DNA damage and repair v1012015
Research type
Research Study
Full title
DNA damage and repair in colorectal cases and controls
IRAS ID
171951
Contact name
Andrew Povey
Contact email
Sponsor organisation
University of Manchester
Duration of Study in the UK
1 years, 5 months, 31 days
Research summary
There is increasing evidence that exposure to a class of chemical carcinogens (known as alkylating agents) may play an important role in causing colorectal cancer. Such exposure can result in the covalent modification of normal DNA bases by alkyl groups (“adducts”) and the resulting DNA adducts can induce gene changes or mutations that are commonly observed in colorectal tumours. We have shown that two adducts known as O6-methylguanine and N7-methylguanine are present in human colorectal DNA and are caused by the reaction of DNA with a reactive chemical that adds a methyl group to DNA bases. In addition to these methyl adducts, human colorectal DNA contains another adduct , O6-carboxymethylguanine, which is likely to arise from the presence within the intestinal tract of a reactive carboxymethylating agent. There are potentially many other alkylating agents that can be formed within the intestinal tract so that the total level of O6-alkylguanine adducts in human colorectal DNA is currently not known and is likely to have been seriously underestimated. The alkyl group of O6-alkylguanine adducts can be removed by a DNA repair protein, which prevents the adverse cellular effects of O6-alkylguanine and so DNA repair may be a critical factor in determining cancer susceptibility.
The aim of this work is to use newly developed assays to quantify levels of specific O6-alkylguanine adducts, total O6-alkylguanine adducts and estimate the levels of total DNA adducts in an existing colorectal tissue sample collection. We have already used samples from this collection to demonstrate that human colorectal DNA contains N7-methylguanine and levels of this adduct are inversely linked to dietary fibre intake. By linking these new assays with this existing tissue collection we can then determine to what extent human colorectal DNA contains different O6-alkylguanines, whether levels of O6-alkylguanines differ between patients, and how these adduct levels vary with diet and with the patient has cancer or not. This study would then provide more specific information as to the role of these alkylating agents in human colorectal cancer risk.REC name
East Midlands - Derby Research Ethics Committee
REC reference
15/EM/0505
Date of REC Opinion
24 Nov 2015
REC opinion
Further Information Favourable Opinion