Genome-wide discovery of somatic regulatory variants in diffuse large B-cell lymphoma

Sarah E. Arthur, Aixiang Jiang, Bruno M. Grande, Miguel Alcaide, Razvan Cojocaru, Christopher K. Rushton, Anja Mottok, Laura K. Hilton, Prince Kumar Lat, Eric Y. Zhao, Luka Culibrk, Daisuke Ennishi, Selin Jessa, Lauren Chong, Nicole Thomas, Prasath Pararajalingam, Barbara Meissner, Merrill Boyle, Jordan Davidson, Kevin R. BushellDaniel Lai, Pedro Farinha, Graham W. Slack, Gregg B. Morin, Sohrab Shah, Dipankar Sen, Steven J.M. Jones, Andrew J. Mungall, Randy D. Gascoyne, Timothy E. Audas, Peter Unrau, Marco A. Marra, Joseph M. Connors, Christian Steidl, David W. Scott, Ryan D. Morin

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Diffuse large B-cell lymphoma (DLBCL) is an aggressive cancer originating from mature B-cells. Prognosis is strongly associated with molecular subgroup, although the driver mutations that distinguish the two main subgroups remain poorly defined. Through an integrative analysis of whole genomes, exomes, and transcriptomes, we have uncovered genes and non-coding loci that are commonly mutated in DLBCL. Our analysis has identified novel cis-regulatory sites, and implicates recurrent mutations in the 3′ UTR of NFKBIZ as a novel mechanism of oncogene deregulation and NF-κB pathway activation in the activated B-cell (ABC) subgroup. Small amplifications associated with over-expression of FCGR2B (the Fcγ receptor protein IIB), primarily in the germinal centre B-cell (GCB) subgroup, correlate with poor patient outcomes suggestive of a novel oncogene. These results expand the list of subgroup driver mutations that may facilitate implementation of improved diagnostic assays and could offer new avenues for the development of targeted therapeutics.

Original languageEnglish
Article number4001
JournalNature Communications
Volume9
Issue number1
DOIs
Publication statusPublished - Dec 1 2018
Externally publishedYes

Fingerprint

Lymphoma, Large B-Cell, Diffuse
genome
subgroups
B-Lymphocytes
Genes
Cells
Genome
Oncogenes
mutations
Mutation
oncogenes
Exome
Germinal Center
Fc Receptors
3' Untranslated Regions
Transcriptome
Deregulation
prognosis
Amplification
Assays

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Arthur, S. E., Jiang, A., Grande, B. M., Alcaide, M., Cojocaru, R., Rushton, C. K., ... Morin, R. D. (2018). Genome-wide discovery of somatic regulatory variants in diffuse large B-cell lymphoma. Nature Communications, 9(1), [4001]. https://doi.org/10.1038/s41467-018-06354-3

Genome-wide discovery of somatic regulatory variants in diffuse large B-cell lymphoma. / Arthur, Sarah E.; Jiang, Aixiang; Grande, Bruno M.; Alcaide, Miguel; Cojocaru, Razvan; Rushton, Christopher K.; Mottok, Anja; Hilton, Laura K.; Lat, Prince Kumar; Zhao, Eric Y.; Culibrk, Luka; Ennishi, Daisuke; Jessa, Selin; Chong, Lauren; Thomas, Nicole; Pararajalingam, Prasath; Meissner, Barbara; Boyle, Merrill; Davidson, Jordan; Bushell, Kevin R.; Lai, Daniel; Farinha, Pedro; Slack, Graham W.; Morin, Gregg B.; Shah, Sohrab; Sen, Dipankar; Jones, Steven J.M.; Mungall, Andrew J.; Gascoyne, Randy D.; Audas, Timothy E.; Unrau, Peter; Marra, Marco A.; Connors, Joseph M.; Steidl, Christian; Scott, David W.; Morin, Ryan D.

In: Nature Communications, Vol. 9, No. 1, 4001, 01.12.2018.

