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Open Access Research article

Functional assays to determine the significance of two common XPC 3'UTR variants found in bladder cancer patients

Boling Qiao1, Gina B Scott2, Faye Elliott3, Laurence Vaslin4, Johanne Bentley5, Janet Hall6, D Timothy Bishop7, Margaret A Knowles8 and Anne E Kiltie9*

Author Affiliations

1 Section of Experimental Oncology, Leeds Institute of Molecular Medicine, Leeds LS9 7TF, UK

2 Section of Experimental Oncology, Leeds Institute of Molecular Medicine, Leeds LS9 7TF, UK

3 Section of Epidemiology and Biostatistics, Leeds Institute of Molecular Medicine, Leeds LS9 7TF, UK

4 INSERM U612, Centre Universitaire, Orsay 91405, France and Institut Curie, Centre Universitaire, Orsay 91405, France

5 Section of Experimental Oncology, Leeds Institute of Molecular Medicine, Leeds LS9 7TF, UK

6 INSERM U612, Centre Universitaire, Orsay 91405, France and Institut Curie, Centre Universitaire, Orsay 91405, France

7 Section of Epidemiology and Biostatistics, Leeds Institute of Molecular Medicine, Leeds LS9 7TF, UK

8 Section of Experimental Oncology, Leeds Institute of Molecular Medicine, Leeds LS9 7TF, UK

9 Section of Experimental Oncology, Leeds Institute of Molecular Medicine, Leeds LS9 7TF, United Kingdom and Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford OX3 7DQ, UK

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BMC Medical Genetics 2011, 12:84  doi:10.1186/1471-2350-12-84

Published: 20 June 2011

Abstract

Background

XPC is involved in the nucleotide excision repair of DNA damaged by carcinogens known to cause bladder cancer. Individuals homozygous for the variant allele of XPC c.1496C > T (p.Ala499Val) were shown in a large pooled analysis to have an increased bladder cancer risk, and we found two 3'UTR variants, *611T > A and c.*618A > G, to be in strong linkage disequilibrium with c.1496T. Here we determined if these two 3'UTR variants can affect mRNA stability and assessed the impact of all three variants on mRNA and protein expression.

Methods

In vitro mRNA stability assays were performed and mRNA and protein expression measured both in plasmid-based assays and in lymphocytes and lymphoblastoid cell lines from bladder and breast cancer patients.

Results

The two 3'UTR variants were associated with reduced protein and mRNA expression in plasmid-based assays, suggesting an effect on mRNA stability and/or transcription/translation. A near-significant reduction in XPC protein expression (p = 0.058) was detected in lymphoblastoid cell lines homozygous for these alleles but no differences in mRNA stability in these lines was found or in mRNA or protein levels in lymphocytes heterozygous for these alleles.

Conclusion

The two 3'UTR variants may be the variants underlying the association of c.1496C > T and bladder cancer risk acting via a mechanism modulating protein expression.