title: DNA repair genes are selectively mutated in diffuse large B cell lymphomas.
abstract: DNA repair mechanisms are fundamental for B cell development, which relies on the somatic diversification of the immunoglobulin genes by V(D)J recombination, somatic hypermutation, and class switch recombination. Their failure is postulated to promote genomic instability and malignant transformation in B cells. By performing targeted sequencing of 73 key DNA repair genes in 29 B cell lymphoma samples, somatic and germline mutations were identified in various DNA repair pathways, mainly in diffuse large B cell lymphomas (DLBCLs). Mutations in mismatch repair genes (EXO1, MSH2, and MSH6) were associated with microsatellite instability, increased number of somatic insertions/deletions, and altered mutation signatures in tumors. Somatic mutations in nonhomologous end-joining (NHEJ) genes (DCLRE1C/ARTEMIS, PRKDC/DNA-PKcs, XRCC5/KU80, and XRCC6/KU70) were identified in four DLBCL tumors and cytogenetic analyses revealed that translocations involving the immunoglobulin-heavy chain locus occurred exclusively in NHEJ-mutated samples. The novel mutation targets, CHEK2 and PARP1, were further screened in expanded DLBCL cohorts, and somatic as well as novel and rare germline mutations were identified in 8 and 5% of analyzed tumors, respectively. By correlating defects in a subset of DNA damage response and repair genes with genomic instability events in tumors, we propose that these genes play a role in DLBCL lymphomagenesis.
authors: Clinical Immunology, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital, Huddinge, Sweden.
authors: Noel F C C
authors: NF
authors: de Miranda
authors: Roujun
authors: R
authors: Peng
authors: Konstantinos
authors: K
authors: Georgiou
authors: Chenglin
authors: C
authors: Wu
authors: Elin
authors: E
authors: Falk Sörqvist
authors: Mattias
authors: M
authors: Berglund
authors: Longyun
authors: L
authors: Chen
authors: Zhibo
authors: Z
authors: Gao
authors: Kristina
authors: K
authors: Lagerstedt
authors: Susana
authors: S
authors: Lisboa
authors: Fredrik
authors: F
authors: Roos
authors: Tom
authors: T
authors: van Wezel
authors: Manuel R
authors: MR
authors: Teixeira
authors: Richard
authors: R
authors: Rosenquist
authors: Christer
authors: C
authors: Sundström
authors: Gunilla
authors: G
authors: Enblad
authors: Mats
authors: M
authors: Nilsson
authors: Yixin
authors: Y
authors: Zeng
authors: David
authors: D
authors: Kipling
authors: Qiang
authors: Q
authors: Pan-Hammarström
mesh_terms: D000483:Alleles; D064447:Checkpoint Kinase 2; D015331:Cohort Studies; D059766:DNA End-Joining Repair / Q000235:genetics; D053843:DNA Mismatch Repair / Q000235:genetics; D004252:DNA Mutational Analysis; D004260:DNA Repair / Q000235:genetics*; D005260:Female; D056426:Genetic Loci / Q000235:genetics; D014644:Genetic Variation; D018095:Germ-Line Mutation / Q000235:genetics; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics*; D008297:Male; D053842:Microsatellite Instability; D009154:Mutation / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D017422:Sequence Analysis, DNA; D014178:Translocation, Genetic
chemical_list: D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases
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