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"
Altmetric Score
MSK Authors
  1. David Golde
    112 Golde
  2. Rosario Notaro
    22 Notaro
  3. Howard T Thaler
    193 Thaler
  4. David Araten
    20 Araten
  5. Rong Hua Zhang
    17 Zhang
  6. Lucio Luzzatto
    104 Luzzatto