Details

Autor(en) / Beteiligte

• de Miranda, Noel F C C
• Peng, Roujun
• Georgiou, Konstantinos
• Wu, Chenglin
• Falk Sörqvist, Elin
• Berglund, Mattias
• Chen, Longyun
• Gao, Zhibo
• Lagerstedt, Kristina
• Lisboa, Susana
• Roos, Fredrik
• van Wezel, Tom
• Teixeira, Manuel R
• Rosenquist, Richard
• Sundström, Christer
• Enblad, Gunilla
• Nilsson, Mats
• Zeng, Yixin
• Kipling, David
• Pan-Hammarström, Qiang

Titel

DNA repair genes are selectively mutated in diffuse large B cell lymphomas

Ist Teil von

• The Journal of experimental medicine, 2013-08, Vol.210 (9), p.1729-1742

Ort / Verlag

United States: The Rockefeller University Press

Erscheinungsjahr

2013

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.