","disp":"Mutational mechanisms shaping the coding and noncoding genome of germinal center derived B-cell lymphomasLeukemia"}],"id":{"doi":["10.1038/s41375-021-01251-z"],"eki":["1788471628"]},"type":{"media":"Online-Ressource","bibl":"article-journal"},"physDesc":[{"extent":"15 S."}],"title":[{"title_sort":"Mutational mechanisms shaping the coding and noncoding genome of germinal center derived B-cell lymphomas","title":"Mutational mechanisms shaping the coding and noncoding genome of germinal center derived B-cell lymphomas"}],"language":["eng"],"name":{"displayForm":["Daniel Hübschmann et al."]},"origin":[{"dateIssuedDisp":"5 May 2021","dateIssuedKey":"2021"}],"recId":"1788471628","person":[{"role":"aut","family":"Hübschmann","display":"Hübschmann, Daniel","given":"Daniel"},{"given":"Kortine","display":"Kleinheinz, Kortine","family":"Kleinheinz","role":"aut"},{"family":"Wagener","display":"Wagener, Rabea","given":"Rabea","role":"aut"},{"role":"aut","display":"Bernhart, Stephan H.","given":"Stephan H.","family":"Bernhart"},{"role":"aut","family":"López","display":"López, Cristina","given":"Cristina"},{"family":"Toprak","given":"Umut","display":"Toprak, Umut","role":"aut"},{"family":"Sungalee","given":"Stéphanie","display":"Sungalee, Stéphanie","role":"aut"},{"family":"Ishaque","given":"Naveed","display":"Ishaque, Naveed","role":"aut"},{"role":"aut","family":"Kretzmer","given":"Helene","display":"Kretzmer, Helene"},{"given":"Markus","display":"Kreuz, Markus","family":"Kreuz","role":"aut"},{"role":"aut","given":"Sebastian Martin","display":"Waszak, Sebastian Martin","family":"Waszak"},{"role":"aut","family":"Paramasivam","display":"Paramasivam, Nagarajan","given":"Nagarajan"},{"role":"aut","display":"Ammerpohl, Ole","given":"Ole","family":"Ammerpohl"},{"given":"Sietse M.","display":"Aukema, Sietse M.","family":"Aukema","role":"aut"},{"role":"aut","given":"Renée","display":"Beekman, Renée","family":"Beekman"},{"role":"aut","display":"Bergmann, Anke K.","given":"Anke K.","family":"Bergmann"},{"family":"Bieg","given":"Matthias","display":"Bieg, Matthias","role":"aut"},{"display":"Binder, Hans","given":"Hans","family":"Binder","role":"aut"},{"family":"Borkhardt","display":"Borkhardt, Arndt","given":"Arndt","role":"aut"},{"display":"Borst, Christoph","given":"Christoph","family":"Borst","role":"aut"},{"family":"Brors","given":"Benedikt","display":"Brors, Benedikt","role":"aut"},{"display":"Bruns, Philipp","given":"Philipp","family":"Bruns","role":"aut"},{"display":"Carrillo de Santa Pau, Enrique","given":"Enrique","family":"Carrillo de Santa Pau","role":"aut"},{"given":"Alexander","display":"Claviez, Alexander","family":"Claviez","role":"aut"},{"display":"Doose, Gero","given":"Gero","family":"Doose","role":"aut"},{"family":"Haake","given":"Andrea","display":"Haake, Andrea","role":"aut"},{"role":"aut","family":"Karsch","given":"Dennis","display":"Karsch, Dennis"},{"display":"Haas, Siegfried","given":"Siegfried","family":"Haas","role":"aut"},{"role":"aut","family":"Hansmann","display":"Hansmann, Martin-Leo","given":"Martin-Leo"},{"display":"Hoell, Jessica I.","given":"Jessica I.","family":"Hoell","role":"aut"},{"given":"Volker","display":"Hovestadt, Volker","family":"Hovestadt","role":"aut"},{"display":"Huang, Bingding","given":"Bingding","family":"Huang","role":"aut"},{"role":"aut","family":"Hummel","display":"Hummel, Michael","given":"Michael"},{"role":"aut","family":"Jäger-Schmidt","display":"Jäger-Schmidt, Christina","given":"Christina"},{"role":"aut","display":"Kerssemakers, Jules","given":"Jules","family":"Kerssemakers"},{"role":"aut","family":"Korbel","given":"Jan Oliver","display":"Korbel, Jan Oliver"},{"family":"Kube","given":"Dieter","display":"Kube, Dieter","role":"aut"},{"role":"aut","family":"Lawerenz","given":"Christian","display":"Lawerenz, Christian"},{"role":"aut","display":"Lenze, Dido","given":"Dido","family":"Lenze"},{"family":"Martens","given":"Joost H. 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SRT |a HUEBSCHMANMUTATIONAL5202 

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