The University of Southampton
University of Southampton Institutional Repository

Whole exome sequencing identifies novel recurrently mutated genes in patients with splenic marginal zone lymphoma

Whole exome sequencing identifies novel recurrently mutated genes in patients with splenic marginal zone lymphoma
Whole exome sequencing identifies novel recurrently mutated genes in patients with splenic marginal zone lymphoma
The pathogenesis of splenic marginal zone lymphoma (SMZL) remains largely unknown. Recent high-throughput sequencing studies have identified recurrent mutations in key pathways, most notably NOTCH2 mutations in >25% of patients. These studies are based on small, heterogeneous discovery cohorts, and therefore only captured a fraction of the lesions present in the SMZL genome. To identify further novel pathogenic mutations within related biochemical pathways, we applied whole exome sequencing (WES) and copy number (CN) analysis to a biologically and clinically homogeneous cohort of seven SMZL patients with 7q abnormalities and IGHV1-2*04 gene usage. We identified 173 somatic non-silent variants, affecting 160 distinct genes. In additional to providing independent validation of the presence of mutation in several previously reported genes (NOTCH2, TNFAIP3, MAP3K14, MLL2 and SPEN), our study defined eight additional recurrently mutated genes in SMZL; these genes are CREBBP, CBFA2T3, AMOTL1, FAT4, FBXO11, PLA2G4D, TRRAP and USH2A. By integrating our WES and CN data we identified three mutated putative candidate genes targeted by 7q deletions (CUL1, EZH2 and FLNC), with FLNC positioned within the well-characterized 7q minimally deleted region. Taken together, this work expands the reported directory of recurrently mutated cancer genes in this disease, thereby expanding our understanding of SMZL pathogenesis. Ultimately, this work will help to establish a stratified approach to care including the possibility of targeted therapy.
1932-6203
e83244
Parry, Marina
de180daf-f090-46cc-bce2-b1865b03bf94
Rose-Zerilli, Matthew J. J.
08b3afa4-dbc2-4c0d-a852-2a9f33431199
Gibson, Jane
855033a6-38f3-4853-8f60-d7d4561226ae
Ennis, Sarah
7b57f188-9d91-4beb-b217-09856146f1e9
Walewska, Renata
326c1001-fcdb-452a-aa53-2c82a1ca39a5
Forster, Jade
de3b2ca3-6775-4bc8-a2f6-239499257160
Parker, Helen
33e0cd81-d45f-49bc-9539-09345d79d895
Davis, Zadie
ea848a46-b564-448f-b77f-840d86b3cbd9
Gardiner, Anne
31ec2c9a-dccb-468f-83d1-d4f03ac88f33
Collins, Andrew
7daa83eb-0b21-43b2-af1a-e38fb36e2a64
Oscier, David G.
c2620a1d-25bb-48f7-9651-f5d023636381
Strefford, Jonathan C.
3782b392-f080-42bf-bdca-8aa5d6ca532f
Parry, Marina
de180daf-f090-46cc-bce2-b1865b03bf94
Rose-Zerilli, Matthew J. J.
08b3afa4-dbc2-4c0d-a852-2a9f33431199
Gibson, Jane
855033a6-38f3-4853-8f60-d7d4561226ae
Ennis, Sarah
7b57f188-9d91-4beb-b217-09856146f1e9
Walewska, Renata
326c1001-fcdb-452a-aa53-2c82a1ca39a5
Forster, Jade
de3b2ca3-6775-4bc8-a2f6-239499257160
Parker, Helen
33e0cd81-d45f-49bc-9539-09345d79d895
Davis, Zadie
ea848a46-b564-448f-b77f-840d86b3cbd9
Gardiner, Anne
31ec2c9a-dccb-468f-83d1-d4f03ac88f33
Collins, Andrew
7daa83eb-0b21-43b2-af1a-e38fb36e2a64
Oscier, David G.
c2620a1d-25bb-48f7-9651-f5d023636381
Strefford, Jonathan C.
3782b392-f080-42bf-bdca-8aa5d6ca532f

Parry, Marina, Rose-Zerilli, Matthew J. J., Gibson, Jane, Ennis, Sarah, Walewska, Renata, Forster, Jade, Parker, Helen, Davis, Zadie, Gardiner, Anne, Collins, Andrew, Oscier, David G. and Strefford, Jonathan C. (2013) Whole exome sequencing identifies novel recurrently mutated genes in patients with splenic marginal zone lymphoma. PLoS ONE, 8 (12), e83244. (doi:10.1371/journal.pone.0083244). (PMID:24349473)

Record type: Article

Abstract

The pathogenesis of splenic marginal zone lymphoma (SMZL) remains largely unknown. Recent high-throughput sequencing studies have identified recurrent mutations in key pathways, most notably NOTCH2 mutations in >25% of patients. These studies are based on small, heterogeneous discovery cohorts, and therefore only captured a fraction of the lesions present in the SMZL genome. To identify further novel pathogenic mutations within related biochemical pathways, we applied whole exome sequencing (WES) and copy number (CN) analysis to a biologically and clinically homogeneous cohort of seven SMZL patients with 7q abnormalities and IGHV1-2*04 gene usage. We identified 173 somatic non-silent variants, affecting 160 distinct genes. In additional to providing independent validation of the presence of mutation in several previously reported genes (NOTCH2, TNFAIP3, MAP3K14, MLL2 and SPEN), our study defined eight additional recurrently mutated genes in SMZL; these genes are CREBBP, CBFA2T3, AMOTL1, FAT4, FBXO11, PLA2G4D, TRRAP and USH2A. By integrating our WES and CN data we identified three mutated putative candidate genes targeted by 7q deletions (CUL1, EZH2 and FLNC), with FLNC positioned within the well-characterized 7q minimally deleted region. Taken together, this work expands the reported directory of recurrently mutated cancer genes in this disease, thereby expanding our understanding of SMZL pathogenesis. Ultimately, this work will help to establish a stratified approach to care including the possibility of targeted therapy.

Other
fetchObject.action_uri=info_doi%2F10.1371%2Fjournal.pone.0083244&representation=PDF - Version of Record
Available under License Other.
Download (261kB)

More information

Published date: 13 December 2013
Organisations: Cancer Sciences, Human Development & Health

Identifiers

Local EPrints ID: 360762
URI: http://eprints.soton.ac.uk/id/eprint/360762
ISSN: 1932-6203
PURE UUID: 53a8e34f-d6d9-452c-8836-4f579b22a6da
ORCID for Matthew J. J. Rose-Zerilli: ORCID iD orcid.org/0000-0002-1064-5350
ORCID for Jane Gibson: ORCID iD orcid.org/0000-0002-0973-8285
ORCID for Sarah Ennis: ORCID iD orcid.org/0000-0003-2648-0869
ORCID for Helen Parker: ORCID iD orcid.org/0000-0001-8308-9781
ORCID for Andrew Collins: ORCID iD orcid.org/0000-0001-7108-0771
ORCID for Jonathan C. Strefford: ORCID iD orcid.org/0000-0002-0972-2881

Catalogue record

Date deposited: 02 Jan 2014 10:56
Last modified: 28 Oct 2023 02:02

Export record

Altmetrics

Contributors

Author: Marina Parry
Author: Jane Gibson ORCID iD
Author: Sarah Ennis ORCID iD
Author: Renata Walewska
Author: Jade Forster
Author: Helen Parker ORCID iD
Author: Zadie Davis
Author: Anne Gardiner
Author: Andrew Collins ORCID iD
Author: David G. Oscier

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×