The University of Southampton
University of Southampton Institutional Repository

Evaluating the genomic landscape of B cell malignancies

Evaluating the genomic landscape of B cell malignancies
Evaluating the genomic landscape of B cell malignancies
Splenic marginal zone lymphoma (SMZL) and chronic lymphocytic leukaemia (CLL) are B cell malignancies, predominately affecting the elderly. The disease course of both SMZL and CLL is highly variable, with some patients dying rapidly within a month whilst other remain stable and live a normal lifespan. Biomarkers are used to help to distinguish those patients who may progress. Genomic abnormalities such as copy number alterations and mutation of genes may have prognostic value in CLL and SMZL. Several technologies were used to assess the genomic landscape in B cell malignancies; low resolution technology such as multiplex ligation-dependant probe amplification (MLPA) and Sanger sequencing as well as higher resolution methods such as SNP 6.0 arrays and next generation sequencing technologies; whole exome sequencing, TruSeq and Nextera XT. MLPA was used to assess both the copy number alterations (CNA) and mutational abnormalities in the well-defined CLL4 clinical trial cohort. Though the technology is restrictive in terms of probe location and sensitivity, there was statistical concordance with Sanger sequencing and fluorescence in situ hybridisation (FISH). Novel CNA, independently associated with survival were uncovered; 1) a very indolent disease course in patients carrying a biallelic 13q deletion with IGHV mutated genes and 2) a very poor prognosis in patients with a 9p deletion. Exome sequencing of CLL (n=6) and SMZL (n=7) patients uncovered novel variants via a bioinformatical pipeline; this pipeline was validated using more traditional sequencing methods. The candidate genes; U2AF1, BIRC3, POT1 and MYD88 are implicated in CLL and were screened in a larger cohorts of patients. Analysis of the 11q loci in relation to ATM and BIRC3 gene mutations, identified alterations of ATM that impact most significantly on survival. Nextera technology was optimised to screen ibrutinib treated CLL patients for BTK and PLCG2 mutations. DNAH9 and SPEN were also sequenced in a small cohort of patients. A breakpoint deletion was identified in the DNAH9 gene, suggesting this gene may be relevant in CLL. Further studies are needed to examine
these newly defined high and low risk groups, and other genetic abnormalities in another well-defined CLL cohort, to ascertain their pathogenic and biological significance.
University of Southampton
Forster, Jade
239097a0-1f53-470f-8d7c-efc786e18a46
Forster, Jade
239097a0-1f53-470f-8d7c-efc786e18a46
Strefford, Jon
3782b392-f080-42bf-bdca-8aa5d6ca532f
Cragg, Mark
ec97f80e-f3c8-49b7-a960-20dff648b78c
Rose-Zerilli, Matthew
08b3afa4-dbc2-4c0d-a852-2a9f33431199

Forster, Jade (2016) Evaluating the genomic landscape of B cell malignancies. University of Southampton, Doctoral Thesis, 430pp.

Record type: Thesis (Doctoral)

Abstract

Splenic marginal zone lymphoma (SMZL) and chronic lymphocytic leukaemia (CLL) are B cell malignancies, predominately affecting the elderly. The disease course of both SMZL and CLL is highly variable, with some patients dying rapidly within a month whilst other remain stable and live a normal lifespan. Biomarkers are used to help to distinguish those patients who may progress. Genomic abnormalities such as copy number alterations and mutation of genes may have prognostic value in CLL and SMZL. Several technologies were used to assess the genomic landscape in B cell malignancies; low resolution technology such as multiplex ligation-dependant probe amplification (MLPA) and Sanger sequencing as well as higher resolution methods such as SNP 6.0 arrays and next generation sequencing technologies; whole exome sequencing, TruSeq and Nextera XT. MLPA was used to assess both the copy number alterations (CNA) and mutational abnormalities in the well-defined CLL4 clinical trial cohort. Though the technology is restrictive in terms of probe location and sensitivity, there was statistical concordance with Sanger sequencing and fluorescence in situ hybridisation (FISH). Novel CNA, independently associated with survival were uncovered; 1) a very indolent disease course in patients carrying a biallelic 13q deletion with IGHV mutated genes and 2) a very poor prognosis in patients with a 9p deletion. Exome sequencing of CLL (n=6) and SMZL (n=7) patients uncovered novel variants via a bioinformatical pipeline; this pipeline was validated using more traditional sequencing methods. The candidate genes; U2AF1, BIRC3, POT1 and MYD88 are implicated in CLL and were screened in a larger cohorts of patients. Analysis of the 11q loci in relation to ATM and BIRC3 gene mutations, identified alterations of ATM that impact most significantly on survival. Nextera technology was optimised to screen ibrutinib treated CLL patients for BTK and PLCG2 mutations. DNAH9 and SPEN were also sequenced in a small cohort of patients. A breakpoint deletion was identified in the DNAH9 gene, suggesting this gene may be relevant in CLL. Further studies are needed to examine
these newly defined high and low risk groups, and other genetic abnormalities in another well-defined CLL cohort, to ascertain their pathogenic and biological significance.

Text
Jade Forster final thesis for e copy - Version of Record
Available under License University of Southampton Thesis Licence.
Download (24MB)

More information

Published date: September 2016
Organisations: University of Southampton, Cancer Sciences

Identifiers

Local EPrints ID: 408724
URI: http://eprints.soton.ac.uk/id/eprint/408724
PURE UUID: d4cd9ff5-5306-4e94-ac03-dd8f0f71e0f6
ORCID for Jon Strefford: ORCID iD orcid.org/0000-0002-0972-2881
ORCID for Mark Cragg: ORCID iD orcid.org/0000-0003-2077-089X
ORCID for Matthew Rose-Zerilli: ORCID iD orcid.org/0000-0002-1064-5350

Catalogue record

Date deposited: 27 May 2017 04:02
Last modified: 14 Mar 2019 01:49

Export record

Contributors

Author: Jade Forster
Thesis advisor: Jon Strefford ORCID iD
Thesis advisor: Mark Cragg ORCID iD
Thesis advisor: Matthew Rose-Zerilli ORCID iD

University divisions

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.

×