The relationship between somatic structural alteration of the genome and healthy ageing

Lead Research Organisation: Queen Mary, University of London
Department Name: Barts Cancer Institute

Abstract

It is increasingly clear that somatic mutations accrue steadily in ageing tissues. However, precisely how this relates to healthy ageing is unknown, and the molecular and cellular mechanisms that cause somatic mutation in otherwise healthy tissue remain poorly defined. Here, we propose to investigate the accrual of structural alterations (SAs) in ageing human colon. We will determine the spectrum of SA that is consistent with healthy ageing (e.g. the SAs that can accrue without leading to a pathology), and profile the size, type and rate of SA accrual to reveal the underlying molecular and cellular mechanisms that underpin 'healthy' human somatic mutagenesis.

Publications

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Studentship Projects

Project Reference Relationship Related To Start End Student Name
BB/M009513/1 01/10/2015 30/09/2023
1902605 Studentship BB/M009513/1 01/10/2017 30/12/2021 Calum Gabbutt
 
Description A number of findings associated with the dynamic behaviour of human epithelium have been made in the course of this award. These include publishing a paper describing the existence of a new homeostatic mechanism within the human gut, termed crypt fusion (in which two neighbouring crypts fuse together into a single daughter crypt), and exploring the effect that the existence of this process has upon previous estimates of the crypt fission rate.
Exploitation Route The existence of crypt fusion within the human colon refines our understanding of homeostasis of the gut, and potentially provides an additional axis upon which selection of mutant phenotypes can occur. Future studies are required to investigate whether fusion is a random process or whether regulatory mechanisms are present.
Sectors Healthcare,Pharmaceuticals and Medical Biotechnology

 
Description Quantitative measurement of clonal evolution in human colon 
Organisation University of Southern California
Country United States 
Sector Academic/University 
PI Contribution We developed a mathematical model to describe the impact of the stem cell dynamics of normal colon epithelial stem cells to the distribution of methylation patterns within a crypt. Further, we developed a Bayesian inference tool to infer the parameters controlling the stem cell replacement process.
Collaborator Contribution Our collaborator at USC provided us with data derived from Illumina EPIC methylation arrays of individual colon and small intestinal crypts from 15 patients. Along with this, our collaborator provided expert pathological insight into the likely stem cell dynamics of glandular tissue and the use of methylation as lineage tracing marker.
Impact The preliminary results of this work have been presented to academic conferences, and a paper is currently being written with a view to publish before the end of the year.
Start Year 2019
 
Description St Mark's hospital collaboration 
Organisation St Mark's Academic Institute
Country United Kingdom 
Sector Academic/University 
PI Contribution I I have had a long standing collaboration with a number of clinical academics at St Mark's hospital, working on predicting cancer development risk in inflammatory bowel disease (with Prof. Ailsa Hart), predicting sporadic colorectal cancer risk (with Dr. Adam Humphries) and understanding adenoma formation in the small intestine in patients with familial predisposition to cancer (with Dr Andrew Latchford). Our laboratory leads the molecular and epidemiological work associated with these three research projects.
Collaborator Contribution St Mark's have provided clinical material, trainee clinical fellows and funding via charitable donations to the St Mark's Institute, to support the projects described above. St Mark's made me an honorary senior scientist in 2016.
Impact The collaboration with St Mark's was particularly instrumental to securing the Barts Charity award "Derivation of biomarkers for cancer risk prediction in Ulcerative Colitis". The multiple publications arising from this collaboration are reported elsewhere. The collaboration is multidisciplinary, involved epidemiological work, molecular biology, histopathology, and translational biomarker research.
Start Year 2013