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A Quantitative Measurement of the Human Somatic Mutation Rate

¹ Division of Hematology and ² Department of Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York; ³ Istituto Nazionale per la Ricerca sul Cancro; and ⁴ University of Genova, Genoa, Italy

Requests for reprints: David J. Araten, Division of Hematology, NYU Cancer Institute, 160 East 34^th Street, New York, NY 10016. Phone: 212-731-5186; Fax: 212-731-5540; E-mail: David.Araten{at}nyumc.org.

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-linked 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 x 10^–7 mutations per cell division (range 2.4 to 29.6 x 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.

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