Abstract
Repetitive tracts within the coding regions of TGFBR2 and BAX are frequently mutated in mismatch repair deficient tumours and are implicated in tumour progression. However, there has been little study of the balance between selection pressure and inherent instability at sequences within these genes. To determine whether TGFBR2 and BAX are inherently prone to mutations in the presence of MMR defects, we studied MMR deficient cells derived from B-lymphocytes. By analysing cells derived from normal tissue we aimed to minimize the effects of selection pressures that bias the apparent frequency of mutation. We definitively show that certain sequences, usually repaired by MMR, are inherently unstable. Using a small pool PCR technique we confirmed these cells exhibit microsatellite instability. Additionally, we demonstrate that MMR deficiency results in an excess of mutations, specifically at the poly(A)10 tract compared to other regions of the TGFBR2 gene (P<0.001). Conversely, an excess of mutations does not appear to arise at the poly(G)8 tract of the BAX gene. These studies provide insight into the mechanism by which TGFBR2 and BAX genes become mutated during tumorigenesis. These findings invoke the notion of ‘unmasking’ specific hypermutable sequences in particular genes adding further complexity to the concept of the mutator phenotype.
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Acknowledgements
We are grateful to Bert Vogelstein for the gift of cell lines lbl-1260 and lbl-1261. We acknowledge technical assistance from Sheila McBeath and assistance with flow cytometry from Martin Waterfall. This work was supported by the following grants; Cancer Research Campaign (SP2326/0201), Scottish Health Department (K-/MRS/50/C2723), The Melville Trust, Edinburgh University Cancer Research Endowment Fund and Urquart Charitable Trust. AL Bacon was funded by MRC PhD Student Fellowship, SM Farington by an RSE Personal Research Fellowship.
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Bacon, A., Farrington, S. & Dunlop, M. Mutation frequency in coding and non-coding repeat sequences in mismatch repair deficient cells derived from normal human tissue. Oncogene 20, 7464–7471 (2001). https://doi.org/10.1038/sj.onc.1204973
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DOI: https://doi.org/10.1038/sj.onc.1204973
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