Research output: Contribution to journalArticle

Arthur, SE, Jiang, A, Grande, BM, Alcaide, M, Cojocaru, R, Rushton, CK, Mottok, A, Hilton, LK, Lat, PK, Zhao, EY, Culibrk, L, Ennishi, D, Jessa, S, Chong, L, Thomas, N, Pararajalingam, P, Meissner, B, Boyle, M, Davidson, J, Bushell, KR, Lai, D, Farinha, P, Slack, GW, Morin, GB, Shah, S, Sen, D, Jones, SJM, Mungall, AJ, Gascoyne, RD, Audas, TE, Unrau, P, Marra, MA, Connors, JM, Steidl, C, Scott, DW & Morin, RD 2018, 'Genome-wide discovery of somatic regulatory variants in diffuse large B-cell lymphoma', Nature Communications, vol. 9, no. 1, 4001. https://doi.org/10.1038/s41467-018-06354-3
Arthur SE, Jiang A, Grande BM, Alcaide M, Cojocaru R, Rushton CK et al. Genome-wide discovery of somatic regulatory variants in diffuse large B-cell lymphoma. Nature Communications. 2018 Dec 1;9(1). 4001. https://doi.org/10.1038/s41467-018-06354-3
Arthur, Sarah E. ; Jiang, Aixiang ; Grande, Bruno M. ; Alcaide, Miguel ; Cojocaru, Razvan ; Rushton, Christopher K. ; Mottok, Anja ; Hilton, Laura K. ; Lat, Prince Kumar ; Zhao, Eric Y. ; Culibrk, Luka ; Ennishi, Daisuke ; Jessa, Selin ; Chong, Lauren ; Thomas, Nicole ; Pararajalingam, Prasath ; Meissner, Barbara ; Boyle, Merrill ; Davidson, Jordan ; Bushell, Kevin R. ; Lai, Daniel ; Farinha, Pedro ; Slack, Graham W. ; Morin, Gregg B. ; Shah, Sohrab ; Sen, Dipankar ; Jones, Steven J.M. ; Mungall, Andrew J. ; Gascoyne, Randy D. ; Audas, Timothy E. ; Unrau, Peter ; Marra, Marco A. ; Connors, Joseph M. ; Steidl, Christian ; Scott, David W. ; Morin, Ryan D. / Genome-wide discovery of somatic regulatory variants in diffuse large B-cell lymphoma. In: Nature Communications. 2018 ; Vol. 9, No. 1.
@article{550c7acb000f4f33935b974a0eff57db,
title = "Genome-wide discovery of somatic regulatory variants in diffuse large B-cell lymphoma",
abstract = "Diffuse large B-cell lymphoma (DLBCL) is an aggressive cancer originating from mature B-cells. Prognosis is strongly associated with molecular subgroup, although the driver mutations that distinguish the two main subgroups remain poorly defined. Through an integrative analysis of whole genomes, exomes, and transcriptomes, we have uncovered genes and non-coding loci that are commonly mutated in DLBCL. Our analysis has identified novel cis-regulatory sites, and implicates recurrent mutations in the 3′ UTR of NFKBIZ as a novel mechanism of oncogene deregulation and NF-κB pathway activation in the activated B-cell (ABC) subgroup. Small amplifications associated with over-expression of FCGR2B (the Fcγ receptor protein IIB), primarily in the germinal centre B-cell (GCB) subgroup, correlate with poor patient outcomes suggestive of a novel oncogene. These results expand the list of subgroup driver mutations that may facilitate implementation of improved diagnostic assays and could offer new avenues for the development of targeted therapeutics.",
author = "Arthur, {Sarah E.} and Aixiang Jiang and Grande, {Bruno M.} and Miguel Alcaide and Razvan Cojocaru and Rushton, {Christopher K.} and Anja Mottok and Hilton, {Laura K.} and Lat, {Prince Kumar} and Zhao, {Eric Y.} and Luka Culibrk and Daisuke Ennishi and Selin Jessa and Lauren Chong and Nicole Thomas and Prasath Pararajalingam and Barbara Meissner and Merrill Boyle and Jordan Davidson and Bushell, {Kevin R.} and Daniel Lai and Pedro Farinha and Slack, {Graham W.} and Morin, {Gregg B.} and Sohrab Shah and Dipankar Sen and Jones, {Steven J.M.} and Mungall, {Andrew J.} and Gascoyne, {Randy D.} and Audas, {Timothy E.} and Peter Unrau and Marra, {Marco A.} and Connors, {Joseph M.} and Christian Steidl and Scott, {David W.} and Morin, {Ryan D.}",
year = "2018",
month = "12",
day = "1",
doi = "10.1038/s41467-018-06354-3",
language = "English",
volume = "9",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",

}

TY - JOUR

T1 - Genome-wide discovery of somatic regulatory variants in diffuse large B-cell lymphoma

AU - Arthur, Sarah E.

AU - Jiang, Aixiang

AU - Grande, Bruno M.

AU - Alcaide, Miguel

AU - Cojocaru, Razvan

AU - Rushton, Christopher K.

AU - Mottok, Anja

AU - Hilton, Laura K.

AU - Lat, Prince Kumar

AU - Zhao, Eric Y.

AU - Culibrk, Luka

AU - Ennishi, Daisuke

AU - Jessa, Selin

AU - Chong, Lauren

AU - Thomas, Nicole

AU - Pararajalingam, Prasath

AU - Meissner, Barbara

AU - Boyle, Merrill

AU - Davidson, Jordan

AU - Bushell, Kevin R.

AU - Lai, Daniel

AU - Farinha, Pedro

AU - Slack, Graham W.

AU - Morin, Gregg B.

AU - Shah, Sohrab

AU - Sen, Dipankar

AU - Jones, Steven J.M.

AU - Mungall, Andrew J.

AU - Gascoyne, Randy D.

AU - Audas, Timothy E.

AU - Unrau, Peter

AU - Marra, Marco A.

AU - Connors, Joseph M.

AU - Steidl, Christian

AU - Scott, David W.

AU - Morin, Ryan D.

PY - 2018/12/1

Y1 - 2018/12/1

N2 - Diffuse large B-cell lymphoma (DLBCL) is an aggressive cancer originating from mature B-cells. Prognosis is strongly associated with molecular subgroup, although the driver mutations that distinguish the two main subgroups remain poorly defined. Through an integrative analysis of whole genomes, exomes, and transcriptomes, we have uncovered genes and non-coding loci that are commonly mutated in DLBCL. Our analysis has identified novel cis-regulatory sites, and implicates recurrent mutations in the 3′ UTR of NFKBIZ as a novel mechanism of oncogene deregulation and NF-κB pathway activation in the activated B-cell (ABC) subgroup. Small amplifications associated with over-expression of FCGR2B (the Fcγ receptor protein IIB), primarily in the germinal centre B-cell (GCB) subgroup, correlate with poor patient outcomes suggestive of a novel oncogene. These results expand the list of subgroup driver mutations that may facilitate implementation of improved diagnostic assays and could offer new avenues for the development of targeted therapeutics.

AB - Diffuse large B-cell lymphoma (DLBCL) is an aggressive cancer originating from mature B-cells. Prognosis is strongly associated with molecular subgroup, although the driver mutations that distinguish the two main subgroups remain poorly defined. Through an integrative analysis of whole genomes, exomes, and transcriptomes, we have uncovered genes and non-coding loci that are commonly mutated in DLBCL. Our analysis has identified novel cis-regulatory sites, and implicates recurrent mutations in the 3′ UTR of NFKBIZ as a novel mechanism of oncogene deregulation and NF-κB pathway activation in the activated B-cell (ABC) subgroup. Small amplifications associated with over-expression of FCGR2B (the Fcγ receptor protein IIB), primarily in the germinal centre B-cell (GCB) subgroup, correlate with poor patient outcomes suggestive of a novel oncogene. These results expand the list of subgroup driver mutations that may facilitate implementation of improved diagnostic assays and could offer new avenues for the development of targeted therapeutics.

UR - http://www.scopus.com/inward/record.url?scp=85054070552&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85054070552&partnerID=8YFLogxK

U2 - 10.1038/s41467-018-06354-3

DO - 10.1038/s41467-018-06354-3

M3 - Article

C2 - 30275490

AN - SCOPUS:85054070552

VL - 9

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 1

M1 - 4001

ER -