Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2012 Mar 6;109(10):3879-84.
doi: 10.1073/pnas.1121343109. Epub 2012 Feb 17.

Discovery and prioritization of somatic mutations in diffuse large B-cell lymphoma (DLBCL) by whole-exome sequencing

Jens G Lohr  1 , Petar Stojanov, Michael S Lawrence, Daniel Auclair, Bjoern Chapuy, Carrie Sougnez, Peter Cruz-Gordillo, Birgit Knoechel, Yan W Asmann, Susan L Slager, Anne J Novak, Ahmet Dogan, Stephen M Ansell, Brian K Link, Lihua Zou, Joshua Gould, Gordon Saksena, Nicolas Stransky, Claudia Rangel-Escareño, Juan Carlos Fernandez-Lopez, Alfredo Hidalgo-Miranda, Jorge Melendez-Zajgla, Enrique Hernández-Lemus, Angela Schwarz-Cruz y Celis, Ivan Imaz-Rosshandler, Akinyemi I Ojesina, Joonil Jung, Chandra S Pedamallu, Eric S Lander, Thomas M Habermann, James R Cerhan, Margaret A Shipp, Gad Getz, Todd R Golub
Affiliations

Discovery and prioritization of somatic mutations in diffuse large B-cell lymphoma (DLBCL) by whole-exome sequencing

Jens G Lohr et al. Proc Natl Acad Sci U S A. .

Abstract

To gain insight into the genomic basis of diffuse large B-cell lymphoma (DLBCL), we performed massively parallel whole-exome sequencing of 55 primary tumor samples from patients with DLBCL and matched normal tissue. We identified recurrent mutations in genes that are well known to be functionally relevant in DLBCL, including MYD88, CARD11, EZH2, and CREBBP. We also identified somatic mutations in genes for which a functional role in DLBCL has not been previously suspected. These genes include MEF2B, MLL2, BTG1, GNA13, ACTB, P2RY8, PCLO, and TNFRSF14. Further, we show that BCL2 mutations commonly occur in patients with BCL2/IgH rearrangements as a result of somatic hypermutation normally occurring at the IgH locus. The BCL2 point mutations are primarily synonymous, and likely caused by activation-induced cytidine deaminase-mediated somatic hypermutation, as shown by comprehensive analysis of enrichment of mutations in WRCY target motifs. Those nonsynonymous mutations that are observed tend to be found outside of the functionally important BH domains of the protein, suggesting that strong negative selection against BCL2 loss-of-function mutations is at play. Last, by using an algorithm designed to identify likely functionally relevant but infrequent mutations, we identify KRAS, BRAF, and NOTCH1 as likely drivers of DLBCL pathogenesis in some patients. Our data provide an unbiased view of the landscape of mutations in DLBCL, and this in turn may point toward new therapeutic strategies for the disease.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Significantly mutated genes in 49 patients with DLBCL. (A) The rate of synonymous and nonsynonymous mutations is displayed as mutations per megabase, with individual DLBCL samples ranked by total number of mutations. (B) The heat map represents individual mutations in 49 patient samples, color-coded by type of mutation. Only one mutation per gene is shown if multiple mutations were found in a sample. Left: Histogram shows the number of mutations in each gene. Percentages represent the fraction of tumors with at least one mutation in the specified gene. Right: The 15 genes with the lowest q1-value, ranked by level of significance. (C) Base substitution distribution of individual samples, ranked in the same order as in A.
Fig. 2.
Fig. 2.
Somatic mutations in DLBCL affect genes of various classes. Sites of somatic mutations in significantly mutated genes called by analysis pipeline and passing manual review. A diagram of the relative positions of somatic mutations is shown for MLL2, TNFRSF14, BTG1, MEF2B, ACTB, and P2RY8. The type of the mutation is indicated in the key (Bottom). The overall validation rate of mutation calls was 97.9% [of 47 selected mutations tested, only one (ACTB G20A) failed to validate; see Table S5].
Fig. 3.
Fig. 3.
Selection for functionally inconsequential mutations in BCL2 and sites of somatic mutations in BCL2. Nonsynonymous mutations in BCL2 are preferentially located outside of BH-domains.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Abramson JS, Shipp MA. Advances in the biology and therapy of diffuse large B-cell lymphoma: moving toward a molecularly targeted approach. Blood. 2005;106:1164–1174. - PubMed
    1. Lenz G, Staudt LM. Aggressive lymphomas. N Engl J Med. 2010;362:1417–1429. - PMC - PubMed
    1. Pfreundschuh M, et al. German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL) Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ B-cell lymphomas: A randomised controlled trial (RICOVER-60) Lancet Oncol. 2008;9:105–116. - PubMed
    1. Glass B, et al. German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL) High-dose therapy followed by autologous stem-cell transplantation with and without rituximab for primary treatment of high-risk diffuse large B-cell lymphoma. Ann Oncol. 2010;21:2255–2261. - PubMed
    1. Alizadeh AA, et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature. 2000;403:503–511. - PubMed

Publication types

LinkOut - more resources