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Carcinogenesis Advance Access published online on April 14, 2005
Carcinogenesis, doi:10.1093/carcin/bgi087
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© The Author 2005. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oupjournals.org
Received January 19, 2005
Revised March 15, 2005
Accepted March 25, 2005

CARCINOGENESIS

Quantitative trait locus analysis reveals two intragenic sites that influence O6-alkylguanine-DNA alkyltransferase activity in peripheral blood mononuclear cells

Geoffrey P. Margison 1*, Jim Heighway 2, Steven Pearson 1, Gail McGown 1, Mary R. Thorncroft 1, Amanda J. Watson 1, Kathryn L. Harrison 3, Sarah J. Lewis 3, Klaus Rohde 4, Philip V. Barber 5, Paul O'Donnell 5, Andrew C. Povey 3, and Mauro F. Santibáñez-Koref 6

1 Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester, United Kingdom
2 University of Liverpool Cancer Research Centre, Liverpool, United Kingdom
3 Centre for Occupational and Environmental Health, University of Manchester, Manchester, United Kingdom
4 Max-Delbrück-Centrum für Molekulare Medizin, Berlin-Buch, Germany
5 North West Lung Cancer Centre, Wythenshawe Hospital, Manchester, United Kingdom
6 Institute of Human Genetics, University of Newcastle, Newcastle upon Tyne, United Kingdom

* To whom correspondence should be addressed.
Geoffrey P. Margison, E-mail: gmargison{at}picr.man.ac.uk


  Abstract

The repair of specific types of DNA alkylation damage by O6-alkylguanine-DNA alkyltransferase (MGMT) is a major mechanism of resistance to the carcinogenic and chemotherapeutic effects of certain alkylating agents. MGMT expression levels vary widely between individuals but the underlying causes of this variability are not known. To address this we used an expressed single nucleotide polymorphism (SNP) and demonstrated that the MGMT alleles are frequently expressed at different levels in peripheral blood mononuclear cells (PBMC). This suggests that there is a genetic component of inter-allelic variation of MGMT levels that maps close to or within the MGMT locus. We then used quantitative trait locus analysis using intragenic SNPs, and found that there are at least two sites influencing inter-individual variation in PBMC MGMT activity. One is characterized by an SNP at the 3' end of the first intron and the second by two SNPs in the last exon. The latter are in perfect disequilibrium and both result in amino acid substitutions; one of them, Ile143Val, affecting an amino acid close to the Cys145 residue at the active site of MGMT. We further showed using in vitro assays that whilst the Val143 variant did not affect the activity of the protein on methylated DNA substrate, it was more resistant to inactivation by the MGMT pseudosubstrate, O6-(4-bromothenyl)guanine. These findings suggest that further investigations of the potential epidemiological and clinical significance of inherited differences in MGMT expression and activity are warranted.


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