Speaker
Ms
Hussain Shahana
(Department of Genetics, University of Leicester, Leicester LE1 7RH, UK)
Description
Radiotherapy (RTH) has a key role in breast cancer (BC) treatment. Studies have shown BC survivors have an excess risk of significant cardiovascular (CV) morbidity 10 years post-treatment, with similar features of an older unirradiated population. One of the underlying mechanisms is thought to be premature CV ageing. We aim to develop a novel biomarker to detect radiation exposure and cardiotoxicity post-RTH.
We have studied whether acute subclinical cardiotoxicity can be detected by cardiac MRI, and if this correlates with in vitro radiosensitivity (RS) and biological ageing (BA) assays; (TRF length, comet assay, Sub G1 peak, genomic methylation) in peripheral blood lymphocytes (PBLs) of 10 left sided BC patients, at pre-RTH, six weeks and one year post-RTH. Cardiac MRI analysis showed no definitive acute or subacute changes post-RTH.
The following changes were observed six weeks post-RTH; a reduction in the in vitro AR (P = 0.002) to irradiation, increase in comet tail DNA (P=0.033), increased levels of urinary 8-oxo-DG (P=0.031), no significant changes were found in genomic methylation or telomere length. When these assays were repeated one year post-RTH, they had returned to pre-treatment levels, suggesting no long term BA effect. To investigate whether the acute BA observed was due to a change in the PBL subpopulation or a possible bystander effect, these assays were repeated in a larger cohort (n=23). We successfully replicated the results of RS and BA assays. There was a significant lymphopenia six weeks post-RTH (P=0.008) however, no significant change in the overall distribution of the PBL subsets was found. Cytotoxic T cells correlated with apoptotic response (P=0.003) but with no other measure of RS or BA.
MiRNA29c has been shown to be a novel biomarker of an unfit heart in humans and is involved in the modulation of apoptosis. We have carried out mouse models showing that cardiac tissue specific MiRNA29c levels are downregulated post-RTH in cardiac tissue (P=0.046) and plasma (P=0.02). We have shown that this reduction in MiRNA29c can also be detected in left-sided BCPs six weeks after radiotherapy commencement (P=0.002).
These findings are important for the radiation community as the timing of in vitro RS and BA assays are key determinants of in vitro PBL radiosensitivity as there is a characteristic uniform response at six weeks which resolves within a year and miRNA29c may be an early indicator of cardiac tissue exposure to radiation.
Primary author
Ms
Hussain Shahana
(Department of Genetics, University of Leicester, Leicester LE1 7RH, UK)
Co-authors
Dr
C Steadman
(Department of Cardiovascular Sciences, University of Leicester, Clinical Sciences Wing, Glenfield General Hospital, Leicester, LE3 9QP)
Dr
C.J Talbot
(Department of Genetics, University of Leicester, Leicester LE1 7RH, UK)
Dr
G.A Tanteles
(Department of Cancer Studies and Molecular Medicine, University of Leicester, Leicester LE1 7RH, UK)
Dr
G.D Jones
(Department of Cancer Studies and Molecular Medicine, University of Leicester, Leicester LE1 7RH, UK)
Dr
G.P McCann
(Department of Cardiovascular Sciences, University of Leicester, Clinical Sciences Wing, Glenfield General Hospital, Leicester, LE3 9QP)
Dr
J.G Barwell
(Department of Genetics, University of Leicester, Leicester LE1 7RH, UK)
Dr
K Bowman
(Department of Cancer Studies and Molecular Medicine, University of Leicester, Leicester LE1 7RH, UK)
Ms
M Naqi
(Department of Genetics, University of Leicester, Leicester LE1 7RH, UK)
Ms
N Datta
(Department of Genetics, University of Leicester, Leicester LE1 7RH, UK)
Dr
N Royle
(Department of Genetics, University of Leicester, Leicester LE1 7RH, UK)
Dr
P Symonds
(Department of Cancer Studies and Molecular Medicine, University of Leicester, Leicester LE1 7RH, UK)
Dr
R Barber
(Department of Genetics, University of Leicester, Leicester LE1 7RH, UK)
Dr
R Camplejohn
(Department of Genetics, University of Leicester, Leicester LE1 7RH, UK)
Mr
R Machhar
(Department of Genetics, University of Leicester, Leicester LE1 7RH, UK)
Dr
T Gant
(MRC Toxicology Unit, University of Leicester, Maurice Shock Building University Road, PO Box 138, Leicester, LE1 9HN)
