A quantitative measurement of the human somatic mutation rate Journal Article
| Authors: | Araten, D. J.; Golde, D. W.; Zhang, R. H.; Thaler, H. T.; Gargiulo, L.; Notaro, R.; Luzzatto, L. |
| Article Title: | A quantitative measurement of the human somatic mutation rate |
| Abstract: | The mutation rate (μ) is a key biological feature of somatic cells that determines risk for malignant transformation, and it has been exceedingly difficult to measure in human cells. For this purpose, a potential sentinel is the X-Iinked PIG-A gene, because its inactivation causes lack of glycosylphosphatidylinositol-linked membrane proteins. We previously found that the frequency (f) of PIG-A mutant cells can be measured accurately by flow cytometry, even when f is very low. Here we measure both f and μ by culturing B-lymphoblastoid cell lines and first eliminating preexisting PIG-A mutants by flow sorting. After expansion in culture, the frequency of new mutants is determined by flow cytometry using antibodies specific for glycosylphosphatidylinositol-linked proteins (e.g., CD48, CD55, and CD59). The mutation rate is then calculated by the formula μ = f/d, where d is the number of cell divisions occurring in culture. The mean μ in cells from normal donors was 10.6 × 10 -7 mutations per cell division (range 2.4 to 29.6 × 10 -7. The mean μ was elevated >30-fold in cells from patients with Fanconi anemia (P < 0.0001), and μ varied widely in ataxia-telangiectasia with a mean 4-fold elevation (P = 0.002). In contrast, μ was not significantly different from normal in cells from patients with Nijmegen breakage syndrome. Differences in μ could not be attributed to variations in plating efficiency. The mutation rate in man can now be measured routinely in B-lymphoblastoid cell lines, and it is elevated in cancer predisposition syndromes. This system should be useful in evaluating cancer risk and in the design of preventive strategies. ©2005 American Association for Cancer Research. |
| Keywords: | controlled study; human cell; somatic mutation; mutation; cancer risk; flow cytometry; accuracy; reproducibility of results; gene; cell division; somatic cell; cancer susceptibility; genetic predisposition to disease; cell line; membrane proteins; b-lymphocytes; cell transformation, neoplastic; cell culture; pilot projects; quantitative analysis; membrane protein; measurement; nijmegen breakage syndrome; gene inactivation; malignant transformation; mutagenesis; mutant; fanconi anemia; ataxia telangiectasia; cd59 antigen; b lymphoblast; lymphoblastoid cell; decay accelerating factor; glycosylphosphatidylinositol; glycosylphosphatidylinositols; cd48 antigen; pig a gene |
| Journal Title: | Cancer Research |
| Volume: | 65 |
| Issue: | 18 |
| ISSN: | 0008-5472 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2005-09-15 |
| Start Page: | 8111 |
| End Page: | 8117 |
| Language: | English |
| DOI: | 10.1158/0008-5472.can-04-1198 |
| PUBMED: | 16166284 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 44" - "Export Date: 24 October 2012" - "CODEN: CNREA" - "Source: Scopus" |
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