My main research interests are in the field of cancer epigenetics. Much of my ongoing work examines genetic and epigenetic changes in chronic lymphocytic leukaemia (CLL), and how we can use this knowledge to better understand the development of malignancies and to develop clinical biomarkers that will benefit patients. My work has been supported by funding from Bright Red and the Leukemia Research Foundation.
Epigenetic changes during the course of patient treatment
CLL has a variable clinical course, with some patients displaying aggressive disease while others can remain untreated for years after diagnosis. The CLL epigenome had previously been considered to be highly stable throughout its course, but our work demonstrated gene-specific epigenetic changes in response to treatment (Barrow et al, 2021, Br J Cancer). We performed epigenome-wide analysis of DNA methylation at two timepoints to reveal genes that are epigenetically disrupted in patients undergoing chemotherapy, which were not observed in patients who were untreated nor during B-cell development. We identified 17 genes that showed differential methylation and expression across three independent patient cohorts, of which HOXA4, MAFB and SLCO3A1 showed an association with post-treatment survival. These findings were complemented by in vitro and ex vivo work demonstrating how epigenetic silencing of the HOXA4 gene modulates sensitivity to frontline therapies.
Increased ADAMTS17 meth. after treatment (A vs B)
Decreased MBOAT2 expression at relapse
RNF144A meth. and post-treatment survival
HOXA4 expression (black) increases Fd sensitivity
Early epigenetic changes in CLL
My study of the epigenetic regulation of retrotransposons identified loci that are strongly, frequently and specifically hypomethylated in CLL (Barrow et al, 2021, Haematologica). As with most cancers, LINE-1 and Alu elements display hypomethylation in CLL, and this loss of methylation was associated with wider epigenetic patterns that are linked to IGHV status; a widely studied prognostic marker in CLL. Further to this, my work demonstrated that loss of Alu methylation was strongest amongst the oldest elements (AluJ), demonstrating a link between evolutionary history within the genome and epigenetic disruption. These epigenetic changes were observable in a minority of prospective blood samples taken from patients up to 17 years before their diagnosis.
Strong hypomethylation of Alu elements
Correlation of Alu methylation with IGHV status
Hypomethylation strongest among older (AluJ) elements
Locus-specific changes highly unique to CLL
I have recently been part of collaborative projects that have identified genetic variants associated with progressive CLL (Lin et al, 2021, Nat Comms) and developed bioinformatics-based methods for identifying subtype-specific vulnerability genes in a range of malignancies (Schwalbe et al, 2021, Oncogene).
My earlier work in the field focussed upon epigenetic changes in solid tumours. My postdoctoral work at Brigham and Women's Hospital (Boston, USA) analysed epigenetic variation at imprinted loci in breast cancer (Barrow et al, 2015, Int J Cancer).
My work at Universitätsklinikum Freiburg (Germany), in collaboration with others at the DKFZ (Heidelberg, Germany) examined smoking-associated epigenetic changes in colorectal tumours. We identified hypermethylation of the APC tumour-suppressor gene as a frequent event in the tumours of patients who were active smokers at the time of diagnosis (Barrow et al, 2017, J Pathol).
Hypermethylation of multiple loci mapping to the APC promoter 1A in the tumours of active smokers
APC promoter hypermethylation is frequent in tumours from active smokers
APC promoter hypermethylation never observed in adjacent mucosa