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

  1. Hübschmann, Daniel ORCID logo
  2. Kleinheinz, Kortine
  3. Wagener, Rabea
  4. Bernhart, Stephan H.
  5. López, Cristina
  6. Toprak, Umut H.
  7. Sungalee, Stephanie
  8. Ishaque, Naveed
  9. Kretzmer, Helene
  10. Kreuz, Markus
  11. Waszak, Sebastian ORCID logo
  12. Paramasivam, Nagarajan
  13. Ammerpohl, Ole
  14. Aukema, Sietse M ORCID logo
  15. Beekman, Renée
  16. Bergmann, Anke K.
  17. Bieg, Matthias
  18. Binder, Hans
  19. Borkhardt, Arndt ORCID logo
  20. Borst, Christoph
  21. Brors, Benedikt ORCID logo
  22. Bruns, Philipp
  23. CARRILLO DE SANTA PAU, ENRIQUE ORCID logo
  24. Claviez, Alexander
  25. Doose, Gero
  26. Haake, Andrea
  27. Karsch, Dennis
  28. Haas, Siegfried
  29. Hansmann, Martin-Leo
  30. Hoell, Jessica I.
  31. Hovestadt, Volker
  32. Huang, Bingding ORCID logo
  33. Hummel, Michael
  34. Jäger-Schmidt, Christina
  35. Kerssemakers, Jules ORCID logo
  36. Korbel, Jan ORCID logo
  37. Kube, Dieter
  38. Lawerenz, Chris
  39. Lenze, Dido
  40. Martens, Joost H. A.
  41. Ott, German
  42. Radlwimmer, Bernhard
  43. Reisinger, Eva
  44. Richter, Julia ORCID logo
  45. Rico, Daniel ORCID logo
  46. Rosenstiel, Philip
  47. Rosenwald, Andreas
  48. Schillhabel, Markus
  49. Stilgenbauer, Stephan
  50. Stadler, Peter F. ORCID logo
  51. Martin-Subero, Jose Ignacio ORCID logo
  52. Szczepanowski, Monika ORCID logo
  53. Warsow, Gregor
  54. Weniger, Marc A.
  55. Zapatka, Marc ORCID logo
  56. Valencia, Alfonso
  57. Stunnenberg, Hendrik G.
  58. Lichter, Peter ORCID logo
  59. Möller, Peter
  60. Loeffler, Markus
  61. Eils, Roland
  62. Klapper, Wolfram ORCID logo
  63. Hoffmann, Steve
  64. Trümper, Lorenz
  65. Küppers, Ralf ORCID logo
  66. Schlesner, Matthias ORCID logo
  67. Siebert, Reiner

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1000 Titel
  • Mutational mechanisms shaping the coding and noncoding genome of germinal center derived B-cell lymphomas
1000 Autor/in
  1. Hübschmann, Daniel |
  2. Kleinheinz, Kortine |
  3. Wagener, Rabea |
  4. Bernhart, Stephan H. |
  5. López, Cristina |
  6. Toprak, Umut H. |
  7. Sungalee, Stephanie |
  8. Ishaque, Naveed |
  9. Kretzmer, Helene |
  10. Kreuz, Markus |
  11. Waszak, Sebastian |
  12. Paramasivam, Nagarajan |
  13. Ammerpohl, Ole |
  14. Aukema, Sietse M |
  15. Beekman, Renée |
  16. Bergmann, Anke K. |
  17. Bieg, Matthias |
  18. Binder, Hans |
  19. Borkhardt, Arndt |
  20. Borst, Christoph |
  21. Brors, Benedikt |
  22. Bruns, Philipp |
  23. CARRILLO DE SANTA PAU, ENRIQUE |
  24. Claviez, Alexander |
  25. Doose, Gero |
  26. Haake, Andrea |
  27. Karsch, Dennis |
  28. Haas, Siegfried |
  29. Hansmann, Martin-Leo |
  30. Hoell, Jessica I. |
  31. Hovestadt, Volker |
  32. Huang, Bingding |
  33. Hummel, Michael |
  34. Jäger-Schmidt, Christina |
  35. Kerssemakers, Jules |
  36. Korbel, Jan |
  37. Kube, Dieter |
  38. Lawerenz, Chris |
  39. Lenze, Dido |
  40. Martens, Joost H. A. |
  41. Ott, German |
  42. Radlwimmer, Bernhard |
  43. Reisinger, Eva |
  44. Richter, Julia |
  45. Rico, Daniel |
  46. Rosenstiel, Philip |
  47. Rosenwald, Andreas |
  48. Schillhabel, Markus |
  49. Stilgenbauer, Stephan |
  50. Stadler, Peter F. |
  51. Martin-Subero, Jose Ignacio |
  52. Szczepanowski, Monika |
  53. Warsow, Gregor |
  54. Weniger, Marc A. |
  55. Zapatka, Marc |
  56. Valencia, Alfonso |
  57. Stunnenberg, Hendrik G. |
  58. Lichter, Peter |
  59. Möller, Peter |
  60. Loeffler, Markus |
  61. Eils, Roland |
  62. Klapper, Wolfram |
  63. Hoffmann, Steve |
  64. Trümper, Lorenz |
  65. Küppers, Ralf |
  66. Schlesner, Matthias |
  67. Siebert, Reiner |
1000 Erscheinungsjahr 2021
1000 Publikationstyp
  1. Artikel |
1000 Online veröffentlicht
  • 2021-05-05
1000 Erschienen in
1000 Quellenangabe
  • 35(7):2002-2016
1000 Copyrightjahr
  • 2021
1000 Lizenz
1000 Verlagsversion
  • https://doi.org/10.1038/s41375-021-01251-z |
  • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8257491/ |
1000 Publikationsstatus
1000 Sprache der Publikation
1000 Abstract/Summary
  • 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.
1000 Sacherschließung
lokal Mutation/genetics [MeSH]
lokal Cell Line, Tumor [MeSH]
lokal Genes, Immunoglobulin/genetics [MeSH]
lokal Adult [MeSH]
lokal Humans [MeSH]
lokal Cell Line [MeSH]
lokal B-Lymphocytes/metabolism [MeSH]
lokal V(D)J Recombination/genetics [MeSH]
lokal Germinal Center/metabolism [MeSH]
lokal Oncogenesis
lokal Immunoglobulin Class Switching/genetics [MeSH]
lokal Lymphoma, B-Cell/genetics [MeSH]
lokal Hep G2 Cells [MeSH]
lokal Article
lokal K562 Cells [MeSH]
lokal Cancer genetics
lokal Human Umbilical Vein Endothelial Cells [MeSH]
lokal MCF-7 Cells [MeSH]
lokal Cancer genomics
lokal Genome/genetics [MeSH]
lokal HeLa Cells [MeSH]
lokal Somatic Hypermutation, Immunoglobulin/genetics [MeSH]
1000 Liste der Beteiligten
  1. https://orcid.org/0000-0002-6041-7049|https://frl.publisso.de/adhoc/uri/S2xlaW5oZWlueiwgS29ydGluZQ==|https://frl.publisso.de/adhoc/uri/V2FnZW5lciwgUmFiZWE=|https://frl.publisso.de/adhoc/uri/QmVybmhhcnQsIFN0ZXBoYW4gSC4=|https://frl.publisso.de/adhoc/uri/TMOzcGV6LCBDcmlzdGluYQ==|https://frl.publisso.de/adhoc/uri/VG9wcmFrLCBVbXV0IEgu|https://frl.publisso.de/adhoc/uri/U3VuZ2FsZWUsIFN0ZXBoYW5pZQ==|https://frl.publisso.de/adhoc/uri/SXNoYXF1ZSwgTmF2ZWVk|https://frl.publisso.de/adhoc/uri/S3JldHptZXIsIEhlbGVuZQ==|https://frl.publisso.de/adhoc/uri/S3JldXosIE1hcmt1cw==|https://orcid.org/0000-0003-3042-9521|https://frl.publisso.de/adhoc/uri/UGFyYW1hc2l2YW0sIE5hZ2FyYWphbg==|https://frl.publisso.de/adhoc/uri/QW1tZXJwb2hsLCBPbGU=|https://orcid.org/0000-0001-5824-0320|https://frl.publisso.de/adhoc/uri/QmVla21hbiwgUmVuw6ll|https://frl.publisso.de/adhoc/uri/QmVyZ21hbm4sIEFua2UgSy4=|https://frl.publisso.de/adhoc/uri/QmllZywgTWF0dGhpYXM=|https://frl.publisso.de/adhoc/uri/QmluZGVyLCBIYW5z|https://orcid.org/0000-0002-6121-4737|https://frl.publisso.de/adhoc/uri/Qm9yc3QsIENocmlzdG9waA==|https://orcid.org/0000-0001-5940-3101|https://frl.publisso.de/adhoc/uri/QnJ1bnMsIFBoaWxpcHA=|https://orcid.org/0000-0002-2310-2267|https://frl.publisso.de/adhoc/uri/Q2xhdmlleiwgQWxleGFuZGVy|https://frl.publisso.de/adhoc/uri/RG9vc2UsIEdlcm8=|https://frl.publisso.de/adhoc/uri/SGFha2UsIEFuZHJlYQ==|https://frl.publisso.de/adhoc/uri/S2Fyc2NoLCBEZW5uaXM=|https://frl.publisso.de/adhoc/uri/SGFhcywgU2llZ2ZyaWVk|https://frl.publisso.de/adhoc/uri/SGFuc21hbm4sIE1hcnRpbi1MZW8=|https://frl.publisso.de/adhoc/uri/SG9lbGwsIEplc3NpY2EgSS4=|https://frl.publisso.de/adhoc/uri/SG92ZXN0YWR0LCBWb2xrZXI=|https://orcid.org/0000-0002-4748-2882|https://frl.publisso.de/adhoc/uri/SHVtbWVsLCBNaWNoYWVs|https://frl.publisso.de/adhoc/uri/SsOkZ2VyLVNjaG1pZHQsIENocmlzdGluYQ==|https://orcid.org/0000-0002-0460-7032|https://orcid.org/0000-0002-2798-3794|https://frl.publisso.de/adhoc/uri/S3ViZSwgRGlldGVy|https://frl.publisso.de/adhoc/uri/TGF3ZXJlbnosIENocmlz|https://frl.publisso.de/adhoc/uri/TGVuemUsIERpZG8=|https://frl.publisso.de/adhoc/uri/TWFydGVucywgSm9vc3QgSC4gQS4=|https://frl.publisso.de/adhoc/uri/T3R0LCBHZXJtYW4=|https://frl.publisso.de/adhoc/uri/UmFkbHdpbW1lciwgQmVybmhhcmQ=|https://frl.publisso.de/adhoc/uri/UmVpc2luZ2VyLCBFdmE=|https://orcid.org/0000-0002-9543-4084|https://orcid.org/0000-0002-6561-2310|https://frl.publisso.de/adhoc/uri/Um9zZW5zdGllbCwgUGhpbGlw|https://frl.publisso.de/adhoc/uri/Um9zZW53YWxkLCBBbmRyZWFz|https://frl.publisso.de/adhoc/uri/U2NoaWxsaGFiZWwsIE1hcmt1cw==|https://frl.publisso.de/adhoc/uri/U3RpbGdlbmJhdWVyLCBTdGVwaGFu|https://orcid.org/0000-0002-5016-5191|https://orcid.org/0000-0001-8809-5195|https://orcid.org/0000-0001-5482-8880|https://frl.publisso.de/adhoc/uri/V2Fyc293LCBHcmVnb3I=|https://frl.publisso.de/adhoc/uri/V2VuaWdlciwgTWFyYyBBLg==|https://orcid.org/0000-0001-8287-5967|https://frl.publisso.de/adhoc/uri/VmFsZW5jaWEsIEFsZm9uc28=|https://frl.publisso.de/adhoc/uri/U3R1bm5lbmJlcmcsIEhlbmRyaWsgRy4=|https://orcid.org/0000-0002-2960-5279|https://frl.publisso.de/adhoc/uri/TcO2bGxlciwgUGV0ZXI=|https://frl.publisso.de/adhoc/uri/TG9lZmZsZXIsIE1hcmt1cw==|https://frl.publisso.de/adhoc/uri/RWlscywgUm9sYW5k|https://orcid.org/0000-0001-7208-4117|https://frl.publisso.de/adhoc/uri/SG9mZm1hbm4sIFN0ZXZl|https://frl.publisso.de/adhoc/uri/VHLDvG1wZXIsIExvcmVueg==|https://orcid.org/0000-0002-6691-7191|https://orcid.org/0000-0002-5896-4086|https://frl.publisso.de/adhoc/uri/U2llYmVydCwgUmVpbmVy
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