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

de Miranda, Noel F. C. C., Peng, Roujun, Georgiou, Konstantinos, Wu, Chenglin, Sorqvist, Elin Falk, Berglund, Mattias, Chen, Longyun, Gao, Zhibo, Lagerstedt, Kristina, Lisboa, Susana, Roos, Fredrik, van Wezel, Tom, Teixeira, Manuel R., Rosenquist, Richard, Sundstrom, Christer, Enblad, Gunilla, Nilsson, Mats, Zeng, Yixin, Kipling, David Glyn and Pan-Hammarstrom, Qiang 2013. DNA repair genes are selectively mutated in diffuse large B cell lymphomas. Journal of Experimental Medicine 210 (9) , pp. 1729-1742. 10.1084/jem.20122842

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: Q Science > QH Natural history > QH426 Genetics
R Medicine > R Medicine (General)
Additional Information: Pdf uploaded in accordance with publisher's policy at http://www.sherpa.ac.uk/romeo/issn/0022-1007/ (accessed 12/03/2014).
Publisher: Rockefeller University Press
ISSN: 0022-1007
Date of First Compliant Deposit: 30 March 2016
Last Modified: 04 Jun 2017 05:28
URI: http://orca-mwe.cf.ac.uk/id/eprint/51512

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