Mutational mechanisms shaping the coding and noncoding genome of germinal center derived B-cell lymphomas
Creators: name: Hübschmann, Daniel
name: Kleinheinz, Kortine
name: Wagener, Rabea
name: Bernhart, Stephan H.
name: López, Cristina
name: Toprak, Umut H.
name: Sungalee, Stephanie
name: Ishaque, Naveed
name: Kretzmer, Helene
name: Kreuz, Markus
name: Waszak, Sebastian M.
name: Paramasivam, Nagarajan
name: Ammerpohl, Ole
name: Aukema, Sietse M.
name: Beekman, Renée
name: Bergmann, Anke K.
name: Bieg, Matthias
name: Binder, Hans
name: Borkhardt, Arndt
name: Borst, Christoph
name: Brors, Benedikt
name: Bruns, Philipp
name: Carrillo De Santa Pau, Enrique
name: Claviez, Alexander
name: Doose, Gero
name: Haake, Andrea
name: Karsch, Dennis
name: Haas, Siegfried
name: Hansmann, Martin-Leo
name: Hoell, Jessica I.
name: Hovestadt, Volker
name: Huang, Bingding
name: Hummel, Michael
name: Jäger-Schmidt, Christina
name: Kerssemakers, Jules N. A.
name: Korbel, Jan O.
name: Kube, Dieter
name: Lawerenz, Chris
name: Lenze, Dido
name: Martens, Joost H. A.
name: Ott, German
name: Radlwimmer, Bernhard
name: Reisinger, Eva
name: Richter, Julia
name: Rico, Daniel
name: Rosenstiel, Philip
name: Rosenwald, Andreas
name: Schillhabel, Markus
name: Stilgenbauer, Stephan
name: Stadler, Peter F.
name: Martín-Subero, José I.
name: Szczepanowski, Monika
name: Warsow, Gregor
name: Weniger, Marc A.
name: Zapatka, Marc
name: Valencia, Alfonso
name: Stunnenberg, Hendrik G.
name: Lichter, Peter
name: Möller, Peter
name: Loeffler, Markus
name: Eils, Roland
name: Klapper, Wolfram
name: Hoffmann, Steve
name: Trümper, Lorenz
name: ICGC MMML-Seq Consortium
name: ICGC DE-Mining Consortium
name: BLUEPRINT Consortium
name: Küppers, Ralf
name: Schlesner, Matthias
name: Siebert, Reiner
Publisher: name: Universität Ulm
Year: 2021
Subjects: subject: Cancer genetics
subject: Cancer genomics
subject: Oncogenesis
subject: SOMATIC HYPERMUTATION
subject: SUPER-ENHANCERS
subject: ORGANIZATION
subject: TRANSLOCATIONS
subject: CLASSIFICATION
subject: PATHOGENESIS
subject: SIGNATURES
subject: TARGETS
subject: FAMILY
subject: GENE
subject: DDC 610 / Medicine &amp; health

description: Abstract 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.