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

Jens G. Lohr, Petar Stojanov, Michael S. Lawrence, Daniel Auclair, Bjoern Chapuy, Carrie Sougnez, Peter Cruz-Gordillo, Birgit Knoechel, Yan Asmann, Susan L Slager, Anne J Novak, Ahmet Dogan, Stephen Maxted Ansell, Brian K. Link, Lihua Zou, Joshua Gould, Gordon Saksena, Nicolas Stransky, Claudia Rangel-Escareño, Juan Carlos Fernandez-LopezAlfredo 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 Matthew Habermann, James R Cerhan, Margaret A. Shipp, Gad Getz, Todd R. Golub

Research output: Contribution to journalArticle

582 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)3879-3884
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number10
DOIs
StatePublished - Mar 6 2012

Fingerprint

Exome
Lymphoma, Large B-Cell, Diffuse
Mutation
Genes
Point Mutation

Keywords

  • Activation-induced deaminase
  • Human genetics
  • Next-generation sequencing

ASJC Scopus subject areas

  • General

Cite this

Discovery and prioritization of somatic mutations in diffuse large B-cell lymphoma (DLBCL) by whole-exome sequencing. / Lohr, Jens G.; Stojanov, Petar; Lawrence, Michael S.; Auclair, Daniel; Chapuy, Bjoern; Sougnez, Carrie; Cruz-Gordillo, Peter; Knoechel, Birgit; Asmann, Yan; Slager, Susan L; Novak, Anne J; Dogan, Ahmet; Ansell, Stephen Maxted; Link, Brian K.; Zou, Lihua; Gould, Joshua; Saksena, Gordon; Stransky, Nicolas; Rangel-Escareño, Claudia; Fernandez-Lopez, Juan Carlos; Hidalgo-Miranda, Alfredo; Melendez-Zajgla, Jorge; Hernández-Lemus, Enrique; Schwarz-Cruz y Celis, Angela; Imaz-Rosshandler, Ivan; Ojesina, Akinyemi I.; Jung, Joonil; Pedamallu, Chandra S.; Lander, Eric S.; Habermann, Thomas Matthew; Cerhan, James R; Shipp, Margaret A.; Getz, Gad; Golub, Todd R.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 109, No. 10, 06.03.2012, p. 3879-3884.

Research output: Contribution to journalArticle

Lohr, JG, Stojanov, P, Lawrence, MS, Auclair, D, Chapuy, B, Sougnez, C, Cruz-Gordillo, P, Knoechel, B, Asmann, Y, Slager, SL, Novak, AJ, Dogan, A, Ansell, SM, Link, BK, Zou, L, Gould, J, Saksena, G, Stransky, N, Rangel-Escareño, C, Fernandez-Lopez, JC, Hidalgo-Miranda, A, Melendez-Zajgla, J, Hernández-Lemus, E, Schwarz-Cruz y Celis, A, Imaz-Rosshandler, I, Ojesina, AI, Jung, J, Pedamallu, CS, Lander, ES, Habermann, TM, Cerhan, JR, Shipp, MA, Getz, G & Golub, TR 2012, 'Discovery and prioritization of somatic mutations in diffuse large B-cell lymphoma (DLBCL) by whole-exome sequencing', Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 10, pp. 3879-3884. https://doi.org/10.1073/pnas.1121343109
Lohr, Jens G. ; Stojanov, Petar ; Lawrence, Michael S. ; Auclair, Daniel ; Chapuy, Bjoern ; Sougnez, Carrie ; Cruz-Gordillo, Peter ; Knoechel, Birgit ; Asmann, Yan ; Slager, Susan L ; Novak, Anne J ; Dogan, Ahmet ; Ansell, Stephen Maxted ; Link, Brian K. ; Zou, Lihua ; Gould, Joshua ; Saksena, Gordon ; Stransky, Nicolas ; Rangel-Escareño, Claudia ; Fernandez-Lopez, Juan Carlos ; Hidalgo-Miranda, Alfredo ; Melendez-Zajgla, Jorge ; Hernández-Lemus, Enrique ; Schwarz-Cruz y Celis, Angela ; Imaz-Rosshandler, Ivan ; Ojesina, Akinyemi I. ; Jung, Joonil ; Pedamallu, Chandra S. ; Lander, Eric S. ; Habermann, Thomas Matthew ; Cerhan, James R ; Shipp, Margaret A. ; Getz, Gad ; Golub, Todd R. / Discovery and prioritization of somatic mutations in diffuse large B-cell lymphoma (DLBCL) by whole-exome sequencing. In: Proceedings of the National Academy of Sciences of the United States of America. 2012 ; Vol. 109, No. 10. pp. 3879-3884.
@article{db276884abbd4fb58fc2b2fa89ccaf85,
title = "Discovery and prioritization of somatic mutations in diffuse large B-cell lymphoma (DLBCL) by whole-exome sequencing",
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.",
keywords = "Activation-induced deaminase, Human genetics, Next-generation sequencing",
author = "Lohr, {Jens G.} and Petar Stojanov and Lawrence, {Michael S.} and Daniel Auclair and Bjoern Chapuy and Carrie Sougnez and Peter Cruz-Gordillo and Birgit Knoechel and Yan Asmann and Slager, {Susan L} and Novak, {Anne J} and Ahmet Dogan and Ansell, {Stephen Maxted} and Link, {Brian K.} and Lihua Zou and Joshua Gould and Gordon Saksena and Nicolas Stransky and Claudia Rangel-Escare{\~n}o and Fernandez-Lopez, {Juan Carlos} and Alfredo Hidalgo-Miranda and Jorge Melendez-Zajgla and Enrique Hern{\'a}ndez-Lemus and {Schwarz-Cruz y Celis}, Angela and Ivan Imaz-Rosshandler and Ojesina, {Akinyemi I.} and Joonil Jung and Pedamallu, {Chandra S.} and Lander, {Eric S.} and Habermann, {Thomas Matthew} and Cerhan, {James R} and Shipp, {Margaret A.} and Gad Getz and Golub, {Todd R.}",
year = "2012",
month = "3",
day = "6",
doi = "10.1073/pnas.1121343109",
language = "English (US)",
volume = "109",
pages = "3879--3884",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "10",

}

TY - JOUR

T1 - Discovery and prioritization of somatic mutations in diffuse large B-cell lymphoma (DLBCL) by whole-exome sequencing

AU - Lohr, Jens G.

AU - Stojanov, Petar

AU - Lawrence, Michael S.

AU - Auclair, Daniel

AU - Chapuy, Bjoern

AU - Sougnez, Carrie

AU - Cruz-Gordillo, Peter

AU - Knoechel, Birgit

AU - Asmann, Yan

AU - Slager, Susan L

AU - Novak, Anne J

AU - Dogan, Ahmet

AU - Ansell, Stephen Maxted

AU - Link, Brian K.

AU - Zou, Lihua

AU - Gould, Joshua

AU - Saksena, Gordon

AU - Stransky, Nicolas

AU - Rangel-Escareño, Claudia

AU - Fernandez-Lopez, Juan Carlos

AU - Hidalgo-Miranda, Alfredo

AU - Melendez-Zajgla, Jorge

AU - Hernández-Lemus, Enrique

AU - Schwarz-Cruz y Celis, Angela

AU - Imaz-Rosshandler, Ivan

AU - Ojesina, Akinyemi I.

AU - Jung, Joonil

AU - Pedamallu, Chandra S.

AU - Lander, Eric S.

AU - Habermann, Thomas Matthew

AU - Cerhan, James R

AU - Shipp, Margaret A.

AU - Getz, Gad

AU - Golub, Todd R.

PY - 2012/3/6

Y1 - 2012/3/6

N2 - 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.

AB - 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.

KW - Activation-induced deaminase

KW - Human genetics

KW - Next-generation sequencing

UR - http://www.scopus.com/inward/record.url?scp=84857942952&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84857942952&partnerID=8YFLogxK

U2 - 10.1073/pnas.1121343109

DO - 10.1073/pnas.1121343109

M3 - Article

C2 - 22343534

AN - SCOPUS:84857942952

VL - 109

SP - 3879

EP - 3884

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 10

ER -