Diffuse large B-cell lymphoma (DLBCL) is the most common form of human lymphoma. Although a number of structural alterations have been associated with the pathogenesis of this malignancy, the full spectrum of genetic lesions that are present in the DLBCL genome, and therefore the identity of dysregulated cellular pathways, remains unknown. By combining next-generation sequencing and copy number analysis, we show that the DLBCL coding genome contains, on average, more than 30 clonally represented gene alterations per case. This analysis also revealed mutations in genes not previously implicated in DLBCL pathogenesis, including those regulating chromatin methylation (MLL2; 24% of samples) and immune recognition by T cells. These results provide initial data on the complexity of the DLBCL coding genome and identify novel dysregulated pathways underlying its pathogenesis.
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We would like to thank T. Palomero, E. Tzilianos, V. Miljkovic and the Genomics Technologies Shared Resource of the Herbert Irving Comprehensive Cancer Center at Columbia University; D. Burgess at Roche NimbleGen (Madison, Wisconsin, USA) and B. Boese at 454 Life Sciences (Branford, Connecticut, USA) for assistance with the whole-exome capture and sequencing procedure; K. Basso and A. Holmes for help with the manual curation and analysis of the copy number data; M. Malladi and Y.K. Lieu for help with the analysis of B2M and CD58; and J. Zhang for filtering the list of candidate mutations against the database of germline variants discovered from the St. Jude Children's Research Hospital-Washington University Pediatric Cancer Genome Project. The Affymetrix SNP6.0 array experiments were processed in part at the Affymetrix Research Services Laboratory. Automated DNA sequencing was performed at Genewiz, Inc. This work was supported by US National Institutes of Health (NIH) Grants PO1-CA092625 and RO1-CA37295 (to R.D.-F.), a Specialized Center of Research grant from the Leukemia & Lymphoma Society (to R.D.-F.), NIH Grant CA121852-05, the Northeast Biodefense Center (U54-AI057158) and the National Library of Medicine (1R01LM010140-01) (to R.R.), and the Associazione Italiana per la Ricerca sul Cancro (AIRC) Special Program Molecular Clinical Oncology-5 per mille (Contract No. 10007, Milan, Italy). A. Chiarenza was on leave from the Division of Hematology, Ospedale Ferrarotto, University of Catania, Catania, Italy.
The authors declare no competing financial interests.
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Pasqualucci, L., Trifonov, V., Fabbri, G. et al. Analysis of the coding genome of diffuse large B-cell lymphoma. Nat Genet 43, 830–837 (2011). https://doi.org/10.1038/ng.892
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