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Mutational mechanisms shaping the coding and noncoding genome of germinal center derived B-cell lymphomas by 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; Ralf Küppers; Matthias Schlesner; Reiner Siebert; ICGC MMML-Seq consortium; ICGC DE-Mining consortium; BLUEPRINT consortium is a Medicine article available to read on EtoBox.

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

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 contribut

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

Author

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; Ralf Küppers; Matthias Schlesner; Reiner Siebert; ICGC MMML-Seq consortium; ICGC DE-Mining consortium; BLUEPRINT consortium

Publisher

Springer Science and Business Media LLC

Published

2021

Language

EN

Field

Medicine (Health Sciences